Clinical trial NCT02780388
Conditions: Adult Onset Rheumatoid Arthritis
Keywords: MEDI4920, VIB4920, CD40L, RA, rheumatoid arthritis
Sponsor: Amgen
Start date: 2016-05-12; Completion date: 2018-08-09
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether VIB4920 (formerly MEDI4920) is safe and well tolerated in participants with adult-onset rheumatoid arthritis (RA).

Detailed description:
Study with completed results acquired from Horizon in 2024. Originally Viela Bio was the sponsor.

Arms: arm 1: Participants will receive a single intravascular (IV) dose of placebo matched to VIB4920 (formerly MEDI4920) once every 2 weeks (Q2W) from Day 1 up to 12 weeks. arm 2: Participants will receive a single IV dose of VIB4920 75 mg Q2W from Day 1 up to 12 weeks. arm 3: Participants will receive a single IV dose of VIB4920 500 mg Q2W from Day 1 up to 12 weeks. arm 4: Participants will receive a single IV dose of VIB4920 1000 mg Q2W from Day 1 up to 12 weeks. arm 5: Participants will receive a single IV dose of VIB4920 1500 mg Q2W from Day 1 up to 12 weeks.
Interventions: intervention 1: VIB4920 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive a single IV dose of VIB4920 Q2W from Day 1 up to 12 weeks. intervention 2: Participants will receive a single IV dose of placebo matched to VIB4920 Q2W from Day 1 up to 12 weeks.

Protocol documents:
Prot_000.pdf: 
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A Phase 1b Randomized, Double-blind, Placebo-controlled 
Multiple-ascending Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, Immunogenicity, 
Pharmacodynamics, and Clinical Response of MEDI4920 in 
Subjects with Adult-onset Rheumatoid Arthritis
Sponsor Protocol Number: D5100C00002
Application Number:
IND 128905
EudraCT Number: 2015-005318-30
Investigational Product:
MEDI4920
Sponsor:
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca, Milstein Building, Granta Park, Cambridge, 
CB21 6GH, UK
Medical Monitor:
, MD
, MedImmune
Phone: 
 Fax:
Contract Research Organization: ICON
Protocol History, Date:
Original Protocol, 15Jan2016
Protocol Amendment 1, 05Apr2016
Protocol Amendment 2, 10Aug2016
Protocol Amendment 3, 29Sep2017
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from MedImmune.
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STUDY DESIGN  
This is a multicenter, randomized, double-blind (investigator, subject, and sponsor will be blinded to treatment 
assignment), placebo-controlled study to evaluate the safety and tolerability of multiple ascending doses of 
MEDI4920 in subjects with adult-onset RA (moderate to severe, as defined by DAS28 CRP ≥ 3.2 at screening) 
with an inadequate response to MTX or other cDMARDs or a biologic anti-tumor necrosis factor alpha agent. 
The study is planned to be conducted at approximately 15 sites in 2 to 4 countries. A maximum of 54 eligible 
subjects are planned for this study. Approximately 40 subjects will be randomized in 3 cohorts to receive either 
75 mg (Cohort 1), 500 mg (Cohort 2), or 1500 mg (Cohort 3) MEDI4920 or placebo Q2W in combination with 
MTX or another cDMARD for up to 12 weeks. An additional 14 subjects will be randomized in a 5:2 ratio to an 
additional cohort (Cohort 4) to better characterize the dose (exposure)-response relationship. The selected dose
of MEDI4920 in Cohort 4  is 1000 mg Q2W.
Cohorts 1 to 3 will start sequentially, with escalation from Cohort 1 to Cohort 2 and Cohort 2 to Cohort 3 
confirmed by a Dose Escalation Committee (DEC) comprised of MedImmune study team members and the 
Study Global Chief Investigator, who will assess in a blinded fashion the safety/tolerability data after the last 
subject in a cohort completes Day 29 (Week 4) of treatment and has AE/safety laboratory data available at that 
time point. There will be a total of three DEC meetings during the study; the first DEC meeting will only review 
data from Cohort 1 whereas the second DEC meeting will review cumulative safety data from the first two dose 
cohorts being tested to date. The third DEC meeting will constitute a thorough evaluation of the cumulative 
safety and tolerability data for Cohorts 1 and 2 in addition to the data up to Day 85 for Cohort 3. After the last 
Cohort 3 subject completes the Day 85 (Week 12) assessments, the primary analysis will be conducted to 
include safety, tolerability, PK, anti-drug antibody (ADA), biomarker, and clinical response. Based on the 
outcome of this analysis, a fourth cohort will be included to better understand the dose (exposure)-response 
relationship. Each subject will participate in the study for up to approximately 30 weeks (includes a 6-week 
screening period, a 12-week treatment period, and a 12-week follow-up period). A screening visit(s) will be 
performed within 6 weeks (42 days) prior to dosing. All subjects will receive investigational product on the 
morning of Day 1. An overnight stay on Day -1 prior to administration of investigational product on Day 1 is 
recommended but not mandatory. If no safety concerns are identified, subjects will be discharged from the study 
site on Day 2 (end of the inpatient treatment period) after all study procedures have been completed. Subjects in 
all cohorts will return to the study site Q2W (Days 8, 15, 29, 43, 57, 71, and 85) for investigational product 
administration and/or specific assessments and blood draws. During the treatment period, assessments of RA 
parameters as well as evaluations of safety, tolerability, PK, and immunogenicity of MEDI4920 will be 
performed. Following the final IV infusion of investigational product, subjects will return to the study site for 
follow-up visits beginning at Week 13 (Day 92) and continuing through Week 24 (Day 169) to evaluate safety, 
tolerability, PK, and ADA of MEDI4920.
TARGET SUBJECT POPULATION  
Male or female adults 18-70 years of age, inclusive, with adult-onset RA diagnosed by European League 
Against Rheumatism /American College of Rheumatology 2010 criteria at least 6 months before screening.
TREATMENT GROUPS AND REGIMENS
A maximum of 54 subjects will be randomized to receive either MEDI4920 or placebo as follows: 10 subjects 
will be randomized in Cohort 1 in a 4:1 ratio to receive 75 mg MEDI4920 (N = 8) or placebo (N = 2) as a single 
IV dose administered over at least 30 minutes Q2W; 14 subjects will be randomized in Cohort 2 in a 5:2 ratio to 
receive 500 mg MEDI4920 (N = 10) or placebo (N = 4) as a single IV dose administered over at least 
60 minutes Q2W; and 16 subjects will be randomized in Cohort 3 in a 3:1 ratio to receive 1500 mg MEDI4920 
(N = 12) or placebo (N = 4) as a single IV dose administered over at least 90 minutes Q2W. An additional 
14 subjects will be randomized in Cohort 4 in a 5:2 ratio to receive 1000 mg MEDI4920 (N = 10) or placebo (N 
= 4) as a single IV dose administered over at least 90 minutes Q2W.
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STATISTICAL ANALYSIS METHODS 
Sample Size: 
No formal sample size calculations are presented for the evaluation of the primary objective of safety and 
tolerability of MEDI4920. The sample size calculations are based on the exploratory endpoint
 The sample size calculation for Week 12 
DAS28 CRP change from baseline is based on combining the data from the cohorts and performing a dose 
response analysis. Based on the assumption
 the sample sizes of 14, 8, 10, 10 and 
12 subjects for the placebo, 75, 500, 1000 mg, and 1500 mg dose groups, respectively, will provide 
approximately 92% power for detecting a statistically significant dose response, using a significance level of 
0.10. The power for dose response has been calculated using a multiple comparison procedure with modeling 
techniques with three candidate models for the dose response (linear, maximum effect attributable to the drug 
[Emax], and a Hill-Emax model). An overall significance level of 0.10 will be used to test for dose response.
Statistical Analyses:
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) by system organ class 
(SOC) and preferred term (PT). Specific AEs will be counted once for each subject for calculating rates, but will 
be presented in total in subject listings. In addition, if the same AE occurs multiple times within a particular 
subject, the highest severity and level of causality will be reported. If any associations of interest between AEs 
and baseline characteristics are observed, additional stratified results may be presented. All treatment-emergent 
AEs will be summarized overall and by MedDRA SOC and PT, by severity, and by relationship to 
investigational product. In addition, summaries of deaths, SAEs and treatment discontinuations due to AEs will 
be provided. Treatment-emergent AEs, treatment-emergent SAEs and AESIs with onset after the start of 
infusion (Day 1) to Day 169/Early Discontinuation Visit inclusive will be summarized by dose. The placebo 
subjects from each cohort will be combined for the summaries. Other safety parameters, including laboratory 
assessments and vital signs, will be summarized by dose.
Interim Analysis:
The primary analysis will be performed when all subjects in Cohort 3 have completed the Day 85 assessments 
or have been withdrawn from the study. The primary analysis will include all assessments on the subjects prior
to the data cut-off for the primary analysis. MedImmune personnel will be unblinded to the subject treatment 
assignments from Cohorts 1 to 3 at the primary analysis (Day 85). The data from the primary analysis will not 
be communicated to personnel at the Contract Research Organization (CRO) or investigational sites or to 
enrolled subjects, until all subjects in Cohorts 1 to 3 have completed the study and database lock has been 
achieved. An additional interim analysis will be performed when all subjects in Cohort 4 have completed the 
Day 85 assessments or have been withdrawn from the study. MedImmune personnel will be unblinded to the 
subject treatment assignments from Cohort 4 for this interim analysis. Study subjects and personnel at the CRO
or investigational sites will remain blinded to Cohort 4 data until all subjects in Cohort 4 have completed the 
study and database lock has been achieved. The final analysis on the subjects will be performed when all 
subjects have completed the safety follow-up.
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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ................................................................................................2
LIST OF ABBREVIATIONS........................................................................................10
1
INTRODUCTION ..............................................................................................13
1.1
Disease Background..................................................................................13
1.1.1Evidence for the CD40 Pathway in RA..............................................14
1.2
MEDI4920 Background............................................................................15
1.3
Summary of Nonclinical Experience .........................................................15
1.4
Summary of Clinical Experience...............................................................17
1.5
Rationale for Conducting the Study...........................................................18
1.6
Potential Risks ..........................................................................................19
1.7
Research Hypotheses ................................................................................21
1.7.1Primary Hypothesis...........................................................................21
1.7.2Secondary Hypothesis .......................................................................21
1.7.3Exploratory Hypotheses ....................................................................22
2
OBJECTIVES AND ENDPOINTS .....................................................................22
2.1
Objectives.................................................................................................22
2.1.1Primary Objective .............................................................................22
2.1.2Secondary Objectives ........................................................................22
2.1.3Exploratory Objectives......................................................................22
2.2
Study Endpoints........................................................................................22
2.2.1Primary Endpoints.............................................................................22
2.2.2Secondary Endpoints.........................................................................23
2.2.3Exploratory Endpoints.......................................................................23
3
STUDY DESIGN................................................................................................23
3.1
Description of Study .................................................................................23
3.1.1Overview………...............................................................................23
3.1.2Treatment Regimen...........................................................................25
3.1.3Dose Escalation and Cohort Progression............................................26
3.2
Rationale for Dose, Population, and Endpoints..........................................27
3.2.1Dose Rationale ..................................................................................27
3.2.2Rationale for Study Population..........................................................28
3.2.3Rationale for Endpoints.....................................................................29
4
MATERIALS AND METHODS.........................................................................30
4.1
Subjects ....................................................................................................30
4.1.1Number of Subjects...........................................................................30
4.1.2Inclusion Criteria...............................................................................30
4.1.3Exclusion Criteria..............................................................................32


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4.1.4Subject Enrollment and Randomization.............................................34
4.1.5Withdrawal from the Study................................................................35
4.1.6Discontinuation of Investigational Product ........................................35
4.1.7Replacement of Subjects ...................................................................36
4.1.8Withdrawal of Informed Consent for Data and Biological Samples ...36
4.2
Schedule of Study Procedures...................................................................37
4.2.1Enrollment/Screening Period.............................................................37
4.2.2Treatment Period...............................................................................38
4.2.3Follow-up Period...............................................................................41
4.3
Description of Study Procedures ...............................................................42
4.3.1Medical History, Physical Examination, Electrocardiogram, Weight, 
Height, and Vital Signs ....................................................42
4.3.1.1
Medical History ...............................................................42
4.3.1.2
Physical Examination, Height, and Weight.......................42
4.3.1.3
Vital Signs .......................................................................43
4.3.1.4
Electrocardiogram............................................................43
4.3.2Clinical Laboratory Tests ..................................................................44
4.3.3Pharmacokinetic Evaluation and Methods .........................................45
4.3.4Immunogenicity Evaluation and Methods..........................................45
4.3.5Biomarker Evaluation and Methods...................................................46
4.3.5.1
Flow Cytometry...............................................................46
4.3.5.2
Autoantibody Panel..........................................................46
4.3.5.3
Exploratory Serum Biomarkers ........................................46
4.3.5.4
Total CD40L Levels.........................................................46
4.3.5.5
Blood Transcriptome........................................................46
4.3.5.6
MBDA Test .....................................................................47
4.3.6Disease Evaluation and Methods .......................................................47
4.3.6.1
Tender and Swollen Joint Counts.....................................47
4.3.6.2
Patient’s Global Assessment of Disease Activity..............48
4.3.6.3
Physician Global Assessment of Disease Activity ............48
4.3.6.4
Acute-phase Reactants .....................................................48
4.3.7Estimate of Volume of Blood to Be Collected ...................................49
4.4
Study Suspension or Termination..............................................................49
4.5
Investigational Products............................................................................50
4.5.1Identity of Investigational Products ...................................................50
4.5.1.1
Investigational Product Handling .....................................51
4.5.1.2
Investigational Product Inspection....................................51
4.5.1.3
Dose Preparation Steps.....................................................51


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4.5.1.4
Reconstitution Procedure .................................................52
4.5.1.5
Preparation of Intravenous Dose.......................................52
4.5.1.6
Intravenous Administration..............................................53
4.5.1.7
Treatment Administration ................................................54
4.5.1.8
Monitoring of Dose Administration..................................54
4.5.1.9
Reporting Product Complaints .........................................55
4.5.2Additional Study Medications ...........................................................55
4.5.2.1
Background Medications for RA......................................55
4.5.3Labeling……….................................................................................57
4.5.4Storage………. .................................................................................57
4.5.5Treatment Compliance ......................................................................57
4.5.6Accountability...................................................................................57
4.6
Treatment Assignment and Blinding .........................................................57
4.6.1Methods for Assigning Treatment Groups .........................................57
4.6.2Methods for Ensuring Blinding..........................................................58
4.6.3Methods for Unblinding ....................................................................58
4.6.3.1
Unblinding in the Event of a Medical Emergency.............58
4.6.4Unblinding for Interim Analysis Purposes .........................................59
4.7
Restrictions During the Study and Concomitant Treatment(s) ...................59
4.7.1Permitted Concomitant Medications..................................................59
4.7.2Prohibited Concomitant Medications.................................................59
4.8
Statistical Evaluation.................................................................................60
4.8.1General Considerations .....................................................................60
4.8.2Sample Size and Power Calculations .................................................61
4.8.3Exploratory Efficacy Analyses ..........................................................61
4.8.3.1
.....................................................................61
4.8.3.2
……....................................................................62
4.8.3.3
....................................62
4.8.4Safety………. ...................................................................................62
4.8.4.1
Analysis of Adverse Events..............................................62
4.8.4.2
Analysis of Clinical Laboratory Parameters......................63
4.8.4.3
Other Safety and Tolerability Endpoints...........................63
4.8.5Analysis of Immunogenicity/Pharmacokinetics .................................63
4.8.6Interim Analysis................................................................................63
5
ASSESSMENT OF SAFETY..............................................................................64
5.1
Definition of Adverse Events ....................................................................64
5.2
Definition of Serious Adverse Events........................................................65
5.3
Definition of Adverse Events of Special Interest .......................................65
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5.4
Recording of Adverse Events....................................................................66
5.4.1Time Period for Collection of Adverse Events...................................66
5.4.2Follow-up of Unresolved Adverse Events..........................................66
5.5
Reporting of Serious Adverse Events ........................................................67
5.6
Other Events Requiring Immediate Reporting ...........................................67
5.6.1Overdose………. ..............................................................................67
5.6.2Hepatic Function Abnormality ..........................................................68
5.6.3Pregnancy………..............................................................................68
5.6.3.1
Maternal Exposure ...........................................................68
6
STUDY AND DATA MANAGEMENT.............................................................69
6.1
Training of Study Site Personnel...............................................................69
6.2
Monitoring of the Study............................................................................69
6.2.1Source Data.......................................................................................70
6.2.2Study Agreements .............................................................................70
6.2.3Archiving of Study Documents..........................................................70
6.3
Study Timetable and End of Study............................................................70
6.4
Data Management .....................................................................................70
6.5
Medical Monitor Coverage........................................................................71
7
ETHICAL AND REGULATORY REQUIREMENTS........................................71
7.1
Ethical Conduct of the Study.....................................................................71
7.2
Subject Data Protection.............................................................................71
7.3
Ethics and Regulatory Review...................................................................72
7.4
Informed Consent......................................................................................73
7.5
Changes to the Protocol and Informed Consent Form................................73
7.6
Audits and Inspections ..............................................................................74
8
REFERENCES ...................................................................................................75
9
CHANGES TO THE PROTOCOL......................................................................79
10
APPENDICES ....................................................................................................83
10.1
Appendix 1 - Signatures............................................................................83
10.2
Appendix 2 - Additional Safety Guidance .................................................86
10.3
Appendix 3 - National Institute of Allergy and Infectious Diseases and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis.......................................................................................90
10.4
Appendix 4 - Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law...........................................................91
10.4.1Introduction.....................................................................................91
10.4.2Definitions ......................................................................................91
10.4.2.1
Potential Hy’s Law ............................................91
10.4.2.2
Hy’s Law ...........................................................91


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10.4.2.3
Identification of Potential Hy’s Law Cases.........92
10.4.3Follow-up………. ...........................................................................93
10.4.3.1
Potential Hy’s Law Criteria Not Met..................93
10.4.3.2
Potential Hy’s Law Criteria Met.........................93
10.4.4Review and Assessment of Potential Hy’s Law Cases .....................93
10.4.5Actions Required When Potential Hy’s Law Criteria Are Met Before 
and After Starting Study Treatment..................................94
10.4.6Actions Required for Repeat Episodes of Potential Hy’s Law..........95
10.4.7References………. ..........................................................................96
10.5
Appendix 5 – Diagnosis of a Potential Thromboembolic Event .................97
10.5.1Clinical Probability Score of Deep Vein Thrombosis - Wells 
Criteria.............................................................................97
10.5.2Clinical Probability Score of Pulmonary Embolism - Wells Criteria 98
LIST OF IN-TEXT TABLES
Table 3.1.2-1
Investigational Product Dose and Treatment Regimen ......................26
Table 4.1.2-1
Highly Effective Methods of Contraception for Females of 
Childbearing Potential ......................................................................32
Table 4.2.1-1
Schedule of Screening Procedures ....................................................37
Table 4.2.2-1
Schedule of Treatment Period Study Procedures...............................39
Table 4.2.3-1
Schedule of Follow-up Procedures....................................................41
Table 4.3.7-1
Estimate of Blood Volume to Be Collected.......................................49
Table 4.5.1-1
Identification of Investigational Products..........................................50
Table 4.5.1.5-1
MEDI4920 Dose Preparation for IV Infusion with an IV Infusion 
Pump ................................................................................................52
Table 4.5.1.5-2
Placebo Dose Preparation for IV Infusion with an IV Infusion Pump 53
Table 4.5.1.6-1
Intravenous Administration of Investigational Product......................54
LIST OF IN-TEXT FIGURES
Figure 3.1.1-1
Study Flow Diagram.........................................................................25


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ACPA
anti-cyclic citrullinated peptide antibody
ACR
American College of Rheumatology
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
Alanine aminotransferase
ANA
anti-nuclear antibody
AST
aspartate aminotransferase 
AUC
area under the concentration-time curve 
BP
blood pressure
CD40L
CD40 ligand
CDAI
Clinical Disease Activity Index
cDMARD
conventional disease-modifying anti-rheumatic drug
CI
confidence interval
Cmax
maximum concentration 
CMV
cytomegalovirus
COPD
chronic obstructive pulmonary disease
CRO
Contract Research Organization
CRP
C-reactive protein
CTLA-4
cytotoxic T lymphocyte antigen-4 
CTPA
computerized tomographic pulmonary angiography
DAS28 CRP
Disease Activity Score in 28 joints using C-reactive protein 
DEC
Dose Escalation Committee
DNA
deoxyribonucleic acid
DMARD
disease-modifying anti-rheumatic drug
DVT
deep vein thrombosis
DZP
dapirolizumab pegol
EBV
Epstein-Barr virus
EDC
electronic data capture
ECG
electrocardiogram
eCRF
electronic case report form
EDV
Early Discontinuation Visit
Emax
maximum effect attributable to the drug
ESR
erythrocyte sedimentation rate
FAAN
Food Allergy and Anaphylaxis Network
FTIH
first time in human 
GCP
Good Clinical Practice
GH
general health


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Abbreviation or 
Specialized Term
Definition
GLP
Good Laboratory Practice
HbcAb
hepatitis B core antibody
HbsAb
hepatitis B surface antibody
HbsAg
hepatitis B surface antigen
HED
Human Equivalent Dose
HSA
human serum albumin 
HSV
herpes simplex virus
HIV
Human Immunodeficiency Virus
HL
Hy’s Law
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IGRA
interferon-gamma release assay
IEC
Independent Ethics Committee
Ig
immunoglobulin
IL
interleukin
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
IXRS
interactive voice/web response system 
JAK
Janus kinase
KLH
keyhole limpet hemocyanin
LFT
liver function test
mAb
monoclonal antibody
MAD
multiple ascending dose
MCP-Mod
multiple comparison procedure with modeling techniques
MBDA
multi-biomarker disease activity
MedDRA
Medical Dictionary for Regulatory Activities
MDGA
Physician’s Global Assessment
MOA
mechanism of action
MTX
methotrexate
NIAIDs
National Institute of Allergy and Infectious Diseases 
NOAEL
no observed adverse effect level 
NSAID
nonsteroidal anti-inflammatory drug
PCR
polymerase chain reaction
PD
pharmacodynamics
PE
pulmonary embolism
PFA
platelet function analyzer
PGA
Patient’s Global Assessment
PK
pharmacokinetics
PT
preferred term
Q2W
once every 2 weeks


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Abbreviation or 
Specialized Term
Definition
RA
rheumatoid arthritis
RBC
red blood cell
RF
rheumatoid factor
RNA
ribonucleic acid
SAD
single ascending dose
SAE
serious adverse event
SC
subcutaneous
sCD40L
soluble CD40L
SID
subject identification
SJC
swollen joint count
SLE
systemic lupus erythematous
SOC
system organ class
TAT
thrombin-antithrombin complex
TB
Tuberculosis
TBL
total bilirubin
TDAR
T-cell-dependent antibody response
TEAE
treatment-emergent adverse event 
TESAE
treatment-emergent serious adverse event
TJC
tender joint count
Tn3
an engineered form of the third fibronectin type III protein domain from human 
Tenascin-C
TNF
tumor necrosis factor
TNFα
tumor necrosis factor alpha
ULN
upper limit of normal
US FDA
United States Food and Drug Administration
VAS
visual analogue scale
V/Q
ventilation-perfusion
VZ
varicella zoster
WBC
white blood cell
w/v
weight/volume 


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1
INTRODUCTION
1.1
Disease Background
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that is associated with 
significant morbidity and mortality. The disease is characterized by inflammation of the 
synovial joints that can result in pain, swelling, and joint damage with secondary deformity 
and progressive disability. Worldwide, the prevalence of RA is estimated to be between 0.6% 
and 1.1% with variations across geographical regions. The incidence is 2-3 times higher in 
women than in men with a peak age of onset between 35 and 55 years of 
age (Symmons, 2002). Uncontrolled active RA causes joint damage, disability, decreased 
quality of life, comorbidities including cardiovascular disease and osteoporosis, and reduced 
life expectancy (Wong et al, 2001).
The immunopathology of RA is complex even from relatively early in the clinical course of 
disease (Tarner et al, 2006; van Baarsen et al, 2013) and B cells are generally accepted to 
contribute to the pathophysiology of RA. Defective central and peripheral B-cell tolerance 
checkpoints in RA result in accumulation of autoreactive B cells (Bugatti et al, 2014), and 
depletion of CD20 positive B cells with rituximab results in clinical improvement in a subset 
of patients. Approximately 80% of patients with RA have detectable levels of rheumatoid 
factors (RFs), which are antibodies of any isotype (immunoglobulin [Ig] M, IgG, IgE) against 
the Fc portion of IgG. The majority of patients with RA also have detectable levels of 
anti-cyclic citrullinated peptide antibodies (ACPAs). Indeed, the presence of RF or ACPA is 
included in the American College of Rheumatology (ACR) 2010 diagnostic criteria for RA.
There are 3 main drug classes commonly used in the treatment of RA: 1) nonsteroidal 
anti-inflammatory drugs (NSAIDs), 2) corticosteroids, which are mainly used as palliative 
therapy, and 3) disease-modifying anti-rheumatic drugs (DMARDs), used to control disease 
activity and prevent structural joint damage. Two main classes of DMARDs are available for 
the treatment of RA: conventional disease-modifying anti-rheumatic drugs (cDMARDs) 
(such as methotrexate [MTX], sulfasalazine, leflunomide, and hydroxychloroquine) and 
biologic DMARDs (such as tumor necrosis factor [TNF]-inhibitors). MTX is the most 
commonly used DMARD for the treatment of moderate and severe RA (Maetzel et al, 1998); 
however, many patients fail to achieve an adequate or sustained response to MTX alone 
(Galindo-Rodriguez et al, 1999). To improve efficacy, MTX is being combined with newer 
biologic agents targeting various components of the immune system, which has induced a 
step-change in the management and treatment of patients with RA. Such therapies include 
anti-TNF alpha (TNFα) agents (etanercept, infliximab, adalimumab, certolizumab and 
golimumab) as well as newer agents targeting different compartments of the immune system, 


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such as B cells, cytotoxic T-lymphocyte antigen-4 (CTLA-4) (abatacept), and interleukin 
(IL)-6 receptors (tocilizumab); newer oral compounds such as inhibitors of Janus kinase 
(JAK; tofacitinib) have also been introduced. These agents are effective at improving the 
signs and symptoms and at slowing or arresting structural damage in patients with RA 
(Klareskog et al, 2004; Singh et al, 2009).
Despite the availability of these biological therapeutic agents for the treatment of RA, nearly 
one third of patients fail to achieve the ACR 20% improvement 
criteria (Weinblatt et al, 2003), and only a minority of patients achieve clinical remission 
(Listing et al, 2006). Thus there is a need for new effective treatments to reduce disease 
activity in patients with RA.
1.1.1 Evidence for the CD40 Pathway in RA
Genome-wide association studies have identified a common variant in the CD40 locus that 
increases the risk of RA (Scheinman, 2013). The CD40 receptor is a member of the TNF 
family of receptors expressed on the plasma membrane of antigen-stimulated B cells, 
macrophage, and dendritic cells (Croft et al, 2013). The CD40 receptor functions to provide a 
co-stimulatory signal for B cells, which have bound antigen. The cognate ligand for CD40 is 
CD40 ligand (CD40L) (also known as CD154) that is expressed on the plasma membrane of 
T cells and other cell types, including platelets. Cell contact-dependent interaction 
between CD40L and CD40 is critical for the development of a comprehensive immune 
response (Ford et al, 2014). The RA risk allele is a gain-of-function allele that increases the 
amount of CD40 on the surface of primary human B lymphocyte cells and probably other 
cell types (Li et al, 2013). The expression of CD40L on CD4+ T helper cells is also 
increased in patients with active RA compared to those in clinical remission or healthy 
controls (Berner et al, 2000; Zhang et al, 2013). Taken together, these observations suggest 
that inhibition of the CD40L/CD40 pathway may be beneficial in RA.
The biology of the CD40/CD40L pathway is not completely understood. Interaction between 
CD40L and CD40 results in proteolytic cleavage of membrane CD40L that generates a 
soluble fragment (sCD40L) retaining the ability to bind to CD40 (Alaaeddine et al, 2012). 
The concentrations of sCD40L are increased in several autoimmune diseases including RA, 
systemic lupus erythematosus (SLE), and Sjogren’s syndrome. The biological significance of 
this is unknown as sCD40L may simply reflect increased activation of platelet and T cells 
resulting in release of sCD40L. Others have proposed that sCD40L may have a counter-
regulatory immunosuppressive role, at least in a cancer setting (Huang et al, 2012). In 
addition, CD40L can bind to receptors other than CD40, namely, the integrins αIIbβ3, α5β1, 


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and αMβ2, and a variety of biological functions for these interactions have been proposed 
(Alaaeddine et al, 2011). 
In previous early clinical studies, the monoclonal anti-CD40L IgG1 antibody, known as 
BG9588 showed signs of potential efficacy in patients with SLE and immune 
thrombocytopenic purpura; however, the clinical development of this agent was halted due to 
clinically significant thromboembolic events (Boumpas et al, 2003; Kuwana 2004).
Furthermore, the clinical program of another anti-CD40L monoclonal antibody (mAb), 
IDEC-131 mAb (which was under evaluation in Phase 1 and 2 trials), was curtailed 
subsequent to the reporting of a thromboembolic event in Crohn’s disease. These mAbs were 
Fc enabled, and subsequent nonclinical studies identified that platelet activation due to 
binding of Fc receptor by immune complexes of anti-CD40L and soluble CD40L was the 
likely mechanism underlying the association between anti-CD40L exposure and 
thrombosis (Langer et al, 2005; Robles-Carrillo, 2010). Recently, UCB reported data on 
CDP7657 (Dapirolizumab pegol [DZP]), an anti-CD40L antibody lacking an Fc domain, in 
non-human primates (Shock et al, 2015) and in healthy volunteers and patients with SLE 
(Tocoian, et al, 2015; Chamberlain et al, 2015). Single and multiple administrations of DZP
over 12 weeks in patients with mild to moderate SLE were well tolerated, and the safety
profile supports further development. Exploratory analyses show greater improvement in 
clinical measures of disease activity in the DZP group vs placebo (Chamberlain et al, 2015).
1.2
MEDI4920 Background
MEDI4920 is briefly described below. Refer to the current Investigator’s Brochure for 
details.
MEDI4920 is a CD40L antagonist that comprises two identical Tn3 modules fused to human 
serum albumin (HSA). Each Tn3 is an engineered form of the third fibronectin type III 
protein domain from human Tenascin C. Polyglycine linkers join the two Tn3 domains and 
the second Tn3 domain to the HSA protein. Each Tn3 binds specifically to human CD40L 
and inhibits its interaction with human CD40. 
1.3
Summary of Nonclinical Experience
MEDI4920 has been evaluated in several toxicology studies (please refer to Investigator’s 
Brochure for more detailed information). The cynomolgus monkey was selected specifically 
for use in these studies as MEDI4920 binds to and neutralizes the pharmacological activity of 
human and cynomolgus monkey CD40L. Human anti-CD40L molecules do not cross-react 
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Several repeat-dose studies (maximum weekly dosing duration of 6 months) and one single 
dose study were conducted to evaluate the safety, pharmacokinetics (PK), and 
pharmacodynamics (PD) of CD40L inhibition by intravenous (IV) and/or subcutaneous (SC) 
administration of MEDI4920 or its parent molecule. 
The no observed adverse effect levels (NOAELs) for repeat-dose studies were the highest 
doses tested for most of the studies: 150 mg/kg weekly IV or SC and 300 mg/kg weekly IV 
for the 5-week studies; 250 mg/kg weekly SC for the 6-month study. The NOAEL for the 
single-dose study was 600 mg/kg IV. 
Weekly IV administration of 150 or 300 mg/kg MEDI4920 to sexually mature cynomolgus 
monkeys for 6 months resulted in early euthanasia of one animal at 150 mg/kg/dose on 
Day 92 associated with declining clinical condition, adverse clinical pathology changes, and 
microscopic evidence of inflammatory cell infiltrates in multiple tissues. In addition, one 
animal dosed at 300 mg/kg/dose had enlarged spleen with nodular and abnormal appearance 
at scheduled necropsy on Day 192. Microscopically, increased amounts of inflammatory cell 
infiltrates in multiple organs and tissues were present in this animal and a systemic 
opportunistic fungal infection was detected; this was considered secondary to the 
pharmacology of MEDI4920. Therefore, no NOAEL was established for IV dosing in the 
6-month study. 
There were no MEDI4920-related clinical observations in any of the other animals. In 
addition, there were no MEDI4920-related changes in body weight, food consumption, 
ophthalmology, electrocardiology or blood pressure (BP) in any animals. There were no 
changes in total serum IgM, IgG, IgE, or IgA levels that were considered to be 
MEDI4920-related. 
There were no MEDI4920-related effects on female reproductive endpoints, including 
menstrual cycling, organ weights, or microscopic pathology. There was no evidence of a 
MEDI4920-related effect on male reproductive parameters, based on an overall weight of 
evidence analysis of testicular volume, sperm concentration and motility, sperm morphology, 
organ weights and histopathology of reproductive and accessory sex organs. 
Clinical pathology evaluations, including hematology, clinical chemistry, 
urinalysis, thrombin-antithrombin complex (TAT), D-dimer, and platelet function analyzer 
(PFA)-100 collagen/epinephrine closure times were performed on all animals in all studies. 
There were no MEDI4920-related adverse findings for any of these parameters in the single 
dose Good Laboratory Practice (GLP) (1468-036), the 1-month GLP (1468-035), the 
6-month GLP (20048035), or the non-GLP (1468-027) studies. 


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Any additional observations noted for hematology, clinical chemistry, or urinalysis 
parameters in the other studies were of small magnitude and transient in nature or were 
within the normal range for naive non-human primates.
In all of the repeat-dose studies, observed maximum concentration (Cmax), observed 
minimum concentration (Ctrough), and area under the concentration-time curve (AUC) 
increased dose proportionally across the dose range after the first and last dose. 
Bioavailability with SC dosing ranged between 73% to 83% in the repeat-dose studies. PD 
sample analysis showed a dose-dependent increase in the levels of sCD40L, consistent with 
the expected accumulation of sCD40L:MEDI4920 complexes.
Immunologic changes included dose-dependent decreases in CD20+ B-lymphocytes (flow 
cytometry) and decreases in T-cell-dependent antibody responses (TDARs); (anti-keyhole 
limpet hemocyanin [KLH] IgG and IgM). 
1.4
Summary of Clinical Experience
As of 25Aug2015 (cutoff date for D5100C00001 Cohort 6 interim analysis), a total of 
46 healthy volunteers have received single IV doses of MEDI4920 over the dose range 3 mg 
to 1000 mg in Study D5100C00001.
Study D5100C00001 is a Phase 1, randomized, blinded, placebo-controlled, single ascending 
dose (SAD) study to evaluate the safety and tolerability of single-ascending IV doses of 
MEDI4920 in healthy adult male subjects and healthy adult female subjects of 
non-childbearing potential. In addition to assessing safety and tolerability, the study also 
characterized the PK of MEDI4920, assessed anti-drug antibody (ADA) to MEDI4920, and 
evaluated the effect of MEDI4920 on TDAR after administration of the KLH antigen. The 
study was conducted at one site in the United Kingdom. A total of up to 56 subjects were 
planned for randomization within this study: 3 subjects were randomized in a 2:1 ratio for 
each of Cohorts 1 and 2 (3 and 10 mg MEDI4920, respectively or placebo) and 10 subjects 
each randomized in a 4:1 ratio for Cohorts 3 to 7 (30, 100, 300, 1000, and 3000 mg
MEDI4920, respectively, or placebo).
When all subjects in Cohort 5 completed Day 43 assessments, a first interim analysis was
conducted to evaluate the safety and tolerability of MEDI4920, PK, ADA, and the level of 
inhibition of the TDAR in Cohorts 1-5. With respect to safety, there were no withdrawals 
from the study, and one serious adverse event (SAE) of fractured tibia was reported in the 
placebo arm. Adverse events (AEs) were generally minor and balanced across placebo and 
MEDI4920 dose groups. One case of herpes zoster reactivation (shingles) was reported in the 


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30 mg dose group (Grade 2, start date Day 79). There were no deaths, no reports of 
thromboembolic events, no severe hypersensitivity or severe infection events, and no
concerns from the laboratory assessment of platelet function and coagulation. PK parameters 
(Cmax and AUC) increased in a dose-proportional fashion, with a half-life of 
approximately 8 days for the 300 mg IV dose. Between 50% to 100% of subjects in 
Cohorts 1 to 4 developed ADAs at at least one time point after dosing, whereas only 3 of 
8 subjects in Cohort 5 developed ADAs after dosing. The ADA positive subjects had faster 
clearance and reduced observed MEDI4920 exposure. According to the pre-specified dose 
escalation criteria, as TDAR inhibition was < 75% vs placebo and no safety concerns were 
observed, Cohort 6 (1000 mg dose) was initiated. An additional 10 subjects were randomized 
in a 4:1 ratio to receive either 1000 mg MEDI4920 or placebo. 
When all subjects in Cohort 6 completed Day 43 assessments, a second interim analysis was 
conducted to evaluate the safety and tolerability of MEDI4920, PK, ADA, and the level of 
inhibition of the TDAR in Cohorts 1-6, in order to evaluate the requirement for
Cohort 7 (3000 mg). The safety profile remained consistent with the safety profile observed 
at the first interim analysis, with no deaths, serious or severe AEs, thromboembolic events, 
severe hypersensitivity or severe infection events, and no concerns from the laboratory 
assessment of platelet function and coagulation. No subjects in Cohort 6 (1000 mg) were 
positive for ADAs up to Day 29, which was the last available ADA time point in Cohort 6 
prior to interim assessments. 
After the second interim analysis, TDAR inhibition was observed in a dose-dependent 
manner. A dose response analysis at Day 43 of the dose cohorts up to and including 1000 mg 
demonstrated a statistically significant linear dose response (p = 0.003) with the 1000 mg 
dose observing a 77% inhibition of the TDAR IgG response compared to 
placebo (95% confidence intervals [CIs]: 41%, 91%).
1.5
Rationale for Conducting the Study
MEDI4920 is being developed for the treatment of B-cell dependent autoimmune diseases. 
The current study is designed to characterize the safety, tolerability, PK, biomarkers, 
immunogenicity, and clinical response of multiple doses of MEDI4920 in subjects with 
moderate to severe RA.
The results from this study will form the basis for decisions regarding appropriate repeat 
dosing strategies of MEDI4920 for future studies in subjects with RA and/or other 
autoimmune conditions.


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1.6
Potential Risks
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/Good Clinical Practice (GCP), and applicable regulatory requirements.
Based on clinical data from Cohorts 1-6 of the SAD study, there are no identified risks for
humans associated with MEDI4920. Potential risks based on the mechanism of action 
(MOA) of MEDI4920 and mitigation plans included in the protocol are summarized below.
Anaphylaxis and Serious Hypersensitivity Reactions 
No severe or serious hypersensitivity reactions have been observed with MEDI4920 at doses 
up to 1000 mg in the SAD study. 
In the current study, subjects will be excluded from participation if they have had a history of 
a severe allergic reaction to any component of the investigational product formulation or to 
any other biologic therapy. The risk of hypersensitivity reactions is considered maximal after 
the first two IV administrations of MEDI4920 (Days 1 and 15). To monitor for infusion 
and/or hypersensitivity reactions, subjects will be in a clinical trial facility and closely 
monitored for 4 hours after the end of the infusion for the first two doses (Days 1 and 15). 
Doses will be administered by IV infusion over minimum times of 30 minutes for the 75 mg 
dose, 60 minutes for the 500 mg dose, 90 minutes for the 1000 mg dose, and 90 minutes for 
the 1500 mg dose. The infusion will be discontinued if there is evidence of infusion reaction 
and supportive treatment may be instituted. Guidelines for monitoring relevant AEs
encompassing hypersensitivity, angioedema and anaphylaxis and for managing acute 
anaphylactic shock and minor allergic episodes will be in place at investigational sites. Study 
sites will include facilities and expertise for emergency care/resuscitation, including access to 
hospital and intensive care unit. 
Serious and/or Opportunistic Infections
No severe or serious infections have been observed in the first time in human (FTIH) SAD 
study. One case of herpes zoster reactivation was reported in a subject receiving 30 mg 
MEDI4920. 
Weekly IV administration of 150 or 300 mg/kg MEDI4920 to sexually mature cynomolgus 
monkeys for 6 months resulted in an opportunistic fungal infection in one animal treated with 
MEDI4920 300 mg/kg IV, and changes suggesting potential systemic infection were 
observed in another animal treated with MEDI4920 150 mg/kg (see Section 1.3).


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Measures taken in the current study to minimize the risk of immunosuppression-related 
infections include the following:
•
During screening, subjects will be excluded from the study if they have had a recent 
(within 12 months) or active hepatitis A infection; if they test positive or have been 
treated for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection; if 
they have evidence of active or untreated latent tuberculosis (TB); if they have a recent 
history (last 12 months) of recurrent herpes zoster and/or opportunistic infection; and/or 
if they are taking immunosuppressant medication (see exclusion criteria in Section 4.1.3
and prohibited concomitant medications in Section 4.7.2).
•
Subjects will not be allowed to receive live (attenuated) vaccine within the 4 weeks prior 
to dosing or during the study until the end of follow-up. 
•
Clinical assessments for signs of infection will be performed at each study visit. Subjects 
will be given instructions on potential signs of infection and instructed to contact 
investigator if they have signs or symptoms of an infection. Blood samples for serology 
and viral polymerase chain reaction (PCR) will be collected at screening and stored to 
assess new vs reactivation of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) in 
case an EBV or CMV infection is reported as an AE during the study.
Unknown Consequences of Exposure in Utero
No embryo-fetal studies have been conducted to date. 
This study requires all female subjects of childbearing potential to use at least one highly 
effective method of contraception from the time of screening up through at least 6 months 
after the final dose of investigational product. The acceptable methods of contraception are 
described in Section 4.1.2.
In addition, the investigator must inform the subjects about the risks involved with some of 
the background medications used in RA and accepted in the current study (eg, MTX or 
leflunomide) as these agents are known to have potential deleterious effects on conception, 
pregnancy and fetal health (see Section 4.1.2).
The requirement for adherence with contraceptive guidance in the protocol and screening for 
pregnancy (serum or urine) will be monitored throughout the duration of the study.
Thrombotic and Embolic Events
Previous clinical trials with anti-CD40L mAbs that were Fc enabled demonstrated increased 
incidence of thromboembolic events, and subsequent nonclinical studies identified that 
platelet activation due to binding of Fc receptor by immune complex of anti-CD40L and 


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soluble CD40L was the likely mechanism underlying the association between anti-CD40L 
exposure and thrombosis. MEDI4920 was engineered to lack Fc fragment. 
No thromboembolic events have been reported in animal studies and in the human SAD 
study with MEDI4920.
To minimize the risk of thromboembolic events in the current study, subjects will be 
excluded from participation if they have a medical history of confirmed venous 
thromboembolism or arterial thrombosis or if they have significant clinical and molecular 
risk factors for thromboembolic events or arterial thrombosis. In addition, any subjects with a 
clinically significant abnormal coagulation panel at screening will be excluded from this 
study (see Section 4.1.3).
Thromboembolic events will be monitored by AE evaluation and physical examinations 
performed during the study. If a subject dosed with MEDI4920 experiences a confirmed or 
suspected thromboembolic event during the evaluation period or follow-up period, the dose 
escalation will be suspended and the event will be fully evaluated (see Section 3.1.3 for 
additional details). 
Immune Complex Disease
The potential risk of immune complex disease is based on the potential risk known to be 
associated with foreign proteins and mAbs. The occurrence of ADA could result in immune 
complex disease (with manifestations such as arthralgia, serum-sickness, nephritis, and 
vasculitis) or altered MEDI4920 levels or activity. Subjects in clinical studies with 
MEDI4920 will be monitored for the presence of ADA and for clinical manifestations that 
may be associated with the formation of specific antibodies to MEDI4920.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
The primary hypothesis is that multiple ascending IV doses up to 1500 mg of MEDI4920 
once every 2 weeks (Q2W) over a 12-week period will be safe and well-tolerated in subjects 
with RA when compared with placebo in combination with MTX or another cDMARD.
1.7.2
Secondary Hypothesis 
A secondary hypothesis has not been established for this study.


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1.7.3
Exploratory Hypotheses
The exploratory hypotheses are that
 
 
.
2
OBJECTIVES AND ENDPOINTS
2.1
Objectives
2.1.1
Primary Objective
To assess the safety and tolerability of multiple ascending IV doses of MEDI4920 in subjects 
with adult-onset RA.
2.1.2
Secondary Objectives
To evaluate the PK and immunogenicity of MEDI4920 in subjects with adult-onset RA.
2.1.3
Exploratory Objectives
1.
2.
3.
4.
2.2
Study Endpoints
2.2.1
Primary Endpoints
1. The incidence of AEs and SAEs.
2. The incidence of treatment-emergent AEs of special interest (AESIs) as follows:
◦
Thrombotic and embolic events
◦
Hepatic function abnormality (meeting the definition of Hy’s Law [HL]; see 
Section 5.6.2)
◦
Anaphylaxis and serious hypersensitivity reactions
◦
Infusion-related reactions
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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◦
Immune complex disease
◦
Serious and/or opportunistic infections (including but not limited to reactivation of 
latent viral infection [varicella zoster (VZ), herpes simplex virus (HSV), EBV, CMV]
and TB)
3. Vital signs, laboratory parameters (including coagulation parameters), electrocardiograms 
(ECGs), and physical examinations.
2.2.2
Secondary Endpoints
The PK profile, PK parameters, and immunogenicity of MEDI4920 will be assessed for each 
cohort
2.2.3
Exploratory Endpoints
1.
2.
3.
4.
5.
3
STUDY DESIGN
3.1
Description of Study
3.1.1
Overview
This is a multicenter, randomized, double-blind (investigator, subject, and sponsor will be 
blinded to treatment assignment), placebo-controlled study to evaluate the safety and 
tolerability of multiple ascending doses (MADs) of MEDI4920 in subjects with adult-onset 
RA (moderate to severe, as defined by DAS28 CRP ≥ 3.2 at screening) with an inadequate 
response to MTX or other cDMARDs or a biologic anti-TNFα agent. 
The study is planned to be conducted at approximately 15 sites in 2 to 4 countries. A 
maximum of 54 eligible subjects are planned for this study. Approximately 40 subjects will 
be randomized in 3 cohorts to receive either 75 mg (Cohort 1), 500 mg (Cohort 2), or 
1500 mg (Cohort 3) MEDI4920, or placebo once Q2W in combination with MTX or another 
cDMARD for up to 12 weeks.
An additional 14 subjects will be randomized in a 5:2 ratio to an additional cohort (Cohort 4), 
to better characterize the dose (exposure) - response relationship. The selected dose of 
MEDI4920 in Cohort 4 is 1000 mg Q2W.
CCI
CCI
CCI
CCI
CCI


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Subjects will undergo a screening period of up to 6 weeks followed by randomization and 
treatment for 12 weeks. Subjects will be followed for an additional 12 weeks after the 
treatment period for safety. Each subject will participate in the study for up to approximately 
30 weeks (includes a 6-week screening period, a 12-week treatment period, and a 12-week 
follow-up period).
Subjects will receive an IV dose of MEDI4920 or placebo Q2W for up to 12 weeks as 
follows:
•
Cohort 1: 75 mg MEDI4920 (N = 8) or placebo (N = 2) as a single IV dose administered 
over at least 30 minutes Q2W
•
Cohort 2: 500 mg MEDI4920 (N = 10) or placebo (N = 4) as a single IV dose 
administered over at least 60 minutes Q2W 
•
Cohort 3: 1500 mg MEDI4920 (N = 12) or placebo (N = 4) as a single IV dose 
administered over at least 90 minutes Q2W 
•
Cohort 4: 1000 mg MEDI4920 (N = 10) or placebo (N = 4) as a single IV dose 
(administered over at least 90 minutes Q2W ) 
Subjects will be administered investigational product via IV infusion using an infusion pump. 
All subjects will receive a total of 7 doses of investigational product (MEDI4920 or placebo)
during the 12-week treatment period. Details about dose escalation can be found in 
Section 3.1.3.
A screening visit(s) will be performed within 6 weeks (42 days) prior to dosing. All subjects 
will receive investigational product on the morning of Day 1. An overnight stay on Day -1 
prior to administration of investigational product on Day 1 is recommended but not 
mandatory. If no safety concerns are identified, subjects will be discharged from the study 
site on Day 2 (end of the inpatient treatment period) after all study procedures have been 
completed. Subjects in all cohorts will return to the study site Q2W (Days 8, 15, 29, 43, 57, 
71, and 85) for investigational product administration and/or specific assessments and blood 
draws, as indicated in Table 4.2.2-1.
During the treatment period, assessments of RA parameters as well as evaluations of safety, 
tolerability, PK, and immunogenicity of MEDI4920 will be performed at the time points 
indicated in Table 4.2.2-1.
Following the final IV infusion of investigational product, subjects will return to the study 
site for follow-up visits beginning at Week 13 (Day 92) and continuing through Week 24 


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(Day 169) to evaluate safety, tolerability, PK and ADA of MEDI4920 as indicated in 
Table 4.2.3-1.
A study flow diagram is presented in Figure 3.1.1-1. 
Figure 3.1.1-1
Study Flow Diagram
Ab = antibody; ADA = anti-drug antibody; D = day; IV = intravenous; PK = pharmacokinetic; Q2W = once 
every 2 weeks
The endpoints to be measured in this study are described in Section 2.2.
3.1.2
Treatment Regimen
A maximum of 54 subjects will be randomized in a 4:1 ratio (Cohort 1), in a 5:2 ratio 
(Cohort 2), in a 3:1 ratio (Cohort 3), and in a 5:2 ratio (Cohort 4) to receive either MEDI4920 
or placebo as described in Table 3.1.2-1:


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Table 3.1.2-1
Investigational Product Dose and Treatment Regimen
Cohort
N 
(active:placebo)
Dose
Treatment Regimen a
1
4:1
75 mg
Single IV dose infused over at least 30 minutes on 
Days 1, 15, 29, 43, 57, 71, and 85
2
5:2
500 mg
Single IV dose infused over at least 60 minutes on 
Days 1, 15, 29, 43, 57, 71, and 85
3
3:1
1500 mg
Single IV dose infused over at least 90 minutes on 
Days 1, 15, 29, 43, 57, 71, and 85
4 
5:2
1000 mg
Single IV dose infused over at least 90 minutes on Days 
1, 15, 29, 43, 57, 71, and 85 
IV = intravenous; TBD = to be determined. 
a
For Cohorts 1-4, investigational product will be administered via IV infusion using an IV infusion pump.
The timing of administration of investigational product will be staggered within each cohort 
to allow for review of safety and tolerability data from the first group of subjects before 
progression to the next group of subjects.
3.1.3
Dose Escalation and Cohort Progression
Cohorts 1 to 3 will start sequentially, with escalation from Cohort 1 to Cohort 2 and Cohort 2 
to Cohort 3 confirmed by a Dose Escalation Committee (DEC) comprised of MedImmune 
study team members and the Study Global Chief Investigator, who will assess in a blinded 
fashion the safety/tolerability data after the last subject in a cohort completes Day 29 
(Week 4) of treatment and has AE/safety laboratory data available at that time point. There 
will be a total of three DEC meetings during the study; the first DEC meeting will only 
review data from Cohort 1 whereas the second DEC meeting will review cumulative safety 
data from first two dose cohorts being tested to date. The third DEC meeting will constitute a 
thorough evaluation of the cumulative safety and tolerability data for Cohorts 1 and 2 in 
addition to the data up to Day 85 for Cohort 3. While this review will not pertain to a dose 
escalation, it will contribute to the decision to instigate Cohort 4 (see below). 
After the last Cohort 3 subject completes the Day 85 (Week 12) assessments, the primary 
analysis will be conducted to include safety, tolerability, PK, ADA, biomarker, and clinical 
response. Based on the outcome of this analysis, a fourth cohort will be included to better 
understand the dose (exposure)-response relationship.
If one or more of the following criteria are met, dose escalation will be suspended and the 
event(s) will be fully evaluated:


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•
A subject dosed with MEDI4920 experiences a confirmed or suspected thromboembolic 
event during the evaluation period or follow-up period. If the thromboembolic event is 
initially reported as “suspected”, because of the unavailability of sufficient information to 
support a definitive diagnosis at that time, the DEC will re-assess the event when 
complete clinical/laboratory information is provided by the study site. A diagnosis 
algorithm (adapted from Wells and Anderson, 2013; Section 10.5 [Appendix 5]), is 
recommended to be used for any case of suspected DVT or PE. This includes clinical 
pre-test probability, D-dimer, and available imaging results. Based on full evaluation of 
the data as well as the diagnosis algorithm, if a thromboembolic event is ruled out or 
considered unlikely, dose escalation can be resumed.
•
At least 2 subjects dosed with MEDI4920 in a single cohort experience either Grade 3 or 
higher treatment-emergent AEs (TEAEs) of the same type (excluding rheumatoid joint 
flares) or any SAE.
•
At least 2 subjects dosed with MEDI4920 in a single cohort experience serious infections. 
•
In addition to the above criteria, the DEC may recommend stopping dose escalation and 
further evaluation of any significant medical event(s) or confirmed clinically significant 
laboratory abnormalities (including coagulation tests) that are considered related to 
investigational product.
If the DEC suspends the dose escalation and subsequently decides to resume dosing at the 
same or higher doses, approval from the relevant regulatory authorities and Independent 
Ethics Committees (IECs) will be obtained prior to dosing.
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
The safety, tolerability, and PD effects of single IV doses of 3000 mg of MEDI4920 are 
currently being evaluated in healthy adult volunteers in the final cohort of study 
D5100C00001. Data from interim analysis 2 are currently available (see Section 1.4).
To date, there are no dose-limiting toxicities known in humans.
The doses selected in the current study aim to explore the dose-response relationship for the 
main exploratory efficacy endpoint in RA
while 
testing safety/tolerability within a well-defined safety margin predicted based on animal data. 
There is no precise relationship between efficacy in autoimmune diseases and PD models 
(suppression of free sCD40L or inhibition of TDAR to a model neoantigen).
A PK-PD model to describe the relationship between total sCD40L plasma concentration (as 
a surrogate PD marker of target engagement) and plasma concentrations of MEDI4920 in 
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healthy subjects from the SAD study has been developed. The free sCD40L suppression after 
repeated dosing was predicted based on this model. The ability of MEDI4920 to inhibit 
TDAR has been demonstrated and quantified in non-human primates and also in the FTIH 
SAD study (D5100C00001). In humans, at single IV dose of 1000 mg (which provides high 
degrees of target engagement in peripheral blood), TDAR inhibition was shown to be 
significant; however the dose-response relationship may not have reached a plateau.
The PK-PD model predicts that a dose of 75 mg Q2W should maintain an approximately 
95% suppression of free sCD40L throughout the entire dosing interval. The safety margin of 
this dose is estimated to be approximately 65 fold (method Human Equivalent Dose [HED]), 
which is calculated using the SC NOAEL of 250 mg/kg weekly demonstrated in the 27-week 
toxicology study in cynomolgus monkeys. Therefore, a 75 mg dose may provide some level 
of clinical response for RA patients while maintaining a good safety profile.
The highest dose level in Cohort 3 (1500 mg Q2W) is also driven by the approximately 
3-fold safety margin (based on HED). A significant clinical response in RA patients is 
expected with this dose.
An intermediate dose of 500 mg Q2W was selected as the medium dose for the study; this 
dose has a safety margin of 10 (based on HED) and is able to inhibit TDAR as shown in the 
SAD study. 
After review of the primary analysis data, which included cumulative safety, PK, and 
biomarker data through Cohort 3, Day 85, the decision was made to explore a fourth dose 
(Cohort 4, 1000 mg Q2W), in order to complete the safety analysis as well as the dose-
response analysis in the exploratory efficacy endpoint. Based on PK-PD modeling data from 
Cohorts 1 to 3 combined with clinical judgement, the 1000 mg Q2W dose selected for 
Cohort 4 is a dose that is expected to result in a clinical response comparable to the 1500 mg 
Q2W dose (highest dose in the study) but with a larger safety margin.
3.2.2
Rationale for Study Population
It is acknowledged that healthy volunteers could also be selected as a study population in a 
Phase 1 MAD study. However, in the current study, subjects with RA were selected as the 
study population for the following reasons:
•
Opportunity to test MEDI4920 in a disease where B-cell targeted therapy (rituximab) is 
known to be clinically effective and where nonclinical evidence suggests the 
CD40L/CD40 pathway is active. 


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•
Potential for providing clinical benefit that can be quantified in a standardized way to 
subjects with RA after 12 weeks of treatment
•
It is important to establish the PK and PD in a patient population with a well-studied 
autoimmune disease such as RA that is characterized by elevated sCD40L compared to 
healthy volunteers.
•
Concerns about exposing healthy volunteers to known and theoretical risks of AEs 
related to MEDI4920 over a 12-week treatment period.
•
There is no well-defined relationship between the level of TDAR inhibition in healthy 
volunteers and clinical efficacy in patients with autoimmune conditions; thus no relevant 
prediction of clinical effectiveness can be provided by assessing TDAR response in a 
MAD study in healthy volunteers. 
•
It is important to understand the potentially inhibitory effect of background 
immunomodulatory therapy given in RA (eg, MTX) on ADAs against MEDI4920.
3.2.3
Rationale for Endpoints 
This is the first study of MEDI4920 in adult subjects with RA and thus it is appropriate that 
the safety and tolerability of MADs constitute the primary endpoint. Additionally, the study 
will assess the PK profile and immunogenicity of MEDI4920 in multiple doses in 
conjunction with the mechanistic effect of MEDI4920 as secondary endpoints.
were 
chosen as key exploratory endpoints, in order to assess early signals of clinical efficacy with 
MEDI4920 in RA that might support further studies in the same indication or in different 
autoimmune conditions.
 and
have been selected due to their high level of 
standardization and wide use in clinical trials in RA. 
Serum will be collected to measure changes in exploratory biomarkers of disease activity, 
such as autoantibodies, and biomarkers associated with the CD40L pathway, including 
biomarkers induced by CD40L signaling. These biomarker measurements will aid in the 
determination of what biological pathways are impacted by MEDI4920 treatment. The 
MBDA panel includes adhesion molecules, growth factors, cytokines, matrix 
metalloproteinases, skeletal proteins, hormones and acute phase proteins. The MBDA panel 
has been demonstrated to be a sensitive and objective measure of clinical disease activity, 
with a strong correlation to DAS28 CRP.
CCI
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4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
A maximum of 54 subjects with adult-onset RA (moderate to severe) are planned for this 
study: 10 subjects will be randomized in a 4:1 ratio in Cohort 1, 14 subjects will be 
randomized in a 5:2 ratio in Cohort 2, and 16 subjects will be randomized in a 3:1 ratio in 
Cohort 3. An additional 14 subjects will be randomized in a 5:2 ratio in Cohort 4.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria. Site staff must contact MedImmune for 
consultation prior to enrolling, randomizing, or administering investigational product to any 
subject who deviates from these criteria:
1. Male or female
2. 18-70 years old (inclusively) at the time of informed consent
3. Adult-onset RA diagnosed by European League Against Rheumatism/ACR 2010 criteria 
(Aletaha et al, 2010). Diagnosis of RA should be established at least 6-months before 
screening.
4. Subjects must be treated with MTX given orally, SC or intramuscular at a dose of 7.5-25 
mg/week for at least 12 weeks and the dose must have been stable for at least 6 weeks 
prior to screening. The following exception is permitted:
◦
MTX-intolerant subjects may enter the study if they are on cDMARDs for at least 
12 weeks and the dose has been stable for at least 6 weeks prior to screening. 
Combination of two or more cDMARDs is allowed if recommended by national 
guidelines and/or standard medical practice. 
5. Subjects who may have been treated with anti-TNFα biologic agents that were stopped 
for any reason (lack of efficacy, safety/tolerability issues or lack of access to drug) at 
least 8 weeks before randomization are eligible. 
6. Subjects treated with an agent with a MOA other than anti-TNF (eg, anti-IL-6, CTLA-4 
or anti-IL-1) are only eligible if at least 3 months or 5 half-lives of the drug (whichever is 
shorter) have passed between the last dose and the randomization visit.
7. DAS28 CRP of ≥ 3.2 at screening.
8. At least 4 tender and 4 swollen joints assessed at screening and confirmed at 
randomization out of the 28 joints assessed for DAS28.
9. Positive for serum RF and/or ACPA at screening, according to the central laboratory’s 
definition of positivity.
10. Age-specific vaccinations, as based on local expert recommendations and local standard 
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11. Written informed consent and any locally required authorization (eg, data privacy) 
obtained from the subject prior to performing any protocol-related procedures, including 
screening evaluations.
12. Willing and able to comply with the protocol, complete study assessments, and complete 
the study period.
13. Females of childbearing potential who are or might become sexually active with a 
nonsterilized male partner during the duration of study must use at least one highly 
effective method of contraception from screening, and must agree to continue using such 
precautions at least 6 months after the final dose of investigational product. It is strongly 
recommended for the male partner of a female subject to also use a male condom plus 
spermicide throughout this period. Cessation of contraception after this point should be 
discussed with a responsible physician. 
◦
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, surgical sterilization includes 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).
◦
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.
14. Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use a condom with spermicide from Day 1 through to the end of the study.
In relationship with inclusion criteria 13 and 14, since some of the background medications 
used in RA and accepted in the current study (eg, MTX or leflunomide) are known to have 
potential deleterious effects on conception, pregnancy and fetal health, the investigator must 
inform the subjects about these risks and should manage every case of planned conception or 
pregnancy according to the local medical practice standards. 


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Table 4.1.2-1
Highly Effective Methods of Contraception for Females of 
Childbearing Potential
Physical Methods
Hormonal Methods
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS) a
•
Bilateral tubal occlusion
•
Vasectomized partner b
•
Sexual abstinence c
Combined (estrogen and progestogen containing 
hormonal contraception)
•
Oral (combined pill)
•
Injectable
•
Transdermal (patch)
Progestogen-only hormonal contraception associated 
with inhibition of ovulation d
•
Injectable
•
Implantable
•
Intravaginal
a
This is also considered a hormonal method.
b
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate).
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject.
d
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(minipill) is not accepted as a highly effective method.
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of birth control.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study. Site staff 
must contact MedImmune for consultation prior to enrolling, randomizing, or administering 
investigational product to any subject who deviates from these criteria:
1. A history of, or current inflammatory joint disease other than RA (eg, gout, reactive 
arthritis, psoriatic arthritis, seronegative spondyloarthropathy, or Lyme disease) or other 
systemic autoimmune disorder (eg, SLE, inflammatory bowel disease, scleroderma, 
inflammatory myopathy, mixed connective tissue disease, or other overlapping 
syndrome). Subjects with polymyalgia rheumatica will be excluded from the study.
2. Subjects with a medical history of confirmed venous thromboembolism or arterial
thrombosis.
3. Subjects with risk factors for venous thromboembolism or arterial thrombosis (eg,
immobilization or major surgery within 12 weeks before screening), prothrombotic status 
(including but not limited to congenital or inherited deficiency of antithrombin III, 
protein C, protein S, or confirmed diagnosis of antiphospholipid syndrome).
4. Subjects with clinically significant abnormal coagulation panel at screening (including 
but not limited to multiple and significant shifts in prothrombin time ratio, activated 
partial thromboplastin time (D-dimer, etc). In case of doubts in assessing coagulation 
abnormalities as being clinically significant, the investigator may contact and discuss 
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5. RA functional class IV, presence of severe systemic comorbidities (extensive vasculitis, 
pericarditis, amyloidosis, lymphoma), hemochromatosis, IgG4-related diseases, 
auto-inflammatory syndromes including Still’s and Felty’s syndrome.
6. Active or recent history (within the last 10 years) of malignancies (except for non-
melanoma skin cancers and in situ cervical carcinoma, treated and considered cured).
7. Pregnancy or lactation.
8. Subjects with recent (within 12 months) or active hepatitis A infection as evidenced by 
clinical history and/or positive test for anti-hepatitis A antibodies.
9. Subjects who have a positive test for, or have been treated for hepatitis B, hepatitis C, or 
HIV infection. Regarding hepatitis B, any of the following would exclude the subject 
from the study: 
◦
Subjects positive for hepatitis B surface antigen (HbsAg) 
◦
Subjects with hepatitis B virus deoxyribonucleic acid (DNA) levels > 200 copies/mL 
(quantified by real-time polymerase chain reaction) in case the subject is positive for 
hepatitis B surface antibody (HbsAb) but negative for HbsAg. 
◦
Positive for hepatitis B core antibody (HbcAb) 
10. Evidence or history of active or untreated latent TB:
◦
Signs or symptoms suggestive of active TB upon medical history or physical 
examination
◦
Positive diagnostic TB test during screening (defined as a positive interferon-gamma 
release assay [IGRA] test for TB at screening).
◦
Subjects with an indeterminate IGRA should undergo a repeat test, and if still 
indeterminate, must be excluded.
11. More than one episode of herpes zoster and/or opportunistic infection in the last 
12 months. 
12. Known history of severe allergy or reaction to any component of the investigational 
product formulation or to any other biologic therapy.
13. Any severe cardiovascular, respiratory, endocrine, gastro-intestinal, hematological, 
neurological, psychiatric, or systemic disorder that could impact the evaluation of safety 
and efficacy assessments or affect the subject’s ability to participate in the study or the 
subject’s safety.
14. 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. This 
includes important and extensive joint pain and swelling not due to RA (eg, severe 
polyarticular osteoarthritis involving small joints in hands and feet). Those medical 
conditions that are only limited to a small number of joints such as localized osteoarthritis
(eg, knee, hip, and spine) can be included in the study.
15. Receipt of live (attenuated) vaccine within the 4 weeks before screening or during the 
study.
16. Last administration of licensed or experimental biologic agents used for treatment of RA 
targeting any other mechanism other than direct anti-TNF blockade, (eg, CTLA-4 and 
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targeting any other mechanisms (eg, JAK inhibitors) for treating RA ≤3 months before 
randomization.
17. Previous treatment with any biologic cell-depleting therapy (eg, rituximab) for RA or 
anti-CD40/CD40L agents.
18. Concurrent treatment with any biologic or nonbiologic DMARDs excluding stable 
background MTX or other cDMARDs including stable sulfasalazine, leflunomide, 
hydroxychloroquine, azathioprine, cyclosporine, or D-penicillamine.
19. Injectable corticosteroids (including intraarticular) or treatment with > 10 mg/day dose 
oral prednisone or equivalent within 4 weeks prior to randomization. Concomitant 
treatment with oral corticosteroids ≤ 10 mg/day prednisone or equivalent is permitted 
provided that the dose is stable for ≥ 4 weeks prior to randomization and remains stable 
for the duration of the treatment period. Inhaled or topical corticosteroids given for 
asthma, chronic obstructive pulmonary disease (COPD) or dermatological conditions are 
allowed provided doses are stable between screening and Day 85 visit. 
20. At screening blood tests, any of the following: 
◦
Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN) 
◦
Alanine aminotransferase (ALT) > 2 × ULN
◦
Alkaline phosphatase (ALP) > 2 × ULN
◦
Total bilirubin (TBL) > 2 × ULN 
◦
Hemoglobin < 75 g/L 
◦
Neutrophils < 1.5 × 109/L
◦
Platelets < 100 × 109/L
21. History of alcohol or drug abuse within 2 years prior to randomization. 
Subjects may be re-screened only once if they do not meet the eligibility criteria related to 
disease activity or previous RA medication wash-out. Subjects not fulfilling any of the other
eligibility criteria cannot be re-screened.
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 [IXRS]), 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. 
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.


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4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments), at any time without prejudice to further treatment. Subjects who withdraw 
consent will be asked about the reason(s) and the presence of any AEs. If the subject is 
willing, the subject will be seen and assessed by the investigator. All AEs will be followed 
up. If a subject withdraws consent from further participation in the study, then no further 
study visits or data collection should take place.
4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:
•
Withdrawal of consent from the study
•
Withdrawal of consent from further treatment with investigational product 
•
Lost to follow-up
•
AE or significant laboratory abnormality that, in the opinion of the investigator and/or the 
sponsor, warrants discontinuation of further dosing
•
Pregnancy or a decision to become pregnant (see Section 5.6.3)
•
Subjects who require biologic DMARD therapy other than MEDI4920
•
Hepatic function abnormality defined as any increase in ALT or AST to greater than 
3 × ULN and concurrent increase in bilirubin to greater than 2 × ULN related to 
MEDI4920:
•
Anaphylaxis or a serious hypersensitivity reaction.
•
Any life-threatening or serious infection or opportunistic infection. Subjects with a 
diagnosis of serious and/or opportunistic infections including but not limited to
reactivation of TB, hepatitis B, or hepatitis C will not receive any further investigational 
product.
•
Any confirmed or suspected serious or severe thromboembolic event
•
AEs of malignancy
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including follow-up of any AEs unless consent 
is withdrawn from further study participation (Section 4.1.5), or the subject is lost to follow-
up.


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4.1.7
Replacement of Subjects
Only subjects who are randomized but do not receive investigational product (MEDI4920 or 
placebo) may be replaced to maintain the stipulated cohort sizes. This would include subjects 
who are randomized and then withdraw consent before receipt of investigational product. 
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 Genetic or Future Research
Samples obtained for genetic or future research will be labeled with a sample identification 
number. If the subject withdraws consent for participating in the genetic or 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 samples from other subjects at 
a secure central laboratory. The subject’s samples 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, the sponsor and the investigator will ensure that these sample(s) are 
destroyed unless the identification number has been removed and the subject can no longer 
be linked to any sample(s). However, if the subject’s samples 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 the screening visit. Assessments 
should be performed in the order shown in the table.
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the blood draws should occur last. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, serum chemistry) to occur at the proper nominal time.
Table 4.2.1-1
Schedule of Screening Procedures  
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -42 to Day -1
Written informed consent
X
IXRS assignment of SID number
X
Medical history
X
Verify eligibility criteria
X
Safety assessments
Assessment of AEs/SAEs
X
Assessment of concomitant medications
X
Complete physical examination (includes weight)
X
Height
X
12-lead ECG a
X
Vital signs b
X
TB test c
X
Blood collection for:
Serum chemistry 
X
Hematology
X
Coagulation parameters:
Screening for deficiency of protein C, protein S, AT3, 
and APL antibodies
X
Baseline coagulation panel
X
Autoantibody panel (RF, RF isotypes, ACPA, ANA, 
anti-Ro, anti-La [serum])
X
Exploratory biomarkers (serum)
X
RNA PAXgene (whole blood)
X
Acute-phase reactants (CRP, ESRd)
X


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Table 4.2.1-1
Schedule of Screening Procedures  
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -42 to Day -1
Virology: hepatitis A, B, C; HIV-1, HIV-2, CMV, EBV
X
Serum β-hCG (females of childbearing potential only)
X
Urine collection for:
Urinalysis
X
Rheumatoid assessments
TJC/SJC: 28 joints count 
X
VAS Patient’s Global Assessment of disease activity
X
Physician’s Global Assessment
X
AE = adverse event; ACPA = anti-cyclic citrullinated peptide antibody; ANA = antinuclear antibody; 
APL = antiphospholipid; AT = anti-thrombin; β-hCG = beta-human chorionic gonadotropin;
CMV = cytomegalovirus; CRP = C-reactive protein; EBV = Epstein-Barr virus; ECG = electrocardiogram; 
ESR = erythrocyte sedimentation rate; HIV = human immunodeficiency virus; IXRS = interactive voice/web 
response system; RF = rheumatoid factor; RNA = ribonucleic acid; SAE = serious adverse event; SID = subject 
identification; TB = tuberculosis; TJC = tender joint count; SJC = swollen joint count; V = visit; VAS = visual 
analogue scale.
a
The screening ECG will be obtained in triplicate (all 3 within a 5-minute time period, at least 1 minute 
apart).
b
Vital sign measurements include body temperature, blood pressure, heart [pulse] rate, and respiratory rate.
c
TB screening will be performed according to the local medical standards. If the local standard requires a 
chest X-ray it must be from within the last 6 months prior to screening and source documents must be 
available. QuantiFERON®-TB Gold test at screening will be mandatory for all subjects and will constitute 
an exclusion criterion per se. 
d
ESR will be analyzed at the local laboratories.
4.2.2
Treatment Period
Table 4.2.2-1 shows all procedures to be conducted during the treatment period (Part A 
through Day 85 [Week 12]).
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, blood draws should occur last. The timing of the first two assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time. All 
laboratory sample collections and assessments on dosing day must be performed at predose, 
unless specified otherwise.


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Table 4.2.2-1
Schedule of Treatment Period Study Procedures  
Study Period
Treatment Period
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
Procedure / Study Day
Day 1
± 1 
Day
Day 2
± 1
Days
Day 8 ± 
1 Day
Day 15
± 1 Day
Day 29
± 1 Day
Day 43
± 1 Day
Day 57
± 1 Day
Day 71
± 1 Day
Day 85
± 1 Day
Randomization
Verify eligibility criteria 
X
IXRS randomization call
X
Safety assessments
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
Assessment of concomitant medications
X
X
X
X
X
X
X
X
X
Complete physical examination (includes weight)
X
Abbreviated physical examination a
X
X
X
X
X
X
X
12-lead ECG
X
X
Vital signs b
X
X
X
X
X
X
X
X
X
Blood collection for:
Serum chemistry 
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Coagulation panel
X
X
X
X
X
X
Autoantibody panel (RF, RF isotypes, ACPA, ANA, 
anti-Ro, anti-La [serum])
X
X
X
X
Exploratory biomarkers (serum)
X 
X
X
X
X
X
RNA PAXgene (whole blood)
X
X
X
X
X
Acute-phase reactants (CRP, ESRc)
X
X
X
X
X
CD4+ counts
X
X
X
X
X
X
X
Flow cytometry (whole blood)
X
X
X
X
Vectra® DA (MBDA) (serum)
X
X
X
X
X
X
Total CD40L (plasma)
X
X
X
X
X
X
PK (plasma)
X d
X
X
X e
X e
X e
X e
ADA (plasma) f
X
X
X
X
Anti-PAD4 antibody (serum)
X
X
X
X
Urine collection for:
Urinalysis
X
X
X
X
X
X


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Table 4.2.2-1
Schedule of Treatment Period Study Procedures  
Study Period
Treatment Period
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
Procedure / Study Day
Day 1
± 1 
Day
Day 2
± 1
Days
Day 8 ± 
1 Day
Day 15
± 1 Day
Day 29
± 1 Day
Day 43
± 1 Day
Day 57
± 1 Day
Day 71
± 1 Day
Day 85
± 1 Day
Urine β-hCG (women of childbearing potential only)
X
X
X
X
X
X
X
Rheumatoid assessments
TJC/SJC: 28 joints count 
X
X
X
X
X
VAS Patient assessment of disease activity
X
X
X
X
X
Physician’s global assessment
X
X
X
X
X
Investigational product administration
X
X
X
X
X
X
X
ADA = anti-drug antibody; AE = adverse event; ACPA = anti-cyclic citrullinated peptide antibody; ANA = antinuclear antibody; Anti-PAD4 = antibody 
against isoform 4 of peptidyl arginine deiminase; β-hCG = beta-human chorionic gonadotropin; CRP = C-reactive protein; ECG = electrocardiogram; ESR = 
erythrocyte sedimentation rate; IXRS = interactive voice/web response system; MBDA = multi-biomarker disease activity; PK = pharmacokinetic; RF = 
rheumatoid factor; RNA = ribonucleic acid; SAE = serious adverse event; CD40L = CD40 ligand; TJC = tender joint count; SJC = swollen joint count; V = 
visit; VAS = visual analogue scale.
Note: An overnight stay prior to administration of investigational product on Day 1 is recommended but not mandatory. An overnight stay post-investigational 
product administration on Day 1 is mandatory.
Note: All laboratory sample collections and assessments on dosing day must be performed at predose, unless specified otherwise.
Note: RA assessments on dosing day should be performed at predose.
a
Abbreviated physical examination includes cardiovascular, respiratory and nervous system examinations.
b
Vital sign measurements include body temperature, blood pressure, heart [pulse] rate, and respiratory rate. On the first two dosing days (Day 1 and 
Day 15), vital signs will be measured within 30 minutes prior to the start of infusion, every 30 minutes (± 5 minutes) during the infusion, at the end of the 
infusion (+ 5 minutes), then at 1 hour, 2 hours and 4 hours after the end of infusion (± 10 minutes). On subsequent dosing days, vital signs will be 
measured within 30 minutes prior to the start of infusion, every 30 minutes (± 5 minutes), and at the end of the infusion (+ 5 minutes). 
c
ESR will be analyzed at the local laboratories.
d
Blood sample for PK on Day 1 collected post-dose only (at the end of infusion).
e
Blood samples for PK on Days 15, 29, 57 and 85 collected pre- and post-dose (at the end of infusion).
f
Blood samples for ADA collected at predose only.


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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 vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, blood draws should occur last. The timing of the first two assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time.
Table 4.2.3-1
Schedule of Follow-up Procedures
Study Period
Follow-up Period
FU 1
FU 2
FU 3
FU4
FU5
Visit Number
V11 
V12
V13 
V14
V15
Procedure / Study Day
Day
92 ± 3 
Days
Day
99 ± 3 
Days
Day
113 ± 3 
Days
Day
141 ± 3 
Days
Day 169
± 3 Days
/EDV
Safety assessments
Assessment of AEs/SAEs
X
X
X
X
X
Assessment of concomitant medications
X
X
X
X
X
Complete physical examination (includes 
weight)
X
Abbreviated physical examination a
X
X
X
X
12-lead ECG
X
Vital signs b
X
X
X
X
X
Blood collection for:
Serum chemistry 
X
X
X
X
X
Hematology
X
X
X
X
X
Coagulation panel
X
X
X
X
X
Autoantibody panel (RF, RF isotypes, ACPA, 
ANA, anti-Ro, anti-La [serum])
X
Exploratory biomarkers (serum)
X
X
RNA PAXgene (whole blood)
X
Acute-phase reactants (CRP, ESRc)
X
X
X
CD4+ counts
X
X
X
Flow cytometry (whole blood)
X
X
Vectra DA (MBDA) (serum)
X
X
Total CD40L (plasma)
X
X
PK (plasma)
X
X
X
X
X
ADA (plasma)
X
X
Urine collection for:
Urinalysis
X
X
X
X
Urine β-hCG (women of childbearing potential 
only)
X
X
X
X


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Table 4.2.3-1
Schedule of Follow-up Procedures
Study Period
Follow-up Period
FU 1
FU 2
FU 3
FU4
FU5
Visit Number
V11 
V12
V13 
V14
V15
Procedure / Study Day
Day
92 ± 3 
Days
Day
99 ± 3 
Days
Day
113 ± 3 
Days
Day
141 ± 3 
Days
Day 169
± 3 Days
/EDV
Rheumatoid assessments
TJC/SJC: 28 joints count 
X
X
X
VAS Patient’s assessment of disease activity
X
X
X
Physician’s global assessment
X
X
X
AE = adverse event; ACPA = anti-cyclic citrullinated peptide antibody; ANA = antinuclear antibody;
β-hCG = beta-human chorionic gonadotropin; CRP = C-reactive protein; ECG = electrocardiogram; EDV = 
Early Discontinuation Visit; ESR = erythrocyte sedimentation rate; FU = follow-up; MBDA = multi-
biomarker disease activity; PK = pharmacokinetic; RF = rheumatoid factor; RNA = ribonucleic acid; SAE = 
serious adverse event; CD40L = CD40 ligand; TJC = tender joint count; SJC = swollen joint count; V = visit; 
VAS = visual analogue scale.
a
Abbreviated physical examination will include cardiovascular, respiratory and nervous system 
examinations.
b
Vital sign measurements include body temperature, blood pressure, heart [pulse] rate, and respiratory 
rate.
c
ESR will be analyzed at the local laboratories.
4.3
Description of Study Procedures
4.3.1
Medical History, Physical Examination, Electrocardiogram, Weight, 
Height, and Vital Signs
4.3.1.1
Medical History
A complete medical history will be obtained at screening and 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, and/or any other diseases or disorders.
4.3.1.2
Physical Examination, Height, and Weight
Complete physical examinations (including weight) and abbreviated physical examinations 
will be performed by a licensed healthcare provider (ie, physician, physician’s assistant, or 
licensed nurse practitioner). Complete physical examinations will include assessment of 
weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems. Abbreviated physical 
examinations will include assessment of cardiovascular, respiratory, and nervous systems. 
Each clinically significant abnormal finding will be recorded in the electronic case report 


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form (eCRF). Physical examinations will be performed at study visits specified in 
Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1. Height will be measured at screening only.
4.3.1.3
Vital Signs
Vital signs (body temperature, BP, heart [pulse] rate, and respiratory rate) will be obtained at 
the visits specified in Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1. 
On the first two dosing days (Day 1 and Day 15), vital signs will be measured within 
30 minutes prior to the start of infusion, every 30 minutes (± 5 minutes) during the infusion,
at the end of the infusion (+ 5 minutes), then at 1 hour, 2 hours and 4 hours after the end of 
infusion (± 10 minutes). On subsequent dosing days, vital signs will be measured within 
30 minutes prior to the start of infusion, every 30 minutes (± 5 minutes), and at the end of the 
infusion (+ 5 minutes). 
4.3.1.4
Electrocardiogram
Twelve-lead ECG recordings will be evaluated at screening and at the visits specified in 
Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1. 
At screening, the ECG will be performed in triplicate (all 3 within a 5-minute time period, at 
least 1 minute apart) and the mean value of the triplicate measurement will be recorded as the 
baseline value. ECGs taken at all other times (ie, during the treatment period) will be single 
assessments.
All ECG recordings will be made with the subject in a supine position having rested in this 
position for at least 5 minutes before the start of the ECG.
All ECGs will be recorded at a speed of 25 mm/seconds with amplitude recording of 
10 mm/mV. At least 3 full complexes must be recorded. A multi-channel ECG machine 
should be used (equals 3 leads recorded simultaneously) and there must be amplitude index 
calibration for each lead.
Electronic software will be used to assess the following parameters: pulse rate, QRS, QT, and 
QTc time intervals. All ECGs must be reviewed by the principal investigator or a qualified 
designee before the subject is permitted to leave the clinic. The occurrence of de- or re-
polarization disorders, arrhythmic disorders or other abnormalities will be assessed and 
obvious changes in ECG parameters from baseline will be assessed by the principal 
investigator for clinical significance. 


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4.3.2
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. The Laboratory Manual pertains to 
samples that will be sent to a licensed central laboratory (ie, samples for clinical laboratory 
safety tests, PK, immunogenicity, and biomarker analysis).
Clinical laboratory safety tests include serum chemistry, hematology, coagulation, urinalysis, 
serum pregnancy tests, and other safety tests (as outlined below). Urine pregnancy tests may 
be performed at the site using a licensed test (dipstick). Clinically significant laboratory 
results should be repeated as soon as possible (preferably within 24 to 48 hours).
The following clinical laboratory tests will be performed (see Table 4.2.1-1, Table 4.2.2-1, 
and Table 4.2.3-1).
Serum Chemistry
•
Calcium
•
ALP
•
Chloride
•
TBL (if result is > 1.5 ULN, indirect and direct 
bilirubin will be measured)
•
Magnesium
•
Creatinine
•
Potassium
•
Blood urea nitrogen 
•
Sodium
•
Glucose
•
Bicarbonate
•
Albumin
•
AST
•
Total protein
•
ALT
•
Uric acid
•
Cholesterol
•
Triglycerides
•
IgA, IgG, IgE, IgM, total Ig
•
Erythrocyte sedimentation rate (ESR)
Note for serum chemistry: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed 
concurrently.
Hematology
•
White blood cell (WBC) count with differential
•
Platelet count
•
Red blood cell (RBC) count
•
Hemoglobin
•
Hematocrit


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Coagulation
•
International normalized ratio
•
D-dimer
•
Prothrombin time
•
Fibrinogen
•
Partial thromboplastin time
•
TAT
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 β-hCG
•
Serum β-hCG (performed at screening only)
Other Safety Tests
•
Hepatitis A antibody (IgM), HbsAg, HbsAb; HbcAb, hepatitis C antibody, hepatitis B virus DNA copy 
number (assessed at screening only)
•
HIV-1 antibody, HIV-2 antibody (assessed at screening only), sample for collection and retention for CMV 
and EBV (at screening only)  
•
Protein S, Protein C, anti-thrombin 3, antiphospholipid antibodies (assessed at screening only)
•
TB test (eg, QuantiFERON-TB Gold Test) as per local standard of care guidelines (assessed at screening 
only)
•
Autoantibody panel: RF, RF isotypes (IgA, IgG, IgM), ACPA, anti-nuclear antibody (ANA), anti-Ro, 
anti-La
•
Acute-phase reactants: C-reactive protein (CRP) and ESR
4.3.3
Pharmacokinetic Evaluation and Methods
Plasma samples to determine the concentration of MEDI4920 will be collected at the visits 
specified in Table 4.2.2-1 and Table 4.2.3-1. MEDI4920 plasma concentrations will be 
measured by MedImmune using a validated immunoassay.
4.3.4
Immunogenicity Evaluation and Methods
Plasma samples will be collected for the assessment of ADA against MEDI4920 at the visits 
specified in Table 4.2.2-1 and Table 4.2.3-1. Samples will be measured for the presence of 
ADA by MedImmune using a validated immunoassay. Sample may be used for further 


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characterization of the ADA response, including possible assessment of neutralizing 
antibody.
4.3.5
Biomarker Evaluation and Methods
4.3.5.1
Flow Cytometry
Blood samples will be collected for the assessment of changes in the number, activation 
status and frequency of major leukocyte populations, including B lymphocytes, 
T lymphocytes, and natural killer cells using flow cytometry according to the schedule of 
events as outlined in Table 4.2.2-1 and Table 4.2.3-1.
A CD40L blockade is expected to reduce the frequency of certain B-cell and 
plasmablast/plasma cell populations and may indirectly also reduce the frequency of T cells 
and other immune cell populations.
4.3.5.2
Autoantibody Panel
Serum will be collected to assess the presence of ACPA, RF, RF isotypes, ANA, anti-Ro, and 
anti-La according to the schedule of events as outlined in Table 4.2.1-1, Table 4.2.2-1, and 
Table 4.2.3-1.
4.3.5.3
Exploratory Serum Biomarkers
Serum will be collected to measure changes in exploratory biomarkers of disease activity, 
autoantibodies associated with RA such as 
 
, according to the schedule of events as outlined in 
Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1.
These biomarker measurements will aid in determining what biological pathways are 
impacted by MEDI4920 treatment. 
4.3.5.4
Total CD40L Levels
Plasma samples will be collected for the measurement of total CD40L levels (free and 
bound) as a measure of target engagement by MedImmune using a qualified immunoassay 
method according to the schedule of events as outlined in Table 4.2.2-1 and Table 4.2.3-1.
4.3.5.5
Blood Transcriptome
Blood RNA will be used to measure the expression levels of genes associated with disease 
activity, specific cell types and signaling including the CD40L-CD40 pathway. These 
CCI
CCI
CCI


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biomarker measurements will aid in the determination of what biological pathways are 
impacted by MEDI4920 treatment. 
A blood sample will be collected using the PAXgene Blood RNA System for the collection, 
transport, and storage of blood and stabilization of intracellular RNA in a closed tube and 
subsequent isolation and purification of intracellular RNA from whole blood for microarray 
analysis and quantitative PCR. RNA PAXgene blood samples will be collected according to 
the schedule of events as outlined in Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1.
4.3.5.6
MBDA Test
A commercially available and validated biomarker panel (Vectra DA) measures 
12 biomarkers and combines them into a single score to assess the key mechanisms and 
pathways that drive RA disease activity. The biomarker panel includes adhesion molecules, 
growth factors, cytokines, matrix metalloproteinases, skeletal proteins, hormones and acute 
phase proteins. The MBDA biomarker panel has been demonstrated to be a sensitive 
objective measure of clinical disease activity, with a strong correlation to DAS28 CRP. 
Changes in MBDA score are also an objective measure of changes in disease activity, 
showing a significant correlation to changes in DAS28 CRP. Serum samples will be collected 
for the Vectra DA (MBDA) biomarker panel according to the schedule of events as outlined 
in Table 4.2.2-1 and Table 4.2.3-1.
4.3.6
Disease Evaluation and Methods
The RA assessments should be performed prior to the treatment infusion if on a dosing day.
4.3.6.1
Tender and Swollen Joint Counts
The tender joint count (TJC) and swollen joint count (SJC) assess the following 28 joints for 
tenderness and swelling: the 8 proximal interphalangeal joints of the fingers, the 
interphalangeal joints of the thumbs (n = 2), the 10 metacarpophalangeal joints plus the 
wrists (n = 2), elbows (n = 2), shoulders (n = 2), and knees (n = 2) (Prevoo et al, 1995).
The TJC and SJC will be assessed by a qualified, independent, blinded Joint Counts 
Assessor. This person will be responsible for completing the TJC and SJC without access to 
any other study-related outcomes. The TJC and SJC will be performed according to the 
schedule of events as outlined in Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1.


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4.3.6.2
Patient’s Global Assessment of Disease Activity
The Patient’s Global Assessment (PGA) of disease activity is a measure of the patient’s 
general health on a 100 mm visual analogue scale (VAS) from 0 mm = best to 
100 mm = worst and will be performed according to the schedule of events as outlined in 
Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1.
4.3.6.3
Physician Global Assessment of Disease Activity
The Physician’s Global Assessment (MDGA) of disease activity is a 100 mm VAS that asks 
the investigator to rate their subject’s current disease activity on a scale of 0 mm (none) to 
100 mm (extremely active). The MDGA will be performed according to the schedule of 
events as outlined in Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1.
4.3.6.4
Acute-phase Reactants
Blood samples for acute-phase reactants, CRP and ESR, will be collected according to the 
schedule of events as outlined in Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1. Both CRP 
and ESR are strong correlates of disease activity in RA. 
Disease Activity Score in 28 Joints Using C-reactive Protein
The DAS28 CRP considers 28 of the 68 TJC and 28 of the 66 SJC, general health (GH; PGA 
[0-100 mm VAS]), plus levels of an acute-phase reactant (CRP [mg/L]). CRP levels are more 
sensitive to short-term changes in disease activity and more specific to inflammatory 
conditions, whereas ESR is less specific and can be influenced by a number of unrelated 
factors, such as age, gender, red blood cell count, or plasma proteins.
DAS28 CRP values will be calculated as follows (Wells et al, 2009):
DAS28 CRP = 0.56 × square root (sqrt) (TJC28) + 0.28 × sqrt(SJC28) + 0.014 × GH +
0.36 × ln(CRP+1) + 0.96
Clinical Disease Activity Index
The CDAI is a composite index (without acute-phase reactant) for assessing disease activity 
and is defined as the sum of the TJC (using 28 joints), the SJC (using 28 joints), the PGA 
(0-100 mm VAS), and the MDGA (0-100 mm VAS). The CDAI has a range from 0 mm to 
76 mm. The greatest advantage associated with CDAI is its potential to be employed in 
evaluation of patients with RA consistently with close frequency and independently of any 
calculating device; therefore, it can essentially be used everywhere and anytime for disease 
activity assessment in RA patients.


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4.3.7
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 169/Early Discontinuation Visit (EDV) is presented in 
Table 4.3.7-1. If repeats of any blood tests are required, the volume of blood collection will 
increase accordingly.
Table 4.3.7-1
Estimate of Blood Volume to Be Collected
Visit Day
Estimated Blood Volume (mL)
Day -42 to Day -1 (Screening)
65.9
Day 1
59.5
Day 2
9
Day 8
35.5
Day 15
48.5
Day 29
58
Day 43
10
Day 57
59
Day 71
10
Day 85
59
Day 92
18.8
Day 99
21.5
Day 113
46.5
Day 141
18.8
Day 169/EDV
52
Total
572
EDV = Early Discontinuation Visit.
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or permanently terminate this study at 
any time. The reasons for temporarily suspending or permanently 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.
2. Subject enrollment is unsatisfactory
3. Non-compliance that might significantly jeopardize the validity or integrity of the study
4. Sponsor decision to terminate development of the investigational product for this 
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If MedImmune determines that temporary suspension or permanent termination of the study 
is required, MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) promptly 
and provide the reason(s) for the suspension/termination. If the study is suspended for safety 
reasons and it is deemed appropriate by the sponsor to resume the study, approval from the 
relevant regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to 
resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Products
MedImmune will provide the investigator(s) with investigational product (Table 4.5.1-1) 
using designated distribution centers. 
Table 4.5.1-1
Identification of Investigational Products 
Investigational Product
Manufacturer
Concentration and Formulation as 
Supplied
MEDI4920 (250 mg/vial)
MedImmune, LLC
20 mL lyophilized vial with a nominal 250 mg
of MEDI4920 at a post-reconstitution 
concentration of 
50 mg/mL, containing 10 mM sodium 
monobasic/dibasic phosphate, 250 mM 
sucrose and 0.02% (w/v) polysorbate 80,
pH 7.4
Placebo
Provided by the site
0.9% saline for injection
(w/v) = (weight/volume)
MEDI4920 will be supplied by MedImmune to the site in containers with identical 
appearances in coded, open-label 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 container within the 
carton). Each carton is labeled with a unique number range that corresponds to the labeled 


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number series of the containers within the carton. Placebo will be prefilled IV saline bags 
sourced by each site.
4.5.1.1
Investigational Product Handling
The investigational product manager will select the MEDI4920 vials assigned by the IXRS to 
prepare the subject’s dose. For subjects assigned to placebo, the sites should use prefilled IV 
saline bags only.
Do not remove MEDI4920 from 2°C to 8°C (36°F to 46°F) storage until all procedures for 
subject dosing have been completed. When preparing a dose for administration, immediately 
remove the vials from the carton and replace the carton in 2°C to 8°C (36°F to 46°F) storage.
The investigational product manager/unblinded study personnel must ensure that only the 
unblinded team members have access to the areas of the pharmacy where the investigational
product is being prepared.
4.5.1.2
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. MEDI4920 is supplied as a 
sterile lyophilized drug product with post-reconstitution concentration of 50 mg/mL.
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 for further 
instructions (Section 4.5.1.9).
4.5.1.3
Dose Preparation Steps
No incompatibilities between MEDI4920 and plastics passing compatibility tests (ie, 
polyethylene bags; polyethylene and polyvinyl chloride infusion lines; polypropylene and 
polycarbonate syringes for IV infusion using IV infusion pump) have been observed. 
MEDI4920 does not contain preservatives and any unused portions must be discarded. 
Preparation of investigational product and IV bags is to be performed aseptically. Total 
in-use storage time from reconstitution of investigational product/needle puncture of the 
investigational product vial to start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2°C to 8°C (36°F to 46°F). If storage time exceeds these limits, a 
new dose must be prepared from new vials.
Each vial of investigational product must be reconstituted with 5.0 mL of sterile water for 
injection to achieve 5.5 mL (5 mL nominal) of 50 mg/mL MEDI4920.


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4.5.1.4
Reconstitution Procedure
Slowly add 5.0 mL of sterile water for injection by tilting the vial to one side such that the 
liquid stream is directed along the vial wall and not directly onto the lyophilized cake. Gently 
swirl the solution and repeat this procedure until all solids are dissolved. DO NOT SHAKE 
OR VIGOROUSLY AGITATE THE VIAL. Visually inspect the solution to ensure that the 
entire content of the lyophilized cake is completely reconstituted. The reconstituted solution 
should appear clear to opalescent. A thin layer of bubbles on the surface of the liquid is 
normal.
4.5.1.5
Preparation of Intravenous Dose
For Subjects Randomized to the MEDI4920 Group:
Preparation of MEDI4920 doses for IV infusion with an IV infusion pump:
The dose preparation steps are as follows:
1. For each of the IV doses (ie, 75, 500, 1000, and 1500 mg), the volume of 0.9% saline 
(weight/volume [w/v]) equivalent to volume of MEDI4920 is removed first and then the 
required volume of MEDI4920 will be added to a prefilled IV bag (Table 4.5.1.5-1). 
Syringes used to prepare the IV bag must be polycarbonate or polypropylene.
2. A vial should be used only one time to prepare a single dose. The required volume of 
MEDI4920 (Table 4.5.1.5-1) will be obtained by pooling the contents of as many 
MEDI4920 vials as necessary (ie, 1 vial for the 75 mg dose, 2 vials for the 500 mg dose, 
4 vials for the 1000 mg dose, and 6 vials for the 1500 mg dose) with an appropriately
sized syringe. For ease of preparation, a 1.5-inch 20-gauge withdrawal needle should be 
used. Use a new needle for withdrawing investigational product from each vial.
3. Gently mix the contents of the IV bag. The admixture should then be inspected to ensure 
the solution is clear.
Table 4.5.1.5-1
MEDI4920 Dose Preparation for IV Infusion with an IV 
Infusion Pump
Dose (mg)
Prefilled IV Bag Size 
(mL)
Volume of Saline Removed 
from IV Bag (mL)
MEDI4920 Dose Volume 
Added to IV Bag (mL)
75
50
1.5
1.5
500
100
10
10
1000
250
20
20
1500
250
30
30
IV = intravenous; FTIH = first time in human; SAD = single ascending dose.
Note: The maximum concentration of reconstituted investigational product solution will not exceed that used 
in the FTIH SAD study.


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For Subjects Randomized to the Placebo Group:
Preparation of placebo for IV infusion with an IV infusion pump:
For each of the doses, the prefilled IV saline bag size to be used is listed in Table 4.5.1.5-2. 
No additional IV bag preparation is required.
Table 4.5.1.5-2
Placebo Dose Preparation for IV Infusion with an IV 
Infusion Pump
Dose (mg)
Prefilled IV Bag Size (mL)
75
50
500
100
1000
250
1500
250
IV = intravenous
During preparation of the investigational product infusion, the capacity of the tubing should 
be calculated in order to adjust the volume of investigational product solution needed to 
prime the IV tubing. This step is necessary because the same volume of saline will be needed 
at completion of the infusion to flush the IV tubing in order to deliver the complete volume 
of investigational product solution. Because the IV tubing contains investigational product 
solution, the flush must be infused using the same infusion rate as that used for the 
investigational product solution in the infusion bag.
For example, if the IV tubing capacity is 15 mL, the IV tubing should be primed with 15 mL 
of investigational product solution from the infusion bag before initiating the infusion. Once 
the infusion bag is empty, the IV tubing should be flushed with at least 15 mL of 0.9% saline 
(w/v) via the infusion pump at the same rate as dosing.
The start time of the infusion will be the time when infusion of the investigational product 
solution from the infusion bag (with IV tubing primed with investigational product solution) 
is started. The stop time of the infusion will be the time when the IV tubing has been flushed 
with a volume of 0.9% normal saline equivalent to IV tubing capacity (eg, 15 mL for the 
example above) to administer the residual investigational product solution.
4.5.1.6
Intravenous Administration
All Cohorts (1-4) will be administered investigational product via IV infusion using an IV 
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Each subject in each cohort must receive the entire volume of investigational product 
solution in the IV bag. Table 4.5.1.6-1 provides the duration of infusion and flow rate by 
dose level. Investigational product must be infused through a low-protein binding 0.2- or 
0.22-μm in-line filter using an IV infusion pump.
Table 4.5.1.6-1
Intravenous Administration of Investigational Product
Cohort
Dose (mg)
Total Volume in 
IV Bag (mL)
Minimum 
Administration Time 
(min)
Flow Rate at 
Minimum Time 
(mL/min)
1
75
50 (IV bag)
30
1.7 mL/min
2
500
100 (IV bag)
60
1.7 mL/min
3
1500
250 (IV bag)
90
2.8 mL/min
4
1000
250 (IV bag)
90
2.8 mL/min 
IV = intravenous; min = minute; TBD = to be determined
4.5.1.7
Treatment Administration
The first day of dosing is considered Day 1.
Each dose of investigational product should be administered using the following guidelines:
•
Female subjects must have a negative urine pregnancy test prior to receiving MEDI4920 
or placebo.
•
A physician must be present at the site or immediately available to respond to 
emergencies during administration of investigational product. Fully functional 
resuscitation facilities should be available.
•
Investigational product will be administered as a single IV infusion as described in 
Table 4.5.1.6-1. 
4.5.1.8
Monitoring of Dose Administration
Vital signs (BP, heart [pulse] rate, respiratory rate, and body temperature) will be obtained as 
outlined in Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.3-1). In addition, if signs and 
symptoms indicative of an infusion reaction occur, the infusion will be stopped or slowed 
according to the judgment of the investigator.
As with any biologic product, 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 
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4.5.1.9
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:
Phone:
Fax:
Mail:
MedImmune
Attn: Product Complaint Department
One MedImmune Way,
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
4.5.2.1
Background Medications for RA 
All permitted background medications from initiation of screening through to the end of the 
study must be recorded in the source records and include the specific indication for use as 
well as the dose, start and stop dates, frequency, and route of administration. 
MTX and Other cDMARDs
All subjects (except patients with intolerance to MTX or having been switched to another 
cDMARD after MTX failure) must be on MTX (7.5 to 25 mg/week) administered the same 
route (oral or injectable), for at least 12 weeks and at a stable dose for at least 6 weeks prior 
to screening. Subjects must continue with the same dose and route of administration for 
MTX during the 12-week treatment period (Days 1 to 85). Any dose changes in background 
MTX should be discussed and agreed with the medical monitor. Changes in MTX dose are 
permitted for safety/tolerability reasons (which must be clearly documented) or, after 
Week 12 for control of disease activity. 
PPD
PPD
PPD
PPD
PPD


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To minimize MTX toxicity, it is recommended that subjects receive 5.0 mg/week folic acid 
during the study as a single or divided dose. 
It is recommended that MTX is withheld if liver function tests (LFTs), particularly ALT or
AST enzymes, are increased to > 3 × ULN and MTX dose should be reduced by 
2.5 mg/week if LFT enzymes are increased between 2 and 3 × ULN. After normalization of 
the LFT, MTX can be reinitiated and/or titrated up to the dose used prior to modulation. In 
case of newly occurred blood cytopenias (WBC < 3 × 109/L, neutrophil count < 2 × 109/L, 
platelet count < 150 × 109/L) MTX should be withheld until blood cell counts recover. 
Protocol-permitted alternative cDMARDs (for subjects with documented MTX intolerance or 
if subjects have been treated with this DMARD after a previous MTX failure) are 
leflunomide, sulfasalazine, hydroxychloroquine, azathioprine, D-penicillamine, and 
cyclosporine. These must be given at the doses specified by the local RA treatment
guidelines and the local Summary of Product Characteristics. Subjects should be treated with 
the alternative cDMARD for at least 12 weeks and at a stable dose for at least 6 weeks prior 
to screening. Subjects must continue with the same dose and route of administration during 
the 12-week treatment period (Days 1 to 85). Changes in dose are permitted for 
safety/tolerability reasons (which must be clearly documented) or, after Week 12 for control 
of disease activity.
Corticosteroids 
Corticosteroids should be maintained at a stable oral dose (< 10 mg equivalent 
prednisone/day) for the duration of the study through to the end of the 12-week treatment 
period unless changes are needed for safety reasons. Any change in background oral 
corticosteroids, or addition of injectable corticosteroids, is prohibited from 4 weeks prior to 
Day 1 up to Week 12 (Day 85), unless used for the treatment of a non-RA AE. It is strongly 
recommended to avoid changes in corticosteroids dosage within 4 weeks prior to the 
Week 12 (Day 85) visit to avoid confounding the evaluation of efficacy. After Week 12, a 
change in oral corticosteroid dose and/or addition of injectable corticosteroids for control of 
disease activity is permitted. A maximum of 2 intra-articular injections of corticosteroids 
(up to 40 mg of triamcinolone or equivalent) can be allowed as required to control 
severe/refractory mono/oligoarthritis during the treatment period (no more than 4 joints 
allowed to be treated). Treated joint(s) will need to be excluded from the joint counts until 
12 weeks post-injection. Intra-articular steroid injections are not allowed within 4 weeks 
prior to the Day 85(Week 12) visit to avoid confounding the evaluation of efficacy. Inhaled 


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or topical corticosteroids given for asthma, COPD, or dermatological conditions are allowed 
provided doses are stable between screening and Day 85 visit.
Analgesics/NSAIDs
Analgesics and NSAIDs given primarily for RA signs and symptoms should be maintained at 
a stable dose for the duration of the study through to the end of the 12-week treatment period 
(Day 85) unless changes are needed for safety/tolerability reasons or inadequate response 
after the Week 12 visit. Subjects should refrain from taking the usual morning dose of 
analgesics on visit days until after all clinical assessments have been completed.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice and local regulatory guidelines. Label text will be translated into 
local languages, as required.
4.5.4
Storage
Investigational product is to be stored at 2 to 8°C (36 to 46°F).
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor 
compliance.
4.5.6
Accountability
The investigator’s or site’s designated unblinded 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 IXRS will be used for randomization to a treatment group and assignment of 
investigational product kit numbers if assigned to an active treatment arm. A subject is 
considered randomized into the study when the investigator notifies the IXRS that the subject 


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meets eligibility criteria and the IXRS provides the assignment of treatment group and 
allocates active treatment if assigned to the active treatment arm.
Subjects will be randomized in a 4:1 ratio (Cohort 1), in a 5:2 ratio (Cohort 2), in a 3:1 ratio 
(Cohort 3), and in a 5:2 ratio (Cohort 4) to receive either MEDI4920 or placebo respectively 
as described in Table 3.1.2-1. 
Investigational product (MEDI4920 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.
4.6.2
Methods for Ensuring Blinding
This is a double-blind study in which MEDI4920 and the saline placebo are not identical in 
appearance. As such, neither the subject/legal representative nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects will be 
aware of the treatment received (ICH E9) (see Section 4.6.4 for unblinding related to interim 
analysis). For maintaining the blinding of the principal investigator, site staff, sponsor, 
Contract Research Organization (CRO) or staff, a local unblinded pharmacy staff member 
will be nominated by each site and will have the responsibility of allocating, dispensing and 
preparing the investigational product in order to maintain the study blind. In addition, a 
separate unblinded monitor will be used for the oversight of investigational product 
management. If 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. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IXRS 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 
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4.6.4
Unblinding for Interim Analysis Purposes 
The primary analysis will be performed when all subjects in Cohort 3 have completed the 
Day 85 assessments or have been withdrawn from the study. The primary analysis will 
include all assessments on the subjects prior to the data cut-off for the primary analysis.
MedImmune personnel will be unblinded to the subject treatment assignments from 
Cohorts 1 to 3 at the primary analysis (Day 85). The data from the primary analysis will not 
be communicated to personnel at the CRO or investigational sites or to enrolled subjects, 
until all subjects in Cohorts 1 to 3 have completed the study and database lock has been 
achieved.
MedImmune personnel will be unblinded for Cohort 4, and the data will be analyzed when 
all subjects in Cohort 4 have completed the Day 85 assessments or have been withdrawn 
from the study. Study subjects and personnel at the CRO or investigational sites will remain 
blinded to Cohort 4 data until all subjects in Cohort 4 have completed the study and database 
lock has been achieved.
The final analysis on the subjects will be performed when all subjects have completed the 
safety follow-up. 
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 over-the-counter products (and any herbal 
supplements), 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 “excluded” as 
listed in Section 4.7.2. Specifically, subjects should 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 must refrain from alcohol consumption for 48 hours prior to all visits.


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Subjects must refrain from strenuous exercise for approximately 48 hours before each study 
day where safety samples will be taken, and Day 169/EDV. Physical therapy including
cold/hot applications, electrical stimulation, and hydrotherapy, applied specifically for RA, is 
not permitted between Days 1 and 85. 
The introduction of the following medications is not permitted from initiation of screening 
through to the end of the study. The sponsor must be notified if any of the following 
medications are given to a subject during the study (with the exception of stable doses of 
DMARDs permitted prior to screening/randomization as applicable): 
1.
Investigational drug therapy other than MEDI4920
2.
Biologic DMARD therapies (such as anti-TNF, recombinant IL-1 receptor antagonist, 
anti-IL-6, CTLA-4 Ig, B-cell depleting therapies, etc) or JAK inhibitors. 
3.
Mycophenolate mofetil, cyclophosphamide, and other alkylating agents 
4.
Live (attenuated) vaccine. Immunization with any live or live attenuated vaccine (ie, 
measles, mumps, rubella and polio vaccine, Bacillus Calmette-Guerin, typhoid, 
yellow fever, cold adapted live influenza strain vaccine, or any other vaccines not yet 
licensed but belonging to this category) is specifically excluded during the treatment 
period (ACIP, 2011). 
5.
Immunoabsorption columns, total lymphatic irradiation, plasmapheresis and IV 
immunoglobulin therapy 
After Day 85, the dose of background cDMARDs and corticosteroids may be adjusted or a 
new additional cDMARD may be added to an existing one (except for combining MTX and 
leflunomide) if it is clinically indicated to improve disease management. 
Subjects must be instructed not to take any medications or over-the-counter products 
(including herbal supplements), 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. 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 
receive any amount of investigational product. Subjects will be analyzed by the randomized 


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treatment group. All efficacy and biomarker analyses will be performed on the ITT 
population unless otherwise specified.
The as-treated population is defined as all subjects who are randomized and treated with 
investigational product. Subjects will be analyzed by the treatment received. All safety 
analyses will be performed on the As-Treated population unless otherwise specified.
4.8.2
Sample Size and Power Calculations
No formal sample size calculations are presented for the evaluation of the primary objective 
of safety and tolerability of MEDI4920. The sample size calculations are based on the 
exploratory endpoint
. 
The sample size calculation for the change from baseline in DAS28 CRP at Week 12 is based 
on combining the data from the cohorts and performing a dose response analysis. Based on 
the assumption 
 
 the sample sizes of 14, 
8, 10, 10 and 12 subjects for the placebo, 75, 500, 1000 and 1500 mg dose groups, 
respectively, will provide approximately 92% power for detecting a statistically significant 
dose response, using a significance level of 0.10.
The power for dose response has been calculated using a multiple comparison procedure with 
modeling techniques (MCP-Mod; Bretz et al, 2005), with three candidate models for the dose 
response (linear, maximum effect attributable to the drug [Emax], and a Hill-Emax model). An 
overall significance level of 0.10 will be used to test for dose response.
4.8.3
Exploratory Efficacy Analyses
4.8.3.1
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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4.8.3.2
4.8.3.3
4.8.4
Safety
4.8.4.1
Analysis of Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) by 
system organ class (SOC) and preferred term (PT). Specific AEs will be counted once for 
each subject for calculating rates, but will be presented in total in subject listings. In addition, 
if the same AE occurs multiple times within a particular subject, the highest severity and 
level of causality will be reported. If any associations of interest between AEs and baseline 
characteristics are observed, additional stratified results may be presented. All TEAEs will be 
summarized overall and by MedDRA SOC and PT, and by severity and relationship to 
investigational product. In addition, summaries of deaths, SAEs and treatment 
discontinuations due to AEs will be provided.
CCI
CCI
CCI
CCI
CCI


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TEAEs, treatment-emergent SAEs (TESAEs) and AESIs with onset after the start of infusion 
(Day 1) to Day 169/EDV inclusive will be summarized by dose. The placebo subjects from 
each cohort will be combined for the summaries.
Other safety parameters, including laboratory assessments and vital signs, will be 
summarized by dose.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Laboratory parameters will be assessed at baseline as well as throughout the study. 
Frequencies of abnormal laboratory measurements will be presented for each laboratory 
parameter. Also, laboratory parameters will be assessed by presenting tables containing 
information related to laboratory shifts from baseline relative to the normal range, as well as 
descriptively over time.
4.8.4.3
Other Safety and Tolerability Endpoints
Other safety parameters, including vital signs and ECGs, will be summarized by dose and 
time point. 
4.8.5
Analysis of Immunogenicity/Pharmacokinetics
The number and percentage of subjects who develop detectable ADA will be summarized by 
dose. The impact of ADA on PK and the association with AEs and SAEs will be assessed. 
Plasma MEDI4920 concentration data at each time point will be tabulated by dose cohort 
together with descriptive statistics. Individual and mean plasma concentration-time profiles 
of MEDI4920 by dose cohort will be generated. Non-compartmental PK data analysis will be 
performed and descriptive statistics for PK parameters will be provided.
4.8.6
Interim Analysis
The primary analysis will be performed when all subjects in Cohort 3 have completed the 
Day 85 assessments or have been withdrawn from the study. The primary analysis will 
include all assessments on the subjects prior to the data cut-off for the primary analysis.
MedImmune personnel will be unblinded to the subject treatment assignments from 
Cohorts 1 to 3 at the primary analysis (Day 85). The data from the primary analysis will not 
be communicated to personnel at the CRO or investigational sites or to enrolled subjects, 
until all subjects in Cohorts 1 to 3 have completed the study and database lock has been 
achieved. 


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An additional interim analysis will be performed when all subjects in the Cohort 4 have 
completed the Day 85 assessments or have been withdrawn from the study. MedImmune
personnel will be unblinded to the subject treatment assignments from Cohort 4 for this 
interim analysis. Study subjects and personnel at the CRO or investigational sites will remain 
blinded to Cohort 4 data until all subjects in Cohort 4 have completed the study and database 
lock has been achieved.
The final analysis on the subjects will be performed when all subjects have completed the 
safety follow-up. 
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for GCP E6(R1) defines an AE as:
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.
AEs may be treatment emergent (ie, occurring after initial receipt of investigational product) 
or nontreatment-emergent. A nontreatment-emergent AE 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 


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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
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 collecting additional 
information by the investigator. 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 this investigational product.
The following AESIs will be particularly monitored in this study (see the Safety Handling
Plan for instructions and timing on completing any additional information required for 
specific types of events related to the categories noted below):
•
Thrombotic and embolic events 
•
Hepatic function abnormality (meeting the definition of HL as described in 
Section 5.6.2).
•
Anaphylaxis and serious hypersensitivity reactions
•
Immune complex disease 


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•
Infusion-related reactions
•
Serious and/or opportunistic infections (including but not limited to reactivation of latent 
viral infection [VZ/HSV/, EBV/CMV] and TB)
5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs 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 the sponsor (see Section 
5.5). See Section 5.2 for the definition of SAEs and Section 10.2 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.
Infusion of biological products is commonly associated with infusion-related reactions. 
Anaphylaxis and infusion-related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion-related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic mAbs delivered through IV 
infusion. These reactions are less common following subsequent exposures. Unlike 
infusion-related reactions, anaphylaxis is a rare event, usually occurring after subsequent 
exposure to an antigen, and it is most commonly accompanied by severe systemic skin and or 
mucosal reactions. The investigator is advised to carefully examine symptoms of adverse 
reactions observed during or shortly after exposure to MEDI4920, and consider the above 
mentioned facts prior to making a final diagnosis. Reactions occurring at the time of or 
shortly after subsequent infusions of investigational product are to be judged by the 
investigator at his/her own discretion. For the investigator’s convenience and to facilitate 
consistency in judgments a copy of the National Institute of Allergy and Infectious Diseases 
(NIAID) and Food Allergy and Anaphylaxis Network (FAAN) guidance for anaphylaxis 
diagnosis is provided in Section 10.3.
5.4.1
Time Period for Collection of Adverse Events
AEs will be collected from time of signature of informed consent throughout the treatment 
period and including the follow-up period (Day 169).
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 


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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.
5.5
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs during the course of the study, the investigator or other site personnel will 
inform the appropriate sponsor representative(s) within 1 day; ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel will inform 
sponsor representatives of any follow-up information on a previously reported SAE within 
1 calendar day; ie, immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the investigator or other site personnel indicates an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
the SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed.
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 Investigator’s Brochure, unless otherwise specified in this protocol.
•
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.


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•
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose with a MedImmune investigational product occurs during the course of the 
study, then the investigator or other site personnel informs appropriate sponsor 
representatives immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see 
Section 5.5. For other overdoses, reporting must occur within 30 days.
5.6.2
Hepatic Function Abnormality
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN may need to be 
reported as AESIs. Refer to Section 10.4 for further instruction on cases of increases in liver 
biochemistry and evaluation of HL.
5.6.3
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.6.3.1
Maternal Exposure
If a subject becomes pregnant during the course of the study, the investigational product 
should be discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be 
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product, then the investigator or other site personnel will 
inform the appropriate sponsor representatives within 1 day; ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated sponsor representative works with the investigator to ensure that all relevant 
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days for SAEs (see Section 5.5) and within 30 days for all other pregnancies. The same 
timelines apply when the outcome information is available.
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.
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 investigational product 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.


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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.
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. If there is 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 (including telephone contact),
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 (including telephone contact) for the last subject in the study. 
6.4
Data Management 
Data management will be performed by the MedImmune Data Management staff according 
to the Data Management Plan.


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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.
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 Informed Consent Form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
MedImmune will not provide individual genotype results to subjects, any insurance 
company, any employer, their family members, general physician or any other third party, 
unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the subject. In exceptional circumstances, however, certain individuals 


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might see both the genetic 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 genetic data. Also regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
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, the 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.


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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.
•
Ensure each subject is notified that he/she is free to discontinue from the study at any 
time.
•
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information is provided.
•
Ensure each subject provides signed and dated informed consent 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 principal 
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, 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 the 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.


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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 
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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League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569-81.
Berner B, Wolf G, Hummel KM, Muller GA, Reuss-Borst MA. Increased expression of 
CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid 
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Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, Vaishnaw A; BG9588 
Lupus Nephritis Trial Group. A short course of BG9588 (anti-CD40 ligand antibody) 
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Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques 
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Ford ML, Adams AB, Pearson TC. Targeting co-stimulatory pathways: transplantation and 
autoimmunity. Nat Rev Nephrol. 2014;10(1):14-24. 


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Galindo-Rodriguez G, Avina-Zubieta JA, Russell AS, Suarez-Almazor ME. Disappointing 
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Huang J, Jochems C, Talaie T, Anderson A, Jales A, Tsang KY, et al., Elevated serum 
soluble CD40 ligand in cancer patients may play an immunosuppressive role, Blood. 
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Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al; TEMPO 
(Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study 
investigators. Therapeutic effect of the combination of etanercept and methotrexate 
compared with each treatment alone in patients with rheumatoid arthritis: double-blind 
randomised controlled trial. Lancet. 2004;363(9410):675-81.
Kuwana M, Nomura S, Fujimura K, Nagasawa T, Muto Y, Kurata Y, et al. Effect of a single 
injection of humanized anti-CD154 monoclonal antibody on the platelet-specific 
autoimmune response in patients with immune thrombocytopenic purpura. Blood. 
2004;103(4):1229-36. Epub 2003 Oct 9.
Langer F, Ingersoll SB, A. Amirkhosravi A, Meyer T, Siddiqui FA, Ahmad S, et al. The role 
of CD40 in CD40L- and antibody-mediated platelet activation. Thromb Haemost. 
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Li G, Diogo D, Wu D, Spoonamore J, Dancik V, Franke L, et al. Human genetics in 
rheumatoid arthritis guides a high-throughput drug screen of the CD40 signaling pathway. 
PLoS Genet. 2013;9(5):e1003487. 
Listing J, Strangfeld A, Rau R, Kekow J, Gromnica-Ihle E, Klopsch T, et al. Clinical and 
functional remission: even though biologics are superior to conventional DMARDs overall 
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Ther. 2006;8(3):R66. Epub 2006 Apr 5.
Maetzel A, Bombardier C, Strand V, Tugwell P, Wells G. How Canadian and US 
rheumatologists treat moderate or aggressive rheumatoid arthritis: a survey. J Rheumatol. 
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Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. 
Modified disease activity scores that include twenty-eight-joint counts: development and 
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Robles-Carrillo L, Meyer T, Hatfield M, Desai H, Davila M, Langer F, et al Anti-CD40L 
immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A 
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2010 Jun 28.
Scheinman R. NF-κB and Rheumatoid Arthritis: Will Understanding Genetic Risk Lead to a 
Therapeutic Reward? For Immunopathol Dis Therap. 2013;4(2):93-110.
Shock A, Burkly L, Wakefield I, Peters C, Garber E, Ferrant J, et al. CDP7657, an anti-
CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses 
without thrombotic complications: an in vivo study. Arthritis Res Ther. 2015; 17:234.
Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, 
et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane 
Database Syst Rev. 2009;(4):CD007848. 
Symmons DP. Epidemiology of rheumatoid arthritis: determinants of onset, persistence and 
outcome. Best Pract Res Clin Rheumatol. 2002;16(5):707-22.
Tarner IH, Neumann E, Gay S, Fathman CG, Muller-Ladner U. Developing the concept of 
adoptive cellular gene therapy of rheumatoid arthritis. Autoimmun Rev. 2006;5(2):148-52. 
Epub 2005 Oct 3.
Tocoian A, Buchan P, Kirby H, Soranson J, Zamacona M, Walley R, et al. First-in-human 
trial of the safety, pharmacokinetics and immunogenicity of a PEGylated anti-CD40L 
antibody fragment (CDP7657) in healthy individuals and patients with systemic lupus 
erythematosus. Lupus. 2015; 24(10):1045-56. doi: 10.1177/0961203315574558. Epub 2015 
Mar 16.
van Baarsen LG, de Hair MJ, Ramwadhdoebe TH, Zijlstra IJ, Maas M, Gerlag DM, Tak PP. 
The cellular composition of lymph nodes in the earliest phase of inflammatory arthritis. Ann 
Rheum Dis. 2013;72(8):1420-4. doi:10.1136/annrheumdis-2012-202990. Epub 2013 May 9.
Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. 
Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the 
treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA 
trial. Arthritis Rheum. 2003;48(1):35-45.
Wells P and Anderson D. The diagnosis and treatment of venous thromboembolism. 
Hematology Am Soc Hematol Educ Program. 2013;2013:457-63.


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Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, et al. Validation of the 
28-joint Disease Activity Score (DAS28) and European League Against Rheumatism 
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with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte 
sedimentation rate. Ann Rheum Dis. 2009;68(6):954-60.
Wong JB, Ramey DR, Singh G. Long-term morbidity, mortality, and economics of 
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therapeutic target for disease. Immunol Lett. 2013;153(1-2):58-61.


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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 3, 29Sep2017
In the original protocol (dated 15Jan2016), 3 dose levels of MEDI4920 (75 mg [Cohort 1], 
500 mg [Cohort 2], or 1500 mg [Cohort 3]) or placebo were planned to be administered Q2W 
in combination with MTX or another cDMARD for up to 12 weeks. An option to include a 
fourth dose cohort (dose not to exceed 1500 mg Q2W) was also included in the original 
protocol, if required, to further characterize the dose-response relationship. 
After review of the primary analysis data, which included cumulative safety, PK, and 
biomarker data through Cohort 3, Day 85, the decision was made to explore a fourth dose 
(Cohort 4, selected to be 1000 mg Q2W) to better characterize the dose-response
relationship. The changes in this protocol amendment are a result of the addition of this 
fourth cohort and are outlined below:
1. Protocol Synopsis: Updated wording in the Study Design, Treatment Groups and 
Regimen, Statistical Analysis Methods sections of the synopsis to include the addition of 
Cohort 4
2. Section 1.6 (Potential Risks); Section 3.1.1 (Overview); Section 3.1.3 (Dose Escalation 
and Cohort Progression); Section 4.1.1 (Number of Subjects): Modified the language to 
reflect the addition of fourth dose cohort (1000 mg Q2W). 
3. Figure 3.1.1-1 (Study Flow Diagram): Modified the study design diagram to include the 
fourth dose cohort (1000 mg Q2W).
4. Section 3.1.2 (Treatment Regimen): Added the treatment regimen for Cohort 4 including 
the dose (1000 mg), and duration of the IV infusion (90 minutes on Days 1, 15, 29, 43, 
57, 71, and 85). 
5. Section 3.2.1 (Dose Rationale): Added additional language to explain that the rationale 
for the selection of the 1000 mg Q2W dose for Cohort 4 was based on PK-PD modeling 
data from Cohorts 1 to 3 as well as clinical judgement and that the dose is expected to 
result in a clinical response comparable to the highest dose in the study (1500 mg Q2W) 
but with a larger safety margin. 
6. Section 4.5.1.5 (Preparation of Intravenous Dose); Section 4.5.1.6 (Intravenous 
Administration): Updated the IV dose preparation and administration language to include 
the 1000 mg dose and the appropriate volume and duration of the IV infusion in
Cohort 4. 
7. Section 4.6.4 (Unblinding for Interim Analysis Purposes); Section 4.8.6 (Interim 
Analysis): Updated the language to reflect the addition of the fourth cohort.


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8. Section 4.8.2 (Sample Size and Power Calculations): Updated the language to reflect the 
addition of the fourth cohort and the resultant change in the power calculations from 80% 
to 92%. 
Protocol Amendment 2, 10Aug2016
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. Main changes to the protocol are summarized below:
1. Protocol Synopsis; Section 3.1.1 (Overview): Updated wording to reflect the current 
number of countries planned for this study; revised wording to clarify that while an 
overnight stay prior to administration of investigational product on Day 1 is
recommended, it is not mandatory. This revision was made to allow sites the flexibility to 
perform all pre-dose study procedures on the same day as the day of investigational 
product administration if absolutely necessary.
2. Section 4.1.2 (Inclusion Criteria): Modified Inclusion Criterion #4 to allow a combination 
of cDMARDs if recommended by national guidelines and/or standard medical practice
instead of just a single cDMARD as outlined in the original protocol; modified Inclusion 
Criterion #9 to remove the specific numerical thresholds for the detection of RF-IgM and 
ACPA2 positivity that were included in the original protocol and instead include a 
generic statement about serum RF and ACPA positivity to accommodate the different 
ranges of detection that may be exhibited by the assays used by the central laboratory. 
3. Section 4.1.3 (Exclusion Criteria): Corrected a typographical error in Exclusion 
Criterion #10 by changing “intermediate” to “indeterminate”. Because MEDI4920 is a 
CD40L antagonist, Exclusion Criterion #17 was updated to specify that subjects who had 
undergone previous treatment with anti-CD40/CD40L agents will also be excluded from 
participation in the study.
4. Table 4.2.1-1 (Schedule of Screening Procedures), Table 4.2.2-1 (Schedule of Treatment 
Period Study Procedures), and Table 4.2.3-1 (Schedule of Follow-up Procedures): Added 
a footnote to specify that ESR will be analyzed at the local laboratories.
5. Table 4.2.2-1: Added a note to specify that an overnight stay prior to administration of 
investigational product on Day 1 is recommended but not mandatory whereas an 
overnight stay post-investigational product administration on Day 1 is mandatory.
6. Section 4.3.2 (Clinical Laboratory Tests): Corrected a typographical error by changing 
the abbreviation for total bilirubin from “TLB” to “TBL”.
7. Section 4.5.1.5 (Preparation of Intravenous Dose): Added sub-headings to clearly 
differentiate between the MEDI4920 and placebo dose preparation steps; relocated the 
following sentence “A vial should be used only one time to prepare a single dose” to the 
MEDI4920 sub-section for clarification as no vials are used for the placebo treatment. 
Protocol Amendment 1, 05Apr2016
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. Main changes to the protocol are summarized below.


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1. Protocol Synopsis, Section 2.2.1 (Primary Endpoints): Revised wording for AESIs to be 
consistent with the standard potential risks language used in other clinical programs in 
MedImmune/AstraZeneca and in other MEDI4920 regulatory documents; added 
additional language for serious and/or opportunistic infections to clarify that the 
evaluations are not limited to just VZ, HSV, EBV, EMV, and TB. These changes will not 
affect the actual endpoints that are planned to be evaluated in the study or the safety 
monitoring of these events.
2. Section 1.6 (Potential Risks): Revised wording pertaining to the potential risks associated 
with MEDI4920 for consistency with the aforementioned changes in the AESI language; 
based on recommendations from the United States Food and Drug Administration (US 
FDA), the language pertaining to thromboembolic events was modified by adding the 
phrase “or suspected” such that dose escalation will be suspended even in the case of a 
suspected thromboembolic event, until additional data allow an informed diagnosis of the 
event to be made.
3. Section 3.1.1 (Overview); Section 6.2 (Monitoring of the Study): Changed the term 
“study drug” to “investigational product” for consistency with wording in the protocol. 
4. Section 3.1.3 (Dose Escalation and Cohort Progression): Based on recommendations 
from the US FDA, the language in the first dose escalation criterion was modified such 
that dose escalation would be suspended even in the case of a suspected thromboembolic 
event; additional language regarding the use of a diagnosis algorithm for determining a 
likely thromboembolic event was added to the first criterion; modified the second dose 
escalation criterion such that dose escalation would be suspended if 2 subjects (instead of 
3) dosed with MEDI4920 in a single cohort experiences either a Grade 3 or higher TEAE 
of the same type or any SAE.
5. Section 4.1.6 (Discontinuation of Investigational Product): Revised the language 
pertaining to anaphylaxis/serious hypersensitivity reactions, serious/opportunistic 
infections, and thromboembolic events for consistency with the aforementioned changes.
6. Section 4.2.2 (Treatment Period); Table 4.2.2-1: Modified wording in the text and table 
note to clarify that all laboratory sample collections and assessments on dosing day 
“must” (instead of “should”) be performed at predose, unless specified otherwise.
7. Section 5.3 (Definition of Adverse Events of Special Interest): Clarified statement 
regarding follow-up for AESIs: indicated that clinical monitoring of AESIs will be 
performed under the instructions of the “Safety Handling Plan”, instead of “Medical 
Monitoring Plan” and that AESIs will not be reported in detail in the eCRF, as stated in 
the original protocol; revised wording for AESIs to harmonize it with standard language 
used in other clinical programs in MedImmune/AstraZeneca and for consistency with the 
changes mentioned above.
8. Section 8 (References): Based on the changes in the amendment per recommendations 
from the US FDA, an additional reference was added to support the algorithm for 
diagnosing a DVT/PE event.
9. Appendix 4; Section 10.4.2.3: (Identification of Potential Hy’s Law Cases);
Section 10.4.4 (Review and Assessment of Potential Hy’s Law Cases): Removed the 
laboratory eCRF as one of the types of documents in which laboratory data are entered as 
it was included in error, and replaced it with the correct document, “Medical Monitoring 
Plan”.


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10. Appendix 5; Section 10.5 (Diagnosis of a Potential Thromboembolic Event): Based on 
the changes in the amendment per recommendations from the US FDA, an additional 
Appendix was added to describe in detail the algorithm that will be used to determine the 
likelihood of a DVT/PE event.


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10 APPENDICES
10.1
Appendix 1 - Signatures


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Sponsor Signature(s)
A Phase 1b Randomized, Double-blind, Placebo-controlled Multiple-ascending Dose Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, Pharmacodynamics,
and Clinical Response of MEDI4920 in Subjects with Adult-onset Rheumatoid Arthritis
I agree to the terms of this protocol.
Signature and date: 
electronic signature appended
Jorn Drappa, MD, Ph.D.,
, Clinical Development
One MedImmune Way, Gaithersburg, MD, 20878, USA
Telephone number: PPD
PPD
PPD


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Signature of Principal Investigator
A Phase 1b Randomized, Double-blind, Placebo-controlled Multiple-ascending Dose Study 
to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, Pharmacodynamics,
and Clinical Response of MEDI4920 in Subjects with Adult-onset Rheumatoid Arthritis
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 guidelines on Good 
Clinical Practice, 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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10.2
Appendix 2 - Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event
Life-threatening
‘Life-threatening’ means that the subject was at immediate risk of death from an AE as it 
occurred or it is suspected that use or continued use of the investigational product would 
result in the subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result 
in death, hospitalization, disability or incapacity but may jeopardize the subject or may 
require medical intervention to prevent one or more outcomes listed in the definition of 
serious. These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; 
medical judgment must be used.
Examples of such events are:
•
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment
•
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine
•
Intensive treatment in an emergency room or at home for allergic bronchospasm
•
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization
•
Development of drug dependency or drug abuse


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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
An event of mild intensity 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
An event of moderate intensity 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
A severe 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
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental 
disabilities that affect or limit the ability of the subject to 
perform activities of daily living (eating, ambulation, toileting, 
etc).
Grade 5
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.


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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. The following factors should be considered when deciding if there is 
a “reasonable possibility” that an AE may have been caused by the investigational product.
•
Did the subject actually receive the suspect investigational product? Did the AE occur in 
a reasonable temporal relationship to the administration of the suspect investigational 
product?
•
Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and 
toxicology) or products of the same pharmacological class, OR could the AE be 
anticipated from its pharmacological properties? Is this event frequently observed in the 
study population regardless of treatment?
•
De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
•
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, or other host or environmental factors.
•
Re-challenge experience. Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? MedImmune would not normally recommend or 
support a re-challenge.
•
Laboratory tests. Did a specific laboratory investigation (if performed) confirm the 
relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist.
If available information describing the event and the circumstances is insufficient to make a 
definitive assessment of causal association the nature of AE, and likelihood of this event 
occurring in the study population should be taken into account (eg, events not typically seen 
in the study population are more likely to lack an alternative explanation).
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
de-challenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE.


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In difficult cases, other factors could be considered such as:
•
Is this a recognized feature of overdose of the investigational product?
•
Is there a known mechanism? Ambiguous cases should be considered as being a 
“reasonable possibility” of a causal relationship unless further evidence becomes 
available to refute this. Causal relationship in cases where the disease under study has
deteriorated due to lack of effect should be classified as “no reasonable possibility”.
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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10.3
Appendix 3 - National Institute of Allergy and Infectious Diseases 
and Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al.
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
NIAIDs and FAAN define anaphylaxis as a serious allergic reaction that is rapid in onset and 
may cause death. They recognize 3 categories of anaphylaxis, with criteria designated to 
capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for all 3 
categories). 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
c.
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline


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10.4
Appendix 4 - Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
10.4.1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report cases of HL. It is not intended to be a comprehensive guide to the management of 
elevated liver biochemistries. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential HL (PHL) criteria at any point during the study.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. 
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug-induced liver injury (DILI) caused by the investigational 
product. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
10.4.2
Definitions
10.4.2.1
Potential Hy’s Law 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of investigational product irrespective of an increase in ALP.
10.4.2.2
Hy’s Law 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the investigational product, can be found to explain the combination of increases; eg, 
elevated ALP indicating cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on 
the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.


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10.4.2.3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL, it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:
•
ALT ≥ 3 × ULN
•
AST ≥ 3 × ULN
•
TBL ≥ 2 × ULN
When a subject meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the investigator (also sent to sponsor 
study representative). 
The investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the investigator will:
•
Notify the sponsor study representative
•
Request a repeat of the test (new blood draw) by the central laboratory
•
Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the 
investigator will without delay:
•
Determine whether the subject meets PHL criteria by reviewing laboratory reports from 
all previous visits (including both central and local laboratory results)
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will:
•
Notify the sponsor study representative
•
Determine whether the subject meets PHL criteria by reviewing laboratory reports from 
all previous visits


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10.4.3
Follow-up
10.4.3.1
Potential Hy’s Law Criteria Not Met
If the subject does not meet PHL criteria the investigator will:
•
Inform the study representative that the subject has not met PHL criteria
•
Perform follow-up on subsequent laboratory results according to the guidance provided 
in the study protocol.
10.4.3.2
Potential Hy’s Law Criteria Met
If the subject does meet PHL criteria the investigator will:
•
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment 
•
Notify the sponsor study representative who will then inform the study team
The medical monitor contacts the investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data. Subsequent to 
this contact the investigator will:
•
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated 
•
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the medical monitor. This includes deciding which tests available in the HL 
laboratory kit should be used.
•
If at any time (in consultation with the medical monitor) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
10.4.4
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the medical 
monitor will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
investigational product. The medical monitor and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 


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According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently
whether the AE meets the criteria for an SAE:
•
If the alternative explanation is not an AE, record the alternative explanation according to 
the Medical Monitoring Plan
•
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the sponsor’s standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:
•
Report an SAE (report term ‘Hy’s Law’) according to sponsor’s standard processes. 
◦
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply
◦
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
•
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above
•
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review.
10.4.5
Actions Required When Potential Hy’s Law Criteria Are Met Before 
and After Starting Study Treatment 
This section is applicable to subjects with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on-study treatment occurrence of PHL criteria being met the investigator will:


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•
Determine if there has been a significant change in the subjects’ condition compared with 
the last visit where PHL criteria were met 
◦
If there is no significant change no action is required
◦
If there is a significant change, notify the study representative, who will inform the 
central study team, then follow the subsequent process described in Section 10.4.3.2
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the medical monitor if there is any uncertainty.
10.4.6
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a subject meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on-study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria 
being met and answer the following question:
•
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study, eg, chronic or progressing malignant disease, severe infection, 
or liver disease, or did the subject meet PHL criteria prior to starting study treatment and 
at their first on study treatment visit as described in Section 10.4.5?
If No: Follow the process described in 10.4.3.1
If Yes: Determine if there has been a significant change in the subject’s condition compared 
with when PHL criteria were previously met:
•
If there is no significant change no action is required
•
If there is a significant change follow the process described in Section 10.4.3.2
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 


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whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the medical monitor if there is any uncertainty.
10.4.7
References
The United States Food and Drug Administration Guidance for Industry (issued July 2009) 
‘Drug-induced liver injury: Premarketing clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM174090.pdf


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10.5
Appendix 5 – Diagnosis of a Potential Thromboembolic Event
10.5.1
Clinical Probability Score of Deep Vein Thrombosis - Wells Criteria
d = days; DVT = deep vein thrombosis; mo = months; wk = weeks
Score ≤ 1 = DVT is clinically unlikely; Score ≥ 2 = DVT is clinically likely
Algorithm for Suspected Deep Vein Thrombosis
In every case of a clinically suspected deep vein thrombosis (DVT), the clinical probability 
score must be calculated using by the aforementioned Wells criteria and a D-dimer test must 
be performed. 
•
If clinical probability shows “DVT unlikely” (ie, score ≤1), and D-dimer value is ≤ULN, 
DVT is excluded. 
•
If clinical probability shows “DVT unlikely” (ie, score ≤1), and D-dimer value is > ULN, 
compression ultrasound will be performed. 
◦
If ultrasound shows no abnormal changes, DVT is excluded. 
◦
If ultrasound shows abnormal changes, compatible with thrombosis, DVT is
confirmed. 
◦
If ultrasound is unavailable/equivocal and D-dimer is only increased at the time of 
event, DVT is considered “likely”. 
•
If clinical probability shows “DVT likely” (ie, score ≥2), compression ultrasound will be 
performed irrespective the D-dimer value. 
◦
If ultrasound shows no abnormal changes, ultrasound should be repeated within 
7 days; if ultrasound again shows no abnormal changes, DVT is excluded. 


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◦
If ultrasound shows abnormal changes compatible with thrombosis, DVT is 
confirmed. 
◦
If ultrasound is unavailable or equivocal, DVT is considered “likely”. 
•
Each situation that cannot be adjudicated using the algorithm above will be considered as 
“DVT likely” and dose escalation will be suspended.
10.5.2
Clinical Probability Score of Pulmonary Embolism - Wells Criteria
bpm = beats per minute; DVT = deep vein thrombosis; PE = pulmonary embolism; wk = week
Score ≤ 4 = PE is clinically unlikely; Score ≥4 = PE is clinically likely
Algorithm for Suspected Pulmonary Embolism:
In every case of suspected pulmonary embolism (PE), clinical probability score must be 
calculated using by the aforementioned Wells criteria and a D-dimer test must be performed.
•
If clinical probability shows “PE unlikely” (ie, score ≤4), and D-Dimer value is ≤ULN,
PE is excluded.
•
If clinical probability shows “PE likely” (ie, score ≥4) or D-dimer value is > ULN, chest 
X-Ray will be performed. 
◦
If chest X-ray is normal, a ventilation-perfusion (V/Q) scan will be performed.  
◦
If chest X-Ray is abnormal, computerized tomographic pulmonary angiography 
(CTPA) will be considered. 
◦
If V/Q scan or CTPA are not available or equivocal, PE is considered “likely” unless 
clinical probability shows “PE unlikely” and D-dimer is > ULN at previous time 
points during the study, including at baseline. 
•
Each situation that cannot be adjudicated using the algorithm above will be considered as 
“PE likely” and dose escalation will be suspended. 
Adapted from Wells P and Anderson D. The diagnosis and treatment of venous 
thromboembolism. Hematology Am Soc Hematol Educ Program. 2013;2013:457-63.



SAP_001.pdf: 
MedImmune 
Statistical Analysis Plan for Protocol D5100C00002 
MEDI4920 
 
27th May 2016; Final V1.0 
CONFIDENTIAL AND PROPRIETARY 
1 of 21 
Statistical Analysis Plan 
 
 
 
A Phase 1b Randomized, Double-blind, Placebo-controlled Multiple-ascending Dose 
Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity, 
Pharmacodynamics and Clinical Response of MEDI4920 in Subjects with Adult-onset 
Rheumatoid Arthritis 
 
Protocol Number: D5100C00002 
 


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Statistical Analysis Plan for Protocol D5100C00002 
MEDI4920 
 
27th May 2016; Final V1.0 
CONFIDENTIAL AND PROPRIETARY 
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TABLE OF CONTENTS 
1 
INTRODUCTION ...........................................................................................................6 
2 
STUDY OVERVIEW .....................................................................................................6 
2.1 
Study Objectives ...................................................................................................6 
2.1.1Primary Study Objective ...............................................................................6 
2.1.2Secondary Study Objectives .........................................................................6 
2.1.3Exploratory Study Objectives .......................................................................6 
2.2 
Study Design .........................................................................................................6 
2.3 
Treatment Assignment and Blinding ....................................................................8 
2.4 
Sample Size...........................................................................................................8 
3 
STATISTICAL METHODS ...........................................................................................9 
3.1 
General Considerations .........................................................................................9 
3.1.1Visit windows ...............................................................................................9 
3.2 
Analysis Populations...........................................................................................11 
3.3 
Study Subjects.....................................................................................................11 
3.3.1Subject Disposition and Completion Status ...............................................11 
3.3.2Demographics and Baseline Characteristics ...............................................12 
3.3.3Investigational Product Exposure ...............................................................12 
3.3.4Concomitant Medications ...........................................................................12 
3.4 
Efficacy Analyses ...............................................................................................12 
3.4.
 ...................................................12 
3.4.1.1 
.......................................................12 
3.4.1.2 
 ..................................13 
3.4.1.3 
.......................................................13 
3.4.1.4 
 .......14 
3.4.1.5 
 ...................................................................14 
3.4.2
 ...........................................15 
3.4.2.1 
3.4.2.2 
................................................15 
3.4.3
 .............................................................................16 
3.5 
Patient Reported Outcomes ................................................................................16 
3.5.1Patient Global Assessment..........................................................................16 
3.6 
Pharmacodynamic Endpoint(s) and Analyses ....................................................16 
3.6.1.1 
Pharmacodynamic Endpoint(s) .................................................16 
3.6.1.2 
Analysis of Pharmacodynamic Endpoint(s) .............................17 
3.7 
Safety Analyses...................................................................................................17 
3.7.1Adverse Events and Serious Adverse Events .............................................17 
3.7.2Adverse Events of Special Interest .............................................................17 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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3.7.3Deaths and Treatment Discontinuations due to Adverse Events ................18 
3.7.4Clinical Laboratory Evaluation ...................................................................18 
3.7.5Other Safety Evaluations ............................................................................19 
3.7.5.1 
Vital Signs .................................................................................19 
3.7.5.2 
Electrocardiogram .....................................................................19 
3.8 
Immunogenicity ..................................................................................................20 
3.9 
Pharmacokinetics ................................................................................................20 
4 
INTERIM ANALYSIS..................................................................................................20 
5 
REFERENCES ..............................................................................................................20 
 
LIST OF IN-TEXT TABLES 
Table 3.1.1-1 
Visit windows for DAS28, CDAI, Joint Counts, Patient Global 
Assessment, Physician Global Assessment, CRP and ESR .................10 
Table 3.1.1-2 
Visit windows for Vectra DA ..............................................................10 
Table 3.1.1-3 
Visit windows for laboratory assessments ...........................................10 
Table 3.1.1-4 
Visit windows for ECGs ......................................................................11 
Table 3.2-1 
Analysis Populations ............................................................................11 
Table 3.4.1.1-1 
................................................................13 
Table 3.4.2.1-1 
 .............................................................................15 
Table 3.7.4-1 
CTC grades ..........................................................................................18 
 
 
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List of Abbreviations 
 
Abbreviation or 
Specialized Term 
Definition 
ACPA 
Anti–cyclic Citrullinated Peptide Antibody 
ADA 
Anti-Drug Antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AIC 
Akaike Information Criteria 
AUC 
Area Under the concentration-time Curve 
ATC 
Anatomical Therapeutic Chemical 
AZ-DD 
AstraZeneca Drug Dicitonary 
BMI 
Body mass index 
CDAI 
Clinical Disease Activity Score 
cDMARD 
Conventional Disease Modifying Anti-Rheumatic Drugs 
Cmax 
Maximum Concentration 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events  
DAS28 
Disease Activity Score using 28 joints 
DMPK 
Drug Metabolism & Pharmacokinetics 
eCRF 
electronic Case Report Form 
ECG 
Electrocardiogram 
ED50 
Dose giving 50% of the maximum effect 
Emax 
Maximum Effect 
ESR 
Erythrocyte Sedimentation Rate  
Ig 
Immunoglobulin 
IM 
Immunogenicity 
ITT 
Intent-to-Treat 
IV 
intravenous 
IXRS 
Interactive voice/web response system 
LOCF 
Last Observation Carried Forward 
MAD 
Multiple Ascending Dose 
MBDA 
Multi-Biomarker Disease Activity 
MCP-mod 
Multiple Comparison Procedure – modelling 
MDGA 
Physician Global Assessment 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams  
MMRM 
Mixed Model for Repeated Measures 


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Abbreviation or 
Specialized Term 
Definition 
MTX 
Methotrexate 
PGA 
Patient Global Assessment 
PK 
Pharmacokinetics 
PRO 
Patient Reported Outcome 
Q2W 
Every 2 weeks 
RA 
Rheumatoid Arthritis 
RF 
Rheumatoid Factor 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
sCD40L 
Soluble CD40 ligand 
SD 
Standard Deviation 
SJC 
Swollen Joint Count 
SPP 
Statistical Programming Plan 
TJC 
Tender Joint Count  
Anti-TNFα 
Anti-Tumour Necrosis Factor alpha 
VAS 
Visual Analogue Score 
 
 
 
 


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1 
INTRODUCTION 
This document describes the statistical analyses for protocol D5100C00002, a multicenter, 
randomized, double-blind, placebo-controlled study to evaluate the safety and tolerability of 
multiple ascending doses of MEDI4920 in subjects with adult-onset rheumatoid arthritis 
(RA) (moderate to severe, as defined by disease activity score in 28 joints using C-reactive 
protein (DAS28 CRP) ≥ 3.2 at screening) with an inadequate response to methotrexate 
(MTX) or other conventional disease-modifying anti-rheumatic drugs (cDMARDs) or a 
biologic anti-tumor necrosis factor alpha (anti-TNFα) agent. 
A separate statistical programming plan (SPP) will contain the table templates, detailed 
specifications and programming code for the statistical analyses. 
2 
STUDY OVERVIEW 
2.1 
Study Objectives 
2.1.1 
Primary Study Objective 
To assess the safety and tolerability of multiple ascending intravenous (IV) doses of 
MEDI4920 in subjects with adult-onset RA. 
2.1.2 
Secondary Study Objectives 
To evaluate the pharmacokinetics (PK) and immunogenicity of MEDI4920 in subjects with 
adult-onset RA. 
2.1.3 
Exploratory Study Objectives 
1. 
2. 
3. 
4. 
 
 
2.2 
Study Design 
This is a multicenter, randomized, double-blind (investigator, subject, and sponsor will be 
blinded to treatment assignment), placebo-controlled study to evaluate the safety and 
tolerability of multiple ascending doses (MADs) of MEDI4920 in subjects with adult-onset 
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RA (moderate to severe, as defined by DAS28 CRP ≥ 3.2 at screening) with an inadequate 
response to MTX or other cDMARDs or a biologic anti-TNFα agent.  
Approximately 40 subjects on stable MTX or another cDMARD will be randomized across 
3 cohorts to receive either 75 mg (Cohort 1), 500 mg (Cohort 2), or 1500 mg (Cohort 3) 
MEDI4920, or placebo once every 2 weeks (Q2W).  
An additional 14 subjects may be randomized to an additional cohort (Cohort 4) if required, 
to understand the dose (exposure) - response relationship. The selected dose and exposure 
(maximum concentration (Cmax) and area under the concentration-time curve (AUC)) will not 
be higher than 1500 mg Q2W and could include a less frequent dosing regimen (eg, once 
every 4 weeks). 
Subjects will undergo a screening period of up to 6 weeks followed by randomization and 
treatment for 12 weeks. Subjects will be followed for an additional 12 weeks after the 
treatment period for safety.  
Subjects will receive an IV dose of MEDI4920 or placebo Q2W for up to 12 weeks as 
follows: 
• Cohort 1: 75 mg MEDI4920 (N = 8) or placebo (N = 2) as a single IV dose administered 
over at least 30 minutes Q2W 
• Cohort 2: 500 mg MEDI4920 (N = 10) or placebo (N = 4) as a single IV dose 
administered over at least 60 minutes Q2W  
• Cohort 3: 1500 mg MEDI4920 (N = 12) or placebo (N = 4) as a single IV dose 
administered over at least 90 minutes Q2W  
• Cohort 4 (Optional): MEDI4920 (N = 10) or placebo (N = 4) as a single IV dose 
(duration of infusion and frequency of administration to be determined)  
 
All subjects will receive a total of 7 doses of investigational product (MEDI4920 or placebo) 
during the 12-week treatment period.  
The primary analysis will be performed when all subjects in Cohort 3 have completed the 
Day 85 assessments or have been withdrawn from the study. The primary analysis will 
include all assessments on the subjects prior to the data cut-off for the primary analysis. 
If a fourth cohort is required, the data will be analyzed when all subjects in the fourth cohort 
have completed the Day 85 assessments or have been withdrawn from the study. 


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The final analysis on the subjects will be performed when all subjects have completed the 
safety follow-up.  
2.3 
Treatment Assignment and Blinding 
An interactive voice/web response system (IXRS) will be used for randomization to a 
treatment group and assignment of investigational product kit numbers if assigned to an 
active treatment arm. A subject is considered randomized into the study when the 
investigator notifies the IXRS that the subject meets eligibility criteria and the IXRS provides 
the assignment of treatment group and allocates active treatment if assigned to the active 
treatment arm. 
Subjects will be randomized in a 4:1 ratio (Cohort 1), in a 5:2 ratio (Cohort 2), in a 3:1 ratio 
(Cohort 3), and in a 5:2 ratio (Optional Cohort 4) to receive either MEDI4920 or placebo 
respectively.  
This is a double-blind study in which MEDI4920 and the saline placebo are not identical in 
appearance. For maintaining the blinding of the principal investigator, site staff, sponsor, 
Contract Research Organization (CRO) or staff, a local unblinded pharmacy staff member 
will be nominated by each site and will have the responsibility of allocating, dispensing and 
preparing the investigational product in order to maintain the study blind. In addition, a 
separate unblinded monitor will be used for the oversight of investigational product 
management.  
MedImmune personnel will be unblinded to the subject treatment assignments at the primary 
analysis (Day 85). The data from the primary analysis will not be communicated to personnel 
at the CRO or investigational sites or to enrolled subjects, until the study is complete. 
2.4 
Sample Size 
No formal sample size calculations are presented for the evaluation of the primary objective 
of safety and tolerability of MEDI4920. The sample size calculations are based on the 
exploratory endpoint 
 
.  
The sample size calculation for the change from baseline in DAS28 CRP at Week 12 is based 
on combining the data from the cohorts and performing a dose response analysis. Based on 
the assumption 
, the sample sizes of 10, 
8, 10 and 12 subjects for the placebo, 75, 500 and 1500 mg dose groups, respectively, will 
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provide approximately 80% power for detecting a statistically significant dose response, 
using a significance level of 0.10. 
The power for dose response has been calculated using a multiple comparison procedure with 
modeling techniques (MCP-Mod; Bretz et al, 2005), with three candidate models for the dose 
response (linear, maximum effect attributable to the drug [Emax], and a Hill-Emax model). An 
overall significance level of 0.10 will be used to test for dose response. 
3 
STATISTICAL METHODS 
3.1 
General Considerations 
All data will be provided in data listings sorted by treatment group and subject number. 
Tabular summaries will be presented by treatment group. Categorical data will be 
summarized by the number and percentage of subjects falling within each category. In 
general, continuous variables will be summarized by descriptive statistics including mean, 
standard error or standard deviation (SD), median, minimum, and maximum. 
Day 1 will be defined as the day of first investigational product administration. Baseline will 
be defined as the last non-missing value prior to the first administration of investigation 
product. The change from baseline will be calculated by subtracting the baseline values from 
the individual post-baseline values. If either the baseline or post-baseline value is missing, 
the change from baseline is set to missing. 
Unless otherwise stated, all efficacy analyses will be conducted with a two-sided test at a 
significance level of α = 0.10. 
Data analyses will be conducted using the SAS® System Version 9.3 or higher (SAS Institute 
Inc., Cary, NC) in a UNIX platform. 
3.1.1 
Visit windows 
Visit windows will be used for all scheduled assessments to allow for by-visit analyses, since 
not all assessments are performed on the scheduled day. Unless specified otherwise, all 
efficacy and safety analyses will be based on the analysis visit windows. The actual 
assessment day will be mapped to the planned study visit following the analysis visit 
windowing rules below:  
• If more than one assessment falls within a visit window, the closest non-missing 
assessment to the scheduled day will be used in the analysis. 


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• If two non-missing assessment actual dates are equidistant from the target day, the 
earlier visit will be used in the analysis.  
The visit windows will be calculated by bisecting the scheduled visit days. The lower limit of 
each window will be the mean of the two adjacent planned study days, rounded up to the 
nearest integer, except for the first post-treatment visit, which will start at 2. The upper limit 
of each window will be the mean of the two adjacent planned study days, rounded down to 
the nearest integer. 
Table 3.1.1-1 
Visit windows for DAS28, CDAI, Joint Counts, Patient 
Global Assessment, Physician Global Assessment, CRP 
and ESR 
Planned study day of visit 
Visit window 
1 
All assessments prior to the first administration of investigation product 
15 
Start of first administration of investigation product – Day 22 
29 
Day 23 - 43 
57 
Day 44 - 71 
85 
Day 72 - 99 
113 
Day 100 - 127 
141 
Day 128 - 155 
169 
Day 156 +  
 
Table 3.1.1-2 
Visit windows for Vectra DA 
Planned study day of visit 
Visit window 
1 
All assessments prior to the first administration of investigation product 
15 
Start of first administration of investigation product – Day 22 
29 
Day 23 - 43 
57 
Day 44 - 71 
85 
Day 72 - 99 
113 
Day 100 - 141 
169 
Day 142 +  
 
Table 3.1.1-3 
Visit windows for laboratory assessments 
Planned study day of visit 
Visit window 
1 
All assessments prior to the first administration of investigation product 
8 
Start of first administration of investigation product – Day 11 
15 
Day 12 - 22 
29 
Day 23 - 43 
57 
Day 44 - 71 
85 
Day 72 - 88 


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Table 3.1.1-3 
Visit windows for laboratory assessments 
Planned study day of visit 
Visit window 
92 
Day 89 - 95 
99 
Day 96 - 106 
113 
Day 107 - 127 
141 
Day 128 - 155 
169 
Day 156 +  
 
Table 3.1.1-4 
Visit windows for ECGs 
Planned study day of visit 
Visit window 
1 
All assessments prior to the first administration of investigation product 
85 
Start of first administration of investigation product – Day 127 
169 
Day 128 + 
 
Vital signs will be summarized according to the eCRF recorded assessment visit. 
3.2 
Analysis Populations 
The analysis populations are defined in Table 3.2-1. 
Table 3.2-1 
Analysis Populations 
Population 
Description 
Intent-to-treat 
(ITT) population 
Subjects who are randomized and who receive at least one dose of study investigational 
product will be included in the ITT population and subjects will be analyzed according to 
their randomized treatment group. 
As-treated 
population 
Subjects who are randomized and who receive at least one dose of study investigational 
product will be included in the as-treated population and subjects will be analyzed 
according to the highest dose they actually receive. 
PK population 
The Pharmacokinetics (PK) Population includes all subjects who receive at least one dose 
of investigational product and have at least one PK sample containing detectable 
MEDI4920.  
 
3.3 
Study Subjects 
3.3.1 
Subject Disposition and Completion Status 
A summary of subject eligibility and randomization as well as treatment group received 
(including summary of subjects randomized but not treated) will be provided. In addition, 
disposition of subjects throughout the study with respect to completion of treatment and 
follow-up will be provided. 


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3.3.2 
Demographics and Baseline Characteristics 
Demographic information related to sex, age, race, weight, height, and body mass index 
(BMI) will be presented by treatment group and for all subjects combined. RA history, 
including years since onset of symptoms, years since diagnosis, current functional capacity 
and number of nodules will be summarized by treatment group and for all subjects combined. 
Previously discontinued RA medications along with the reason for discontinuation will be 
summarized by treatment group and for all subjects combined. 
A summary of baseline disease characteristics will include DAS28 CRP, swollen joint count, 
tender joint count, Physician’s global assessment (MDGA), Patient’s global assessment 
(PGA), CRP, erythrocyte sedimentation rate (ESR), Clinical Disease Activity Index (CDAI), 
anti-cyclic citrullinated peptide antibody (ACPA) (positive/negative) and rheumatoid factor 
(RF) (positive/negative).  
3.3.3 
Investigational Product Exposure 
The summary of investigational product exposure will include descriptive statistics for the 
total number of doses received, total amount of MEDI4920 (mg) administered to each 
treatment arm and the relative dose intensity. The relative dose intensity is defined as the 
total amount of MEDI4920 administered throughout the trial divided by the planned total 
dose. 
3.3.4 
Concomitant Medications 
Concomitant medications for RA and other current co-morbidities will be coded using the 
current version of AZ-DD and summarized for each treatment group and for all subjects 
combined by ATC level 1 and preferred term. The background dose of methotrexate and 
corticosteroids use will also be summarized by treatment group and for all subjects 
combined. 
3.4 
Efficacy Analyses 
. 
3.4.1 
3.4.1.1 
 
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3.4.1.2 
 
 
3.4.1.3 
 
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3.4.1.4 
 
3.4.1.5 
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3.4.2 
3.4.2.1 
3.4.2.2 
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3.4.3 
3.5 
Patient Reported Outcomes 
3.5.1 
Patient Global Assessment 
The only Patient Reported Outcome (PRO) is the PGA. The analysis of the PGA is described 
in section 3.4.2.2. 
3.6 
Pharmacodynamic Endpoint(s) and Analyses 
3.6.1.1 
Pharmacodynamic Endpoint(s) 
A commercially available and validated biomarker panel (Vectra DA) measures 12 
biomarkers and combines them into a single score to assess the key mechanisms and 
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pathways that drive RA disease activity. The biomarker panel includes adhesion molecules, 
growth factors, cytokines, matrix metalloproteinases, skeletal proteins, hormones and acute 
phase proteins. The Vectra DA biomarker panel has been demonstrated to be a sensitive 
objective measure of clinical disease activity, with a strong correlation to DAS28 (CRP). 
Changes in Vectra DA score are also an objective measure of changes in disease activity, 
showing a significant correlation to changes in DAS28 (CRP). 
3.6.1.2 
Analysis of Pharmacodynamic Endpoint(s) 
The same MMRM analysis as for DAS28 (CRP) will be repeated with Vectra DA change 
from baseline at each post-baseline visit as the dependent variable. The analysis will only 
include the on-treatment assessments. 
Plots of Vectra DA and its component biomarkers will be presented with study day on the x-
axis and result on the y-axis. The mean with standard error bars will be plotted by dose. If 
appropriate, the y-axis will be presented with log-spacing. 
3.7 
Safety Analyses 
3.7.1 
Adverse Events and Serious Adverse Events 
Adverse events (AEs) will be coded by MedDRA version 18.0 or higher and the type 
incidence, severity and relationship to study investigational product will be summarized. 
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. All treatment-emergent AEs will be summarized 
overall, as well as categorized by MedDRA System Organ Class and Preferred Term. The 
placebo subjects from each cohort will be combined for the summaries. 
3.7.2 
Adverse Events of Special Interest 
The following adverse events of special interest (AESIs) have been defined in the protocol: 
• Thromboembolic events / bleeding events 
• Hepatic function abnormality (meeting the definition of Hy’s Law [HL]) 
• Acute and delayed hypersensitivity reactions including anaphylaxis, immune complex 
disease and infusion-related reactions 
• Infections including serious and opportunistic infections (includes reactivation of latent 
viral infection [varicella zoster/herpes simplex virus, Epstein-Barr virus/ 
cytomegalovirus] and tuberculosis) 
 


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The AESIs will be identified by medical review of the AEs prior to unblinding the study. All 
treatment emergent AESIs will be summarized by special interest category and preferred 
term. 
3.7.3 
Deaths and Treatment Discontinuations due to Adverse Events 
Deaths and treatment discontinuation due to AEs will be summarized and listed by treatment 
group. 
3.7.4 
Clinical Laboratory Evaluation 
Serum chemistry, hematology, coagulation and urinalysis parameters will be collected in this 
study, analyzed by central laboratory and will be used to investigate the safety of MED4920. 
For continuous variables of laboratory tests, all data at baseline and at each scheduled visit 
will be summarized by treatment group using descriptive statistics. Changes from baseline to 
each scheduled time point of post-dose will also be summarized using descriptive statistics. 
For categorical variables of laboratory tests, the frequency and percentage in each category of 
the item at baseline and at each scheduled visit of post-dose will be presented for each 
treatment group.  
Boxplots of each laboratory variable by study visit will be presented for each treatment 
group. The boxplots will contain all the data. The boxes will extend to the limits of the 
interquartile range and the whiskers will extend to the most extreme observation within 1.5 
times the interquartile range from the nearest quartile. The data will be plotted on a 
logarithmic scale when it improves interpretability of the plot. Reference lines will be 
included on the boxplots for the limits of the normal range. 
Laboratory results will also be summarized by Common Terminology Criteria for Adverse 
Events (CTCAE) grade by visit for the parameters included in Table 3.7.4-1. 
Table 3.7.4-1 
CTC grades 
Lab parameter 
Toxicity grade 
Lab values 
White blood cell count (10^9/L) 
Grade 0 
≥ LLN 
 
Grade 1 
≥ 3 - <LLN 
 
Grade 2 
≥ 2 - <3 
 
Grade 3 
≥ 1 - <2 
 
Grade 4 
<1 
 
 
 
Platelets (10^9/L) 
Grade 0 
≥ LLN 
 
Grade 1 
≥ 75 - <LLN 
 
Grade 2 
≥ 50 - <75 
 
Grade 3 
≥ 25 - <50 


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Table 3.7.4-1 
CTC grades 
Lab parameter 
Toxicity grade 
Lab values 
 
Grade 4 
<25 
 
 
 
Lymphocytes (10^9/L) 
Grade 0 
≥ LLN 
 
Grade 1 
≥ 0.8 - <LLN 
 
Grade 2 
≥ 0.5 - <0.8 
 
Grade 3 
≥ 0.2 - <0.5 
 
Grade 4 
<0.2 
 
 
 
Neutrophils (10^9/L) 
Grade 0 
≥ LLN 
 
Grade 1 
≥ 1.5 - <LLN 
 
Grade 2 
≥ 1.0 - <1.5 
 
Grade 3 
≥ 0.5 - <1.0 
 
Grade 4 
<0.5 
 
 
 
ALT (IU/L) 
Grade 0 
≤ ULN 
 
Grade 1 
> ULN - ≤3*ULN 
 
Grade 2 
> 3*ULN - ≤5*ULN 
 
Grade 3 
> 5*ULN - <20*ULN 
 
Grade 4 
>20*ULN 
 
 
 
AST (IU/L) 
Grade 0 
≤ ULN 
 
Grade 1 
> ULN - ≤3*ULN 
 
Grade 2 
> 3*ULN - ≤5*ULN 
 
Grade 3 
> 5*ULN - <20*ULN 
 
Grade 4 
>20*ULN 
 
 
 
Bilirubin (umol/L) 
Grade 0 
≤ ULN 
 
Grade 1 
> ULN - ≤1.5*ULN 
 
Grade 2 
> 1.5*ULN - ≤3*ULN 
 
Grade 3 
> 3*ULN - <10*ULN 
 
Grade 4 
>10*ULN 
 
3.7.5 
Other Safety Evaluations 
3.7.5.1 
Vital Signs 
Vital sign results will be summarized with descriptive statistics (number of subjects, mean, 
SD, median, minimum and maximum) at each time point. The changes from baseline will 
also be summarized with descriptive statistics by post-baseline visit. 
3.7.5.2 
Electrocardiogram 
The overall interpretation of the ECG results (Normal; Abnormal, not Clinically Significant; 
and Abnormal, Clinically Significant) will be summarized using frequency count and 
percentages by visit and treatment groups.  


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3.8 
Immunogenicity 
The anti-drug antibody (ADA) results will be summarized by the number and percentage of 
subjects positive for ADA at baseline and positive at any post-baseline visit. The incidence 
rate of persistent positive and transient positive will also be presented. Persistent positive and 
transient positive are defined as follows: 
• Persistent positive is defined as positive at ≥ 2 post-baseline assessments (with ≥ 16 
weeks between first and last positive) or positive at last post-baseline assessment 
• Transient positive is defined as negative at last post-baseline assessment and positive 
at only one post-baseline assessment or at ≥ 2 post-baseline assessments (with < 16 
weeks between first and last positive) 
3.9 
Pharmacokinetics 
Descriptive statistics of MEDI4920 serum concentrations by treatment group and visit will be 
provided. Mean and individual serum MEDI4920 concentration-time profiles by treatment 
group will be plotted. The PK components of the CSR will be generated and reported by 
MedImmune’s Clinical Pharmacology & DMPK group. Separately from the CSR, population 
PK modeling may be performed and reported, and potential correlation between PK exposure 
and pharmacodynamic biomarker, efficacy/safety response may be evaluated. 
4 
INTERIM ANALYSIS 
No interim analyses will be performed. 
The primary analysis will be performed when all subjects in Cohort 3 have completed the 
Day 85 assessments or have been withdrawn from the study. The primary analysis will 
include all assessments on the subjects prior to the data cut-off for the primary analysis. 
If a fourth cohort is required, the data will be analyzed when all subjects in the fourth cohort 
have completed the Day 85 assessments or have been withdrawn from the study. 
The final analysis on the subjects will be performed when all subjects have completed the 
safety follow-up.  
5 
REFERENCES 
Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques 
in dose-response studies. Biometrics. 2005;61(3):738-48. 


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Wells G, Becker JC, Teng J, Dougados M, Schiff M, Smolen J, et al. Validation of the 28-
joint Disease Activity Score (DAS28) and European League Against Rheumatism response 
criteria based on C-reactive protein against disease progression in patients with rheumatoid 
arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann 
Rheum Dis. 2009 Jun;68(6):954-60.