Clinical trial NCT02574637
Conditions: Crohn's Disease
Keywords: MEDI2070 inflammatory bowel disease moderate to severe Crohn's Disease IL-23
Sponsor: AstraZeneca
Start date: 2016-01-05; Completion date: 2018-01-29
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2b study to evaluate the efficacy and safety of brazikumab (MEDI2070) in participants with moderate to severe Crohn's disease who have failed or are intolerant to anti-tumor necrosis factor-alpha (anti-TNFα) therapy.

Detailed description:
This is a four-part Phase 2b study comprised of a 16-week, double-blind, placebo-controlled, Induction Period, a 12-week double-blind, placebo-controlled, Maintenance Period, a 24-week, Open-label Period and a post-treatment 28 week observational safety follow-up period designed to evaluate the short-term efficacy and the short- and long term safety of brazikumab in participants with moderate to severe, active Crohn's disease (CD) who have failed or are intolerant to anti-TNFα therapy as determined by the Investigator.

Arms: arm 1: Placebo-matching brazikumab intravenous (IV) infusion and subcutaneous (SC) injection at Weeks 0 and 4 followed by placebo-matching brazikumab SC injection at Weeks 8 and 12 in the induction phase and at Weeks 16, 20 and 24 in the maintenance phase. Participants received brazikumab 210 mg, SC injection every 4 weeks up to Week 48 in the open-label period. arm 2: Brazikumab 700 mg, IV infusion and placebo-matching brazikumab, SC injection at Weeks 0 and 4 followed by brazikumab 210 mg, SC injection at Weeks 8 and 12 in the induction phase. Participants received brazikumab 210 mg, SC injection every 4 weeks in the maintenance phase and open-label period up to Week 48. arm 3: Brazikumab 280 mg, IV infusion and placebo-matching brazikumab, SC injection at Week 0 followed by brazikumab 210 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 4, followed by brazikumab 210 mg, SC injection at Weeks 8 and 12 in the induction phase. Participants received brazikumab 210 mg, SC injection every 4 weeks in the maintenance phase and open-label period up to Week 48. arm 4: Brazikumab 210 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 0 followed by brazikumab 105 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 4, followed by brazikumab 105 mg, SC injection at Weeks 8 and 12 in the induction phase. Participants received brazikumab 105 mg, SC injection every 4 weeks up to Week 24 in the maintenance phase. Participants received brazikumab 210 mg, SC injection, every 4 weeks up to Week 48 in the open-label period. arm 5: Brazikumab 70 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 0 followed by brazikumab 35 mg, SC injection and placebo-matching brazikumab, IV infusion at Week 4, followed by brazikumab 35 mg, SC injection at Weeks 8 and 12 in the induction phase. Participants received brazikumab 35 mg, SC injection every 4 weeks up to Week 24 in the maintenance phase. Participants received brazikumab 210 mg, SC injection, every 4 weeks up to Week 48 in the open-label period.
Interventions: intervention 1: Brazikumab IV Infusion intervention 2: Brazikumab SC Injection intervention 3: Placebo
Intervention descriptions: intervention 1: Brazikumab IV infusion as per protocol specified dosing schedule. intervention 2: Brazikumab IV infusion as per protocol specified dosing schedule. intervention 3: Placebo-matching Brazikumab IV infusion as per protocol specified dosing schedule.

Protocol documents:
Prot_SAP_000.pdf: 
 
NCT02574637 
 
Study ID: D5170C00002 
 
Title: Evaluation of Efficacy and Safety of MEDI2070 in Subjects With Active, Moderate to Severe 
Crohn’s Disease 
 
Protocol and Statistical Analysis Plan Date: 27‐Mar‐2018 


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A Phase 2b Double-blind, Multi-dose, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of MEDI2070 in Subjects with 
Moderate to Severe Crohn’s Disease Who Have Failed or Are 
Intolerant to Anti-tumor Necrosis Factor-alpha Therapy
Sponsor Protocol Number: D5170C00002
Application Number:
IND number: 111773
EudraCT number: 2015-000609-38
Investigational Product:
MEDI2070
Sponsor:
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca, Milstein Building, Granta Park, Cambridge, 
CB21 6GH, UK
AstraZeneca AB, SE-151 85 Sodertalje, Sweden
Medical Monitor:
Contract Research                Quintiles Inc                                                                                                         
Organization:
4820 Emperor Blvd                                                          
Durham, NC, USA 27703
Protocol History, Date:
Original Protocol, 06Aug2015
Protocol Amendment 1, 18Nov2015


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PROTOCOL SYNOPSIS
TITLE
A Phase 2b Double-blind, Multi-dose, Placebo-controlled Study to Evaluate the Efficacy and Safety of 
MEDI2070 in Subjects with Moderate to Severe Crohn’s Disease Who Have Failed or Are Intolerant to 
Anti-tumor Necrosis Factor-alpha Therapy
HYPOTHESES
Primary Hypothesis: Administration of MEDI2070 will result in reduced intestinal inflammation, which will 
translate into an improved clinical remission rate (as measured by the Crohn’s Disease Activity Index [CDAI]) 
compared with placebo in subjects with moderate to severe Crohn’s disease (CD) who have failed or are 
intolerant to anti-tumor necrosis factor-alpha (TNFα) therapy.
OBJECTIVES
Primary Objective
To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission based on the CDAI score at 
Week 8 in subjects with moderate to severe CD who have failed or are intolerant to anti-TNFα therapy.
Induction Period Secondary Objectives: 
1.
To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 16 based on the
Simple Endoscopic Score for Crohn’s Disease (SES-CD)
2.
To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 16 based on the
SES-CD
3.
To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 8 based on the
Patient-reported Outcomes 2 score (PRO2)
4.
To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 8 based on the PRO2
5.
To evaluate the efficacy of MEDI2070 versus placebo to induce clinical response at Week 8 based on the
CDAI
6.
To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 16 based on the PRO2
7.
To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 16 based on the PRO2
8.
To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission at Week 16 based on
the CDAI
9.
To evaluate the efficacy of MEDI2070 versus placebo to induce clinical response at Week 16 based on the
CDAI
10.
To demonstrate safety and tolerability of MEDI2070 therapy
11.
To characterize the pharmacokinetics (PK) and immunogenicity of MEDI2070
12.
To characterize the dose-response and exposure-response relationships
Maintenance Period Secondary Objectives: 
1.
To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission based on CDAI score at
Week 28
2.
To evaluate the efficacy of MEDI2070 versus placebo on remission at Week 28 based on the SES-CD
3.
To evaluate the efficacy of MEDI2070 versus placebo on remission at Week 28 based on the PRO2
4.
To evaluate the efficacy of MEDI2070 versus placebo on modified sustained remission, defined as
remission at both Week 16 and at Week 28 based on the SES-CD
5.
To evaluate the efficacy of MEDI2070 versus placebo on modified sustained remission, defined as
remission at both Week 8 and at Week 28 based on the PRO2
6.
To evaluate the efficacy of MEDI2070 versus placebo on modified sustained clinical remission, defined as
clinical remission at both Week 8 and at Week 28 based on the CDAI


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7.
To evaluate the efficacy of MEDI2070 versus placebo on response at Week 28 based on the SES-CD
8.
To evaluate the efficacy of MEDI2070 versus placebo on response at Week 28 based on the PRO2
9.
To evaluate the efficacy of MEDI2070 versus placebo on clinical response at Week 28 based on the CDAI
10.
To demonstrate safety and tolerability of MEDI2070 therapy
11.
To characterize the PK and immunogenicity of MEDI2070
 
 
STUDY ENDPOINTS]
Primary Endpoint
CDAI clinical remission (CDAI score < 150) at Week 8
Induction Period Secondary Endpoints:
•
SES-CD remission at Week 16 
•
SES-CD response at Week 16 
•
PRO2 remission at Week 8 
•
PRO2 response at Week 8 
•
CDAI clinical response at Week 8 
•
Abdominal pain remission at Week 8
•
Abdominal pain response at Week 8
•
Loose/liquid stool frequency remission at Week 8
•
Loose/liquid stool frequency response at Week 8
•
PRO2 remission at Week 16 
•
PRO2 response at Week 16 
•
CDAI clinical remission at Week 16
•
CDAI clinical response at Week 16 
•
Abdominal pain remission at Week 16
•
Abdominal pain response at Week 16
•
Loose/liquid stool frequency remission at Week 16
•
Loose/liquid stool frequency response at Week 16
 
 
•
Serum MEDI2070 concentration levels collected during the induction period 
•
Incidence of anti-drug antibodies (ADA) against MEDI2070
Maintenance Period Secondary Endpoints:


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•
CDAI clinical remission at Week 28
•
SES-CD Remission at Week 28
•
PRO2 Remission at Week 28
•
CDAI Modified sustained clinical remission at Weeks 8 and 28
•
CDAI clinical response at Week 28
•
SES-CD Response at Week 28 
•
PRO2 Response at Week 28 
•
Abdominal pain remission at Week 28
•
Abdominal pain response at Week 28
•
Loose/liquid stool frequency remission at Week 28
•
Loose/liquid stool frequency response at Week 28
•
Serum MEDI2070 concentration levels collected during the maintenance period 
•
Incidence of ADA against MEDI2070 
 
 
 
Induction and Maintenance Periods Safety Endpoints:
•
Incidence and severity of treatment-emergent adverse events (TEAEs)
•
Incidence of treatment-emergent serious AEs (TESAEs)
•
Incidence and severity of treatment-emergent adverse events of special interest (AESIs), including:
◦
Incidence and severity of infusion/injection-site reactions 
◦
Incidence and severity of hypersensitivity reactions
◦
Incidence of malignancies
◦
Major cardiac events, defined as myocardial infarction, stroke, or cardiovascular death
◦
Incidence and severity of ocular adverse events (AEs), including cataracts 
•
Incidence of AEs leading to investigational product discontinuation
•
Incidence of specific laboratory abnormalities


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STUDY DESIGN
This is a 3-part Phase 2b study comprising a 16-week, double-blind, placebo-controlled, induction period;
a 12-week, double-blind, placebo-controlled, maintenance period; and a 24-week, open-label period designed to 
evaluate the short-term efficacy and the short- and long-term safety of MEDI2070 in subjects with moderate to 
severe, active CD who have failed or are intolerant to anti-TNFα therapy as determined by the investigator. 
Subjects will be stratified based on the number of prior anti-TNFα agents that they have failed or not tolerated 
(1 vs > 1). 
Approximately 342 subjects at approximately 300 centers worldwide will be randomly assigned to 1 of 
5 treatment groups to receive intravenous (IV) and subcutaneous (SC) investigational product (MEDI2070 or 
placebo) once every 4 weeks (Q4W) during the double-blind, placebo-controlled, induction and maintenance 
periods. Subjects who complete the double-blind, placebo-controlled, maintenance period (Week 28) will have 
the option to enter a 24-week, open-label period in which they will receive open-label MEDI2070 (210 mg SC) 
Q4W (Weeks 28 through 48). All subjects will be followed for safety at 3 visits over 28 weeks (Weeks 60, 70, 
and 80 for subjects completing the open-label period) after their last dose of investigational product.
TARGET SUBJECT POPULATION
The subjects in this study will be 18 to 80 years of age, inclusive, with moderate to severe, active CD who, as 
determined by the investigator, have failed or are intolerant to anti-TNFα therapy. This includes subjects who 
have received an anti-TNFα agent at a dose approved for the treatment of CD and did not respond initially 
(ie, primary non-response), or responded initially but then lost response with continued therapy (ie, secondary 
non-response), or were intolerant to the medication.
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION
Subjects will receive investigational product (MEDI2070 or placebo) by IV infusion and/or SC injection at 
Week 0 (Day 1) then once Q4W during the 16-week, double-blind, placebo-controlled, induction period 
(ie, Weeks 4, 8, and 12) and the 12-week, double-blind, placebo-controlled, maintenance period (ie, Weeks 16, 
20, and 24). All subjects who complete the double-blind, maintenance period will have the option to enter the 
24-week, open-label period. All subjects entering the open-label period will receive open-label MEDI2070 
(210 mg SC) once Q4W (ie, Weeks 28, 32, 36, 40, 44, and 48). 
A total of approximately 342 subjects will be randomly assigned to 1 of 5 treatment groups:
Treatment    
Group
Double-blind Period
Open-label 
Period
Induction
Maintenance
Week 0
Week 4
Weeks 8 and 
12
Weeks 16, 20, 
and 24
Weeks 28, 32, 
36, 40, 44, and 
48
1 - High                  
(n = 76)
700 mg 
MEDI2070 IV 
+ placebo SC
700 mg 
MEDI2070 IV 
+ placebo SC
210 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
210 mg       
MEDI2070 SC
2 - High-medium 
(n = 76)
280 mg 
MEDI2070 IV 
+ placebo SC 
210 mg 
MEDI2070 SC 
+ placebo IV 
210 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
210 mg         
MEDI2070 SC
3 - Low-medium 
(n = 76)
210 mg 
MEDI2070 SC 
+ placebo IV 
105 mg 
MEDI2070 SC 
+ placebo IV 
105 mg 
MEDI2070 SC
105 mg 
MEDI2070 SC
210 mg         
MEDI2070 SC
4 - Low                    
(n = 38)
70 mg       
MEDI2070 SC 
+ placebo IV 
35 mg 
MEDI2070 SC 
+ placebo IV 
35 mg 
MEDI2070 SC
35 mg 
MEDI2070 SC
210 mg         
MEDI2070 SC
5 - Placebo  
(n = 76)
Placebo SC 
and IV
Placebo SC 
and IV
Placebo SC
Placebo SC
210 mg         
MEDI2070 SC


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STATISTICAL ANALYSIS PLAN  
Sample size:  
With a total sample size of approximately 342 and a randomization ratio of 2:1:2:2:2, the sample sizes are 76, 
38, 76, 76, and 76 for placebo and MEDI2070 low, low-medium, high-medium, and high dose groups, 
respectively. A 10% dropout rate is assumed for each treatment group during the induction period.
Assuming a placebo CDAI remission rate of 12% and MEDI2070 high dose CDAI clinical remission rate of 
31% at Week 8 of the induction period, approximately 76 subjects per treatment group will provide at least 85% 
power to detect a 19% difference in CDAI clinical remission rates at Week 8 between MEDI2070 high dose 
versus placebo, using a two-sided test at a significance level of α = 0.10. The minimum detectable difference in 
CDAI clinical remission rates at Week 8 will be 11%. 
Assuming a 5% placebo SES-CD remission rate and 20% MEDI2070 high dose SES-CD remission rate at 
Week 16 of the induction period, the given sample size will provide at least 81% power to detect a 
15% difference in SES-CD remission rates at Week 16 between MEDI2070 high dose versus placebo using a 
two-sided test at a significance level of α = 0.10. The minimum detectable difference in SES-CD remission rates 
at Week 16 will be 10%.  
In addition, recent data suggest that subjects with elevated baseline levels of serum IL-22 may have enhanced 
treatment response to MEDI2070 therapy. The power is also estimated for CDAI clinical remission at Week 8 
in the high-IL-22 subpopulation. Assuming approximately 50% of subjects have elevated baseline levels of 
serum IL-22, and assuming these subjects are approximately equally distributed between treatment groups,
there will be 38 high-IL-22 subjects in the MEDI2070 high dose and placebo groups, respectively. Assuming a 
placebo CDAI clinical remission rate of 15% and MEDI2070 high dose CDAI clinical remission rate of 42% at 
Week 8 of the induction period, 38 subjects per treatment group will provide at least 80% power to detect a 
difference of 27% between the MEDI2070 high dose group and placebo within the high-IL-22 subpopulation, 
using a two-sided test at a significance level of α = 0.10. The minimum detectable difference in CDAI clinical 
remission rates at Week 8 within high-IL-22 subpopulation will be 17%.  
Statistical analyses:  
The primary analysis will be conducted in ITT population. The primary efficacy endpoint is CDAI clinical 
remission at Week 8 of the induction period. The primary comparison of interest will be MEDI2070 high dose 
group versus placebo. The comparisons between MEDI2070 high-medium dose versus placebo, low-medium 
dose versus placebo, and MEDI2070 low dose versus placebo will also be conducted.  
For the primary efficacy endpoint and other dichotomous endpoints, difference in response rates between 
MEDI2070 dose groups and placebo group and associated 90% confidence interval will be provided. P-values 
for comparisons between any MEDI2070 dose groups and placebo will be obtained from a logistic regression 
model adjusting for prior anti-TNFα use (1 vs > 1). In the event the number of responses is too small (ie, < 5), 
exact logistic regression will be performed instead. The statistically significant treatment effect will be tested 
against two-sided alpha level of 0.10. A sensitivity analysis will be performed by extending the logistic 
regression model planned above via adjusting for baseline CDAI score and/or other baseline covariates for 
subjects in the ITT population. In addition, a stratified Cochran Mantel Haenszel test or a stratified exact test 
may be performed in the event of small number of responses. Further, the subgroup analysis will be conducted 
for primary and key secondary endpoints to verify the treatment effect in pre-specified individual strata.
Missing data for dichotomous endpoints will be handled using the non-responder imputation method through 
the end of the placebo-controlled, double-blind period.
For continuous endpoints, comparisons between any MEDI2070 dose groups and placebo will be performed 
using a mixed-effects repeated-measures model adjusting for prior anti-TNFα use (1 vs > 1) assuming missing 
at random mechanism. Other methods to handle the missing data may be explored. The details will be described 
in the Statistical Analysis Plan (SAP).
The dose-response trend for the induction period will be tested. The details will be described in the SAP.  
Interim analysis:    
An interim analysis may be conducted when at least 75% of the total planned number of subjects has completed 
the Week 16 visit or withdrawn prior to the Week 16 visit. This analysis would evaluate primary and secondary 
endpoints through Week 16. Since this is a Phase 2b study, the interim analysis is intended to assist internal 
decision making and does not include a possibility to stop for efficacy or futility. Thus, there is no alpha level
adjustment for the final analysis. To ensure the blinding of each subject’s treatment assignment throughout the 


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placebo-controlled, double-blind, maintenance period, the interim analysis will be performed by a limited 
number of sponsor personnel who are not involved in the conduct of the study. Study site personnel and sponsor 
personnel who are associated directly with the conduct of this study and study subjects will remain blinded to 
the subject-specific treatment assignment as well as the outcomes of the interim analysis until the completion of 
the double-blind, maintenance period. 
The primary analysis will be performed when all subjects complete the initial 16-week, induction period. A 
further analysis is planned when all subjects complete the 28-week, randomized, placebo-controlled, 
double-blind period. All data available by the time of the primary analysis database snapshot will be included in 
the analysis, including available data through Week 28 and the open-label period for a certain proportion of 
subjects. The final analysis for the study, including all study periods and all data, will be performed at the end 
of the study. 
A Data Monitoring Committee will review safety data on a regular basis until the last subject completes 
Week 28.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ..........................................................................................................2
LIST OF ABBREVIATIONS..................................................................................................14
1
INTRODUCTION.........................................................................................................16
1.1
Disease Background ...........................................................................................16
1.3
Summary of Nonclinical Experience..................................................................17
1.4
Summary of Clinical Experience........................................................................18
1.5
Rationale for Conducting the Study ...................................................................19
1.5.1Benefit-risk Assessment .............................................................................20
1.6
Research Hypotheses ..........................................................................................21
1.6.1Primary Hypothesis.....................................................................................21
1.6.2Secondary Hypotheses................................................................................21
2
OBJECTIVES ...............................................................................................................21
2.1
Objectives ...........................................................................................................21
2.1.1Primary Objective.......................................................................................21
2.1.2Secondary Objectives .................................................................................21
2.1.2.1
Induction Period........................................................................21
2.1.2.2
Maintenance Period ..................................................................22
2.2
Study Endpoints..................................................................................................23
2.2.1Primary Endpoint........................................................................................24
2.2.2Secondary Endpoint(s)................................................................................24
2.2.2.1
Induction Period........................................................................24
2.2.2.2
Maintenance Period ..................................................................24
2.2.4Safety Endpoints.........................................................................................26
3
STUDY DESIGN..........................................................................................................26
3.1
Description of the Study .....................................................................................26
3.1.1Overview……….........................................................................................26
3.1.2Treatment Regimen.....................................................................................29
3.1.3Management of Investigational Product Related Toxicities.......................29
3.2
Study Design and Dose Rationale ......................................................................29


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3.2.1Dose Rationale............................................................................................29
3.2.2Rationale for Study Population...................................................................30
3.2.3Rationale for Endpoints ..............................................................................31
4
MATERIALS AND METHODS..................................................................................31
4.1
Subjects...............................................................................................................31
4.1.1Number of Subjects ....................................................................................31
4.1.2Inclusion Criteria ........................................................................................31
4.1.3Exclusion Criteria .......................................................................................34
4.1.4Subject Enrollment and Randomization .....................................................36
4.1.5Withdrawal from the Study.........................................................................37
4.1.6Discontinuation of Investigational Product ................................................37
4.1.7Replacement of Subjects.............................................................................38
4.1.8Withdrawal of Informed Consent for Data and Biological Samples..........38
4.2
4.3
Description of Study Procedures ........................................................................49
4.3.1Efficacy………...........................................................................................49
4.3.1.1
Crohn’s Disease Activity Index................................................49
 
4.3.3Medical History, Physical Examination, Vital Signs, and 
Electrocardiogram.....................................................................55
4.3.3.1
Medical, Surgical, and Crohn’s Disease History......................55
4.3.3.2
Chest X-ray...............................................................................55
4.3.3.3
Physical and Neurological Examinations .................................55
4.3.3.4
Visual Acuity Tests and Ophthalmoscopy Examination ..........56
4.3.3.5
Vital Signs.................................................................................56


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4.3.7Biomarker Evaluation and Methods ...........................................................59
4.3.7.1
Blood Biomarker Evaluation ....................................................59
4.3.7.2
Stool Analysis of Fecal Calprotectin and Microbiome.............60
4.3.8Pharmacogenomics.....................................................................................60
4.4
Study Suspension or Termination.......................................................................61
4.5
4.5.1.7
Reporting Product Complaints..................................................70
4.5.2Additional Study Medications ....................................................................71
4.5.4Storage………. ...........................................................................................71
4.5.5Treatment Compliance................................................................................71
4.5.6Accountability.............................................................................................71
4.6
Treatment Assignment and Blinding..................................................................72
4.6.1Methods for Assigning Treatment Groups .................................................72
4.6.2Methods for Ensuring Blinding ..................................................................73
4.6.3Methods for Unblinding..............................................................................73
4.6.3.1
Unblinding in the Event of a Medical Emergency ...................73
4.6.3.2
Unblinding for Planned Analysis Purposes ..............................73
4.7
Restrictions During the Study and Concomitant Treatment(s)...........................74
4.7.1Permitted Concomitant Medications ..........................................................74
4.7.2Prohibited Concomitant Medications .........................................................75
4.8
Statistical Evaluation ..........................................................................................76
4.8.1General Considerations...............................................................................76
4.8.2Sample Size and Power Calculation...........................................................77
4.8.3Analysis Populations...................................................................................78
4.8.3.1
Intent to Treat Population .........................................................78
4.8.3.2
As-treated Population ...............................................................78
4.8.3.3
Pharmacokinetics Population....................................................78


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4.8.3.4
Open-label Population ..............................................................78
4.8.4Efficacy………...........................................................................................79
4.8.4.1
Primary Efficacy Analysis........................................................79
4.8.4.2
Additional Analyses of the Primary Endpoint..........................79
4.8.4.3
Secondary Efficacy Analyses ...................................................80
4.8.5Safety………. .............................................................................................83
4.8.5.1
Analysis of Adverse Events......................................................83
4.8.5.2
Analysis of Clinical Laboratory, Vital Sign, and ECG 
Parameters..................................................................84
4.8.6Patient-reported Outcomes .........................................................................85
4.8.7Analysis of Immunogenicity/Pharmacokinetics .........................................85
4.8.8Additional Analyses....................................................................................85
4.8.9Data Monitoring Committee.......................................................................86
5
ASSESSMENT OF SAFETY .......................................................................................87
5.1
Definition of Adverse Events .............................................................................87
5.2
Definition of Serious Adverse Events ................................................................88
5.3
Definition of Adverse Events of Special Interest ...............................................88
5.3.1Hepatic Function Abnormality (Hy’s Law)................................................89
5.3.2Infusion Reactions ......................................................................................89
5.3.3Other Adverse Events of Special Interest...................................................89
5.4
Recording of Adverse Events .............................................................................89
5.4.1Time Period for Collection of Adverse Events...........................................90
5.4.2Follow-up of Unresolved Adverse Events..................................................90
5.4.3Recording of Adverse Events of Special Interest.......................................90
5.4.3.1
Infusion-related Reactions ........................................................90
5.4.3.2
Other Adverse Events of Special Interest.................................90
5.5
Reporting of Serious Adverse Events.................................................................90
5.6
Other Events Requiring Immediate Reporting ...................................................91
5.6.1Overdose……….........................................................................................91
5.6.2Hepatic Function Abnormality ...................................................................92
5.6.3Other Adverse Events of Special Interest...................................................92
5.6.4Pregnancy………........................................................................................92
5.6.4.1
Maternal exposure.....................................................................92
5.6.4.2
Paternal exposure......................................................................93
6
STUDY AND DATA MANAGEMENT......................................................................93


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6.1
Training of Study Site Personnel........................................................................93
6.2
Monitoring of the Study......................................................................................94
6.2.1Source Data.................................................................................................94
6.2.2Study Agreements.......................................................................................94
6.2.3Archiving of Study Documents ..................................................................95
6.3
Study Timetable and End of Study.....................................................................95
6.3.1Subject Completion.....................................................................................95
6.3.2Site Completion ..........................................................................................95
6.3.3End of Study ...............................................................................................95
6.4
Data Management...............................................................................................95
6.5
Medical Monitor Coverage.................................................................................96
7
ETHICAL AND REGULATORY REQUIREMENTS ................................................96
7.1
Ethical Conduct of the Study..............................................................................96
7.2
Subject Data Protection ......................................................................................96
7.3
Ethics and Regulatory Review............................................................................97
7.4
Informed Consent ...............................................................................................98
7.5
Changes to the Protocol and Informed Consent Form........................................98
7.6
Audits and Inspections........................................................................................99
9
CHANGES TO THE PROTOCOL.............................................................................103
9.1
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LIST OF IN-TEXT TABLES
 
 
LIST OF IN-TEXT FIGURES


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ADA
anti-drug antibody(ies)
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the serum concentration-time curve
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
Cmax
maximum concentration
CRP
C-reactive protein
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture
e-diary
electronic diary
EU
European Union
GCP
Good Clinical Practice
GI
gastrointestinal
GMP
Good Manufacturing Practice
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
IBD
inflammatory bowel disease
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFNγ
interferon-gamma
IgG2
immunoglobulin G2
IL
interleukin
IL-23R
interleukin-23 receptor 
IRB
Institutional Review Board
ITT
Intent to Treat
IV
intravenous(ly)
IVRS/IWRS
interactive voice/web response system


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Abbreviation or 
Specialized Term
Definition
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MS
multiple sclerosis
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
V4.03
NK
natural killer
PE
polyethylene
PGIC-IBD
Patient Global Impression of Change-Inflammatory Bowel Disease
PK
pharmacokinetic(s)
PPD
purified protein derivative
PRO
patient-reported outcome
PRO2
Patient-Reported Outcomes-2 score
PVC
polyvinyl chloride
Q4W
every 4 weeks
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous(ly)
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SID
subject identification 
SRT
Safety Review Team
SUSAR
suspected unexpected serious adverse reaction 
TB
tuberculosis
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TNFα
tumor necrosis factor-alpha
ULN
upper limit of normal
USA
United States of America
w/v
weight per volume


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1
INTRODUCTION
1.1
Disease Background
Crohn’s disease (CD) is a chronic transmural inflammatory disease of unknown etiology that 
most commonly affects the distal ileum and colon, and may occur in any part of the 
gastrointestinal (GI) tract. CD occurs most commonly between the ages of 15 and 35 years, 
although patients of any age may be affected. Patients with CD have uncontrolled 
inflammation that causes direct or collateral damage to the intestinal mucosa. The leading 
current hypothesis is that, in genetically predisposed individuals, this inflammation can result 
either from persistence of inflammatory stimulus, due to impaired gut barrier function, or 
from a dysregulated inflammatory response (Sandborn et al, 2008; Rutgeerts et al, 2003). 
Clinical signs and symptoms include chronic diarrhea, abdominal pain, cachexia, abdominal 
mass, or tenderness, as well as the overt signs of fistulae. The disease course is variable; 
patients can experience a severe initial flare followed by few symptoms over the next 
10 years (43%) or symptoms that are chronic and persistent (19%) or relapsing remitting 
(32%; Baumgart and Sandborn, 2012).
Commonly used medical therapies include aminosalicylates (including sulfasalazine and 
mesalamine), systemic corticosteroids, immunosuppressive agents (eg, azathioprine and 
methotrexate), antibacterial agents, and biologic agents (eg, adalimumab, infliximab, 
certolizumab, and vedolizumab). Despite the availability of these medical therapies, the 
remaining morbidity and the complications of CD (eg, intestinal obstruction and or 
perforation, fistula formation, malnutrition) continue to warrant new therapies.
Interleukin (IL)-23, a member of the IL-12 family of cytokines, is a heterodimeric cytokine 
consisting of 2 subunits: p40 and p19. The p40 subunit is shared by IL-12 and IL-23 as a 
common subunit, and is targeted by inhibitors of IL-12/23 (eg, ustekinumab and 
briakinumab). The main known effects of IL-23 are to drive the differentiation of 
T-helper 17 cells, as well as macrophages, natural killer (NK) cells, dendritic cells, and 
innate lymphoid cells leading to up-regulation of IL-17, IL-22, tumor necrosis factor-alpha 
(TNFα), granulocyte-macrophage colony-stimulating factor, and interferon-gamma (IFNγ), 
and down-regulation of IL-10 (Eken et al, 2014).
Studies in patients have demonstrated that IL-23 is upregulated in cells and target tissues of 
CD and ulcerative colitis, while IL-12 is not (Schmidt et al, 2005). Similar observations have 
been reported in psoriatic lesion skin (Lee et al, 2004), dendritic cells from patients with 
multiple sclerosis (MS; Vaknin-Dembinsky et al, 2006), and active lesions from patients with 
MS (Li et al, 2007). Genome-wide association studies in CD and psoriasis patients showed 


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significant association between polymorphisms in the unique IL-23 receptor (IL-23R) 
component and disease (Cargill et al, 2007; Duerr et al, 2006). Furthermore, allelic variants 
of IL-23R have shown significant correlation with the frequency of ulcerative colitis 
(Cargill et al, 2007), rheumatoid arthritis (Farago et al, 2008), ankylosing spondylitis 
(Burton et al, 2007), and MS (Illes et al, 2008).
In the clinic, anti-IL-12/23p40 antibodies (eg, ustekinumab and briakinumab) have been 
shown to induce clinical responses in CD (Phase 2 studies; Toedter et al, 2009; 
Sandborn et al, 2008; Mannon et al, 2004) and psoriasis (Phase 2 and Phase 3 studies; 
Gordon et al, 2012; Kimball et al, 2012; Langley et al, 2012; Gottlieb et al, 2011; 
Reich et al, 2011; Strober et al, 2011; Leonardi et al, 2008; Papp et al, 2008). Phase 1 and 
Phase 2 clinical studies with anti-IL-23 antibodies MEDI2070 (Amgen Study 20080767) and 
CNTO 1959 (Sofen et al, 2011) in subjects with psoriasis have demonstrated clinical efficacy 
comparable with antibodies targeting both IL-12 and IL-23, indicating that therapeutic effects 
of the anti-IL-12/23p40 antibodies may be due to neutralization of IL-23 alone.
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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Refer to the current version of the Investigator’s Brochure for details.
1.5
Rationale for Conducting the Study
CD is a chronic, relapsing-remitting, inflammatory disease of the GI tract. Some patients may 
have persistent clinically active disease. The current treatment options for patients with 
moderate to severe CD, refractory to standard therapies that include 5-aminosalicylates, 
glucocorticosteroids, 6-mercaptopurine, azathioprine, methotrexate, anti-TNFα mAbs, and 
vedolizumab are limited. MEDI2070 is being developed as a treatment for CD to reduce 


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intestinal inflammation and improve signs and symptoms. Study CD-IA-MEDI2070-1147 
demonstrated improved clinical responses and remission rates as measured by CDAI. This 
study, D5170C00002, seeks to confirm those observations, and to extend them to include 
assessments of clinical responses as demonstrated by improvement of symptoms and of 
colonic mucosal appearance as observed on endoscopy.
1.5.1
Benefit-risk Assessment
Results from previous clinical studies have provided safety and tolerability data for 
MEDI2070 and shown significantly greater efficacy for MEDI2070 compared with placebo 
for achieving CDAI response, CDAI 100-point improvement, and decreases in C-reactive 
protein (CRP) and fecal calprotectin (Study CD-IA-MEDI2070-1147). No safety risk of 
MEDI2070 was identified. In Study CD-IA-MEDI2070-1147, TEAEs, TEAEs of ≥ Grade 3 
severity, TESAEs and TEAEs leading to discontinuation of investigational product occurred 
in equivalent numbers of subjects in the placebo and MEDI2070 groups. TEAEs related to 
investigational product and adverse events of special interest (AESIs), including infections, 
were more common in the placebo group. The combination of observed efficacy and 
apparent safety in the Phase 2a study (CD-IA-MEDI2070-1147) suggests an acceptable 
benefit-risk balance to justify exposing approximately 5-fold more subjects with moderate to 
severe CD to the range of doses planned in this study.
Although no safety risks for MEDI2070 have been identified, the immunoregulatory role of 
IL-23 in humans is not completely understood. Potential risks include infections, 
malignancies, complications associated with vaccination, infusion reactions, injection-site 
reactions, hypersensitivity, immune complex disease, and neurological and visual toxicities. 
Subjects will be closely monitored during the study with regular full blood analysis including 
differential white cell count and serum chemistry to monitor the risk of infection. Visual 
acuity tests, ophthalmoscopy, and complete physical and neurologic examinations will be 
performed at screening and during the study. In addition, live/attenuated vaccinations will not 
be permitted during the study. Exclusion criteria have been formulated to ensure that subjects 
at increased potential risk due to the mechanism of action of MEDI2070 are not enrolled in 
the study.
In addition, an independent Data Monitoring Committee (DMC) will monitor and protect the 
safety of the subjects through review of safety data on a regular basis throughout the 
double-blind period of the study; ie, until the last subject completes Week 28 (see Section 
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1.6
Research Hypotheses
1.6.1
Primary Hypothesis
Administration of MEDI2070 will result in reduced intestinal inflammation, which will 
translate into an improved clinical remission rate (as measured by the CDAI) compared with 
placebo in subjects with moderate to severe CD who have failed or are intolerant to 
anti-TNFα therapy.
1.6.2
Secondary Hypotheses
1.
Administration of MEDI2070 will result in reduced intestinal inflammation, which will 
translate into an improved appearance of the colonic and ileal mucosa (as measured by 
the Simple Endoscopic Score for Crohn’s Disease [SES-CD]) compared with placebo in 
subjects with moderate to severe CD who have failed or are intolerant to anti-TNFα 
therapy.
2.
Administration of MEDI2070 will result in reduced intestinal inflammation, which will 
translate into an improved clinical remission rate (as measured by the Patient-Reported 
Outcomes-2 score [PRO2] and its individual components) compared with placebo in 
subjects with moderate to severe CD who have failed or are intolerant to anti-TNFα 
therapy.
3.
 
 
2
OBJECTIVES
2.1
Objectives
2.1.1
Primary Objective
The primary objective of the study is to evaluate the efficacy of MEDI2070 versus placebo to 
induce clinical remission based on the CDAI score at Week 8 in subjects with moderate to 
severe CD who have failed or are intolerant to anti-TNFα therapy.
2.1.2
Secondary Objectives
2.1.2.1
Induction Period
1. To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 16 
based on the SES-CD 
2. To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 16 
based on the SES-CD
3. To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 8 
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4. To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 8 
based on the PRO2 
5. To evaluate the efficacy of MEDI2070 versus placebo to induce clinical response at 
Week 8 based on the CDAI 
6. To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 16 
based on the PRO2
7. To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 16 
based on the PRO2
8. To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission at 
Week 16 based on the CDAI 
9. To evaluate the efficacy of MEDI2070 versus placebo to induce clinical response at 
Week 16 based on the CDAI
10. To demonstrate safety and tolerability of MEDI2070 therapy
11. To characterize the PK and immunogenicity of MEDI2070
12. To characterize the dose-response and exposure-response relationships
 
2.1.2.2
Maintenance Period
1. To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission based 
on CDAI score at Week 28 
2. To evaluate the efficacy of MEDI2070 versus placebo on remission at Week 28 based on 
the SES-CD
3. To evaluate the efficacy of MEDI2070 versus placebo on remission at Week 28 based on 
the PRO2 
4. To evaluate the efficacy of MEDI2070 versus placebo on modified sustained remission, 
defined as remission at both Week 16 and at Week 28 based on the SES-CD
5. To evaluate the efficacy of MEDI2070 versus placebo on modified sustained remission, 
defined as remission at both Week 8 and at Week 28 based on the PRO2
6. To evaluate the efficacy of MEDI2070 versus placebo on modified sustained clinical 
remission, defined as clinical remission at both Weeks 8 and 28 based on the CDAI
7. To evaluate the efficacy of MEDI2070 versus placebo on response at Week 28 based on 
the SES-CD
8. To evaluate the efficacy of MEDI2070 versus placebo on response at Week 28 based on 
the PRO2
9. To evaluate the efficacy of MEDI2070 versus placebo on clinical response at Week 28 
based on the CDAI
10. To demonstrate safety and tolerability of MEDI2070 therapy
11. To characterize the PK and immunogenicity of MEDI2070
12.
 


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2.2
Study Endpoints
Remission and response will be assessed by both clinical and PRO measures. The following 
definitions will be used:
•
CDAI clinical remission: CDAI score of < 150
•
CDAI clinical response: Decrease from baseline in the CDAI of ≥ 100 points
•
SES-CD remission: Total SES-CD score ≤ 4, with:
◦
No subscore > 2, and
◦
Segments scored at baseline that cannot be observed on a subsequent examination 
will be scored with an imputed value unchanged from baseline 
•
SES-CD response: Decrease from baseline in SES-CD ≥ 50%; segments scored at 
baseline that cannot be observed on a subsequent examination will be scored with an 
imputed value unchanged from baseline. 
•
PRO2 remission (loose/liquid stool frequency/abdominal pain): Remission achieved for 
both abdominal pain and loose/liquid stool frequency
•
PRO2 response: (loose/liquid stool frequency/abdominal pain): Remission or response in 
one symptom (either abdominal pain or stool frequency) plus response in the other
◦
Abdominal pain remission: On an 11-point (0 to 10) pain scale: During 1 week, no 
daily score > 2
◦
Abdominal pain response: On an 11-point (0 to 10) pain scale: ≥ 30% reduction in 
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◦
Loose/liquid stool frequency remission: Counting stools identified as Type 6 or 7 on 
Bristol Stool Scale, during 1 week, each daily loose loose/liquid stool count ≤ 3
◦
Loose/liquid stool frequency response: Counting stools identified as Type 6 or 7 on 
Bristol Stool Scale, ≥ 30% reduction in weekly loose/liquid stool count compared to 
baseline
2.2.1
Primary Endpoint
The primary endpoint is CDAI clinical remission (CDAI score < 150) at Week 8.
2.2.2
Secondary Endpoint(s)
2.2.2.1
Induction Period
1. SES-CD remission at Week 16 
2. SES-CD response at Week 16 
3. PRO2 remission at Week 8 
4. PRO2 response at Week 8 
5. CDAI clinical response at Week 8 
6. Abdominal pain remission at Week 8
7. Abdominal pain response at Week 8
8. Loose/liquid stool frequency remission at Week 8
9. Loose/liquid stool frequency response at Week 8
10. PRO2 remission at Week 16 
11. PRO2 response at Week 16 
12. CDAI clinical remission at Week 16 
13. CDAI clinical response at Week 16
14. Abdominal pain remission at Week 16
15. Abdominal pain response at Week 16
16. Loose/liquid stool frequency remission at Week 16
17. Loose/liquid stool frequency response at Week 16
 
 
20. Serum MEDI2070 concentration levels collected during the induction period 
21. Incidence of ADA against MEDI2070 
2.2.2.2
Maintenance Period
1. CDAI clinical remission at Week 28
2. SES-CD remission at Week 28


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3. PRO2 remission at Week 28
4. CDAI Modified sustained clinical remission at Week 8 and Week 28
7. CDAI clinical response at Week 28
8. SES-CD response at Week 28 
9. PRO2 response at Week 28 
10. Abdominal pain remission at Week 28
11. Abdominal pain response at Week 28
12. Loose/liquid stool frequency remission at Week 28
13. Loose/liquid stool frequency response at Week 28
14. Serum MEDI2070 concentration levels collected during the maintenance period 
15. Incidence of ADA against MEDI2070 


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2.2.4
Safety Endpoints
1. Incidence and severity of TEAEs
2. Incidence of TESAEs
3. Incidence and severity of treatment-emergent AESIs, including:
a.
Incidence and severity of infusion/injection-site reactions 
b. Incidence and severity of hypersensitivity reactions
c.
Incidence of malignancies
d. Major cardiac events, defined as myocardial infarction, stroke, or cardiovascular 
death
e.
Incidence and severity of ocular AEs, including cataracts
4.
Incidence of AEs leading to investigational product discontinuation
5.
Incidence of specific laboratory abnormalities
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview……….
This is a 3-part Phase 2b study (Figure 3.1.1-1) comprising a 16-week, double-blind, 
placebo-controlled, induction period; a 12-week, double-blind, placebo-controlled, 
maintenance period; and a 24-week, open-label period designed to evaluate the short-term 
efficacy and the short- and long-term safety of MEDI2070 in subjects with moderate to 
severe, active CD who have failed or are intolerant to anti-TNFα therapy as determined by 
the investigator. Subjects will be stratified based on the number of prior anti-TNFα agents 
that failed or were not tolerated (1 vs > 1). 
Approximately 342 subjects at approximately 300 centers worldwide will be randomly 
assigned to 1 of 5 treatment groups to receive IV and SC investigational product (MEDI2070 
or placebo) once Q4W during the double-blind, placebo-controlled, induction and 
maintenance periods. Subjects who complete the double-blind, placebo-controlled,
maintenance period (Week 28) will have the option to enter a 24-week, open-label period in 
which they will receive open-label MEDI2070 (210 mg SC) Q4W (Weeks 28 through 48).  
All subjects will be followed for safety at 3 visits over 28 weeks (Weeks 60, 70, and 80 for 
subjects completing the open-label period) after their last dose of investigational product.  
An interim analysis may be conducted when at least 75% of the total planned number of 
subjects has completed the Week 16 Visit or withdrawn prior to the Week 16 Visit. The 
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this study and the study subjects would remain blinded to the subject-specific treatment 
assignment as well as the results of this analysis until the completion of the double-blind,
maintenance period. No changes to the conduct of this study or data analysis are planned
based on the interim analysis.
The primary analysis will be performed when all subjects complete the initial 16-week,
induction period. A further analysis is planned when all subjects complete the 28-week,
randomized, placebo-controlled, double-blind period. The final analysis, including all study 
periods and all data, will be performed at the end of the study. 


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Subjects will be randomized to 1 of 5 treatment groups using a 
 formulation of 
MEDI2070 (Table 3.1.2-1).
Table 3.1.2-1
Treatment Regimen
Treatment 
Group
Double-blind Period
Open-label 
Period
Induction
Maintenance
Week 0
Week 4
Weeks 8 and 
12
Weeks 16, 20, 
and 24
Weeks 28, 32, 
36, 40, 44, and 
48
1 - High                  
(n = 76)
700 mg 
MEDI2070 IV 
+ placebo SC
700 mg 
MEDI2070 IV 
+ placebo SC
210 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
210 mg       
MEDI2070 SC
2 - High-medium 
(n = 76)
280 mg 
MEDI2070 IV 
+ placebo SC 
210 mg 
MEDI2070 SC 
+ placebo IV 
210 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
210 mg          
MEDI2070 SC
3 - Low-medium 
(n = 76)
210 mg 
MEDI2070 SC 
+ placebo IV 
105 mg 
MEDI2070 SC 
+ placebo IV 
105 mg 
MEDI2070 SC
105 mg 
MEDI2070 SC
210 mg          
MEDI2070 SC
4 - Low                   
(n = 38)
70 mg       
MEDI2070 SC 
+ placebo IV 
35 mg 
MEDI2070 SC 
+ placebo IV 
35 mg 
MEDI2070 SC
35 mg 
MEDI2070 SC
210 mg          
MEDI2070 SC
5 - Placebo 
(n = 76)
Placebo SC 
and IV
Placebo SC 
and IV
Placebo SC
Placebo SC
210 mg          
MEDI2070 SC
IV = intravenous; SC = subcutaneous
3.1.3
Management of Investigational Product Related Toxicities
MEDI2070 has no identified toxicities. There is no provision for dose reduction or increase. 
No antidotes or other treatments to directly reverse the effect of MEDI2070 are available. In 
the event of suspected toxicity, supportive medical care should be provided, in close 
consultation with the sponsor’s medical monitor/study physician.
3.2
Study Design and Dose Rationale
 
 
 
 


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3.2.2
Rationale for Study Population
Subjects in this study will be 18 to 80 years of age, inclusive, with moderate to severe, active 
CD who, as determined by the investigator, have failed or are intolerant to anti-TNFα agents. 
This includes subjects who have received an anti-TNFα agent at a dose approved for the 
treatment of CD and did not respond initially (ie, primary non-response), or responded 
initially but then lost response with continued therapy (ie, secondary non-response), or were 
intolerant to the medication. This subject population was selected as it is anticipated that this 
will be the target population for treatment with an anti-IL-23 antibody. In the Phase 2a study 
(CD-IA-MEDI2070-1147), MEDI2070 demonstrated efficacy, without an identified safety 
risk, in a population of 18 to 65 years of age with moderate to severe, active CD. This study 
seeks to confirm and expand upon those observations, and to extend them into an older 
population 66 to 80 years of age. Most currently available treatments for moderate to severe 
CD, including glucocorticosteroids, immunomodulators, and anti-TNFα agents are associated 
with significant adverse effects. The mechanism of action of MEDI2070, and the results of 
the Phase 2a study in subjects with CD, suggests that MEDI2070 has the potential to offer 
effective treatment in the elderly with a reduced risk of adverse effects.


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3.2.3
Rationale for Endpoints
The primary and some of the secondary endpoints chosen have been extensively used in 
previous CD development programs and are considered suitable to demonstrate the beneficial 
effects of MEDI2070 in the subject population. The CDAI measures the severity of active 
disease using symptom scores that are monitored over the prior week and defines response or 
remission of CD, and has been the acceptable regulatory endpoint for evaluating treatment 
efficacy in CD.
Other secondary endpoints include measures of efficacy in CD, which together with the 
safety and tolerability of MEDI2070 will be critical in establishing its potential clinical utility 
as a CD treatment, and may have relevance as acceptable regulatory endpoints in the near 
future.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Approximately 342 subjects at approximately 300 centers worldwide will be randomized for 
this study.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Age 18 to 80 years, inclusive, at the time of screening
 
 
 
5. Moderate to severely active CD, as defined by:
a.
CDAI score
 AND
b. Evidence of active intestinal mucosal inflammation,
 
 
 


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7. Prior treatment with at least one anti-TNFα agent at a dose approved for the treatment of 
CD with failure to respond initially (ie, primary non-response), or initial response 
followed by loss of response with continued therapy (ie, secondary non-response
 
 
 
 
 
 
 
8.
Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use at least one highly effective method of contraception from screening, 
and must agree to continue using such precautions
 
 
 


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9.
Nonsterilized males who are sexually active with a female partner of childbearing 
potential must use condom and spermicide
 
 
 
 
 
. 
10. Subjects have no known history of active tuberculosis (TB)
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ii. Documented history of a completed course of adequate prophylaxis for latent TB 
(per local standard of care) 
 
 
 
 
 
 
 
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
 
 
 
3. A clinical manifestation of short bowel syndrome (defined as requiring oral or parenteral 
supplemental or total nutrition in order to maintain stable body weight)
 
6. A stricture with obstructive symptoms within 3 months prior to Day 1
7. Bowel surgery within 12 weeks prior to Day 1, or has planned bowel surgery within 
24 weeks from Day 1
8. Subject has ileostomy and/or colostomy
9. Subject has clinical evidence of an infected abscess during screening
10. Bowel perforation or evidence of non-inflammatory obstruction during the 6 months 
prior to Day 1
11. Stool positive for Clostridium difficile toxin at screening
 
 
 
 


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22. Subject has evidence of a recent (within 6 months of Day 1) infection, requiring inpatient 
hospitalization
23. Subject received treatment for infection with IV or oral (within 14 days of Day 1) 
antibiotics or antivirals
24. Subject received any type of live attenuated vaccine < 4 weeks prior to Day 1 or is 
planning to receive any such vaccine over the course of the study
25. Subject tested positive for hepatitis B virus surface antigen, hepatitis C virus antibody, 
and/or human immunodeficiency virus (HIV) at screening
26. Subject has any underlying condition that predisposes subject to infections (eg, history of 
splenectomy)
27. Subject has known history of drug or alcohol abuse within 1 year of Day 1. 
 
 
28. History of cancer, except for basal cell carcinoma or in situ carcinoma of the cervix 
treated with apparent success with curative therapy ≥ 12 months prior to screening 
 
 
 
 


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31. Subject is currently enrolled in another investigational device or drug study, or less than 
30 days or 5 half-lives, whichever is longer, since ending another investigational device 
or drug study(s), or receiving other investigational agent(s)
 
33. Subject is pregnant, breastfeeding, or plans to become pregnant during the study
 
 
 
 
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained (see Section 7.4 for details). Once informed consent is obtained, a subject 
identification (SID) number will be assigned by a central interactive voice/web response 
system (IVRS/IWRS), and the screening evaluations may begin to assess study eligibility 
(inclusion/exclusion) criteria. The SID number will be used to identify the subject during the 
screening process and throughout study participation, if applicable. 
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.
For the 28-week, double-blind period of the study, the IVRS/IWRS will be used for 
randomization of subjects to a treatment arm and assignment of blinded investigational 
product kit numbers. Subjects will be stratified based on the number of prior anti-TNFα 
agents that failed or were not tolerated (1 vs > 1). The randomization will be based on 
permutation block algorithm. The maximum number of subjects within each stratum will not 
be set a priori. During the 24-week, open-label period of the study, all subjects will receive 
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Subjects who fail to meet eligibility criteria may be rescreened once, if in the opinion of the 
investigator the assessments undertaken were not considered representative of the usual 
status of a subject’s CD or general health.
4.1.5
Withdrawal from the Study
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). Such subjects 
will always be asked about the reason(s) and the presence of any AEs. If possible, they will 
be seen and assessed by an investigator and every attempt will be made to complete the early 
termination visit assessments (see Early Termination Visit and Safety Follow-up Period, 
Section 4.2.3). AEs will be followed up. If a subject withdraws 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:
1. Withdrawal of consent from further treatment with investigational product or lost to 
follow-up
2.
An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing
3.
Subject has had, or requires intra-abdominal surgery
4.
Pregnancy (see Section 5.6.4) or intention to become pregnant
5.
Subject receives any live vaccine
6.
Severe noncompliance to this study protocol, as determined by the investigator or 
medical monitor
7.
Recurrence of significant CD symptoms, that warrants escalation in therapy, according 
to investigator judgment, at any time during the study
8.
Subject develops a malignant neoplasm
9.
Mycobacterial infections, systemic fungal infections, or viral infections requiring 
hospitalization or parenteral antiviral therapy
10. Failure to receive a scheduled dose of investigational product within the dosing window 
during the double-blind periods of the study (Section 3.1.2)
11. Failure to receive 2 consecutive scheduled doses of investigational product within the 
dosing window during the open-label period of the study (Section 3.1.2)
Subjects who are permanently discontinued from further receipt of investigational product, 
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having permanently discontinued treatment. Subjects who permanently discontinue treatment 
may either be considered to have completed the study or not to have completed the study.
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety for 28 weeks after the last dose of investigational product, including the 
collection of any protocol specified blood, urine, or fecal specimens, unless consent is 
withdrawn or the subject is lost to follow-up or enrolled in another clinical study. In addition, 
subjects who are permanently discontinued from further receipt of investigational product 
will be referred for appropriate medical care by the investigator, as required. Such referral 
will be taken in coordination with the subjects’ personal physician.
Subjects will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (as defined in Section 6.3.3) such that there is insufficient 
information to determine the subject’s status at that time.
Note: Subjects refusing to return to the site or to continue participation in the study should be 
documented as “withdrawal of consent” rather than “lost to follow-up.” Investigators should 
document attempts to re-establish contact with missing subjects throughout the study period. 
If contact with a missing subject is re-established, the subject should not be considered lost to 
follow-up and any evaluations should resume according to this protocol.
4.1.7
Replacement of Subjects
Subjects who withdraw from the study after having been randomized will not be replaced.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
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Samples Obtained for Genetic Research or Future Research
Samples obtained for genetic research or future research will be labeled with a sample 
identification number. If the subject withdraws consent for participating in the genetic 
research 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 genetic research or future research, 
this additional research may not start immediately and may start at any time during the 
storage period. The subject’s sample(s) including any specimens of extracted 
deoxyribonucleic acid (DNA) 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 genetic research or future research, the samples 
will be destroyed by the sponsor once they are no longer required for the main study.
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the sponsor for genetic research or future research, the investigator will arrange to have it 
destroyed. If consent is withdrawn after the subject’s sample(s) have been sent to the sponsor 
for genetic research or future research, the sponsor and the investigator will ensure that these 
sample(s) are destroyed unless the sample 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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4.3
Description of Study Procedures
4.3.1
Efficacy……….
4.3.1.1
Crohn’s Disease Activity Index
The CDAI is a composite index with weighted domains that quantifies the global disease 
severity in a single numerical score. It is the oldest and most widely used of several 
multi-item instruments that have been developed and is validated for use in clinical studies to 
measure disease activity in CD (Best et al, 1976; Sands and Ooi, 2005). The CDAI measures 
the severity of active disease using symptom scores that are monitored over the previous 
week and includes subject-reported symptoms, physician-assessed signs, and laboratory 
markers. The CDAI score is calculated by summing weighted scores for subjective items 
(number of liquid or very soft stools, abdominal pain and general well-being) recorded by a 
diary during a 1-week period, and objective items (associated symptoms, taking antidiarrheal 
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and body weight). The CDAI scores range from 0 to 600, with higher scores indicating 
greater disease activity. Subjects with scores of < 150, 150 to 219, and 220 to 450 represent 
remission, mild disease, and moderate to severe disease, respectively; whereas subjects with 
scores of > 450 have very severe disease (Buxton et al, 2007). The CDAI will be calculated 
at the site in order to determine the eligibility for the study. 
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4.3.3
Medical History, Physical Examination, Vital Signs, and 
Electrocardiogram
4.3.3.1
Medical, Surgical, and Crohn’s Disease History
A complete medical and surgical history will be performed at screening and will include CD 
history, and current medical conditions, past or present cardiovascular disorders, respiratory, 
GI, renal, hepatic, neurological, endocrine, lymphatic, hematologic, immunologic, 
dermatological, psychiatric, genitourinary, and drug history or any other diseases or 
disorders. Smoking history and alcohol consumption will also be collected.
4.3.3.2
Chest X-ray
Subjects with a positive PPD test, or an indeterminate QuantiFERON-TB test, or subjects 
with a history of using anti-TNFα agents for a treatment course of 1 year or longer, who have 
discontinued an anti-TNFα agent within 6 months prior to screening, must obtain a 
subsequent chest x-ray that shows no evidence of active TB. If required, a chest x-ray will be 
completed during the screening period. The chest x-ray may be substituted with 
documentation of a previous chest x-ray performed within 1 month prior to the first dose of 
investigational product according to the inclusion criteria.
4.3.3.3
Physical and Neurological Examinations
Physical examinations will be performed by a physician, physicians’ assistant, or certified 
nurse practitioner, and will include examination of the following: general appearance, head, 
ears, eyes, nose, throat, neck, skin, cardiovascular system, respiratory system, abdominal 
system, and basic neurological examination. The subject’s weight (each study visit) will be 
recorded in kg with one decimal place, and height (Screening visit only) will be recorded in 
cm. If converting from inches, height will be recorded to one decimal place. Measurements 
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performed according to the Schedule of Study Procedures in
 
 
Demographic characteristics such as sex, race, and ethnicity will also be collected.
4.3.3.4
Visual Acuity Tests and Ophthalmoscopy Examination
The visual acuity test and ophthalmoscopic examination should be performed according to 
the Schedule of Study Procedures in 
. The 
visual acuity test will be used to determine the smallest letters a person can read on a 
standardized chart (eg, Snellen chart or other suitable chart) or a card held 4 to 6 meters 
(14 to 20 feet) away. The test should be done in a health care provider’s office or other 
suitable environment. The subject will be asked to stand or sit approximately 6 meters 
(20 feet) from the eye chart with both eyes open. One eye should be gently covered while the 
subject reads out loud the smallest line of letters they can see on the chart. Best corrected 
visual acuity (use of corrective refractive lenses is permitted) should be recorded.  
The ophthalmoscopic examination should include visually magnified inspection of the 
internal eye structures and also assessment of the quality of the eye’s red reflex after the 
pupil has been dilated. The appearance of the optic disc and retinal vasculature should be 
examined and any anomalies in the appearance of the internal ocular structures should be 
recorded. The presence or absence of cataracts should be noted. 
4.3.3.5
Vital Signs
Vital signs (blood pressure, temperature, pulse rate, and respiration rate) will be obtained at 
all study visits after the subject has been resting for at least 5 minutes. Subjects are instructed 
to avoid any hot or cold drinks for 30 minutes if an oral temperature assessment is 
performed.
 
 
 
 
 


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Injection-Site Reactions
The site of injection will be assessed at every visit at which there is an SC injection through 
the end of the open-label period. Injection-site reactions will be recorded as AEs according to 
the criteria described in Section 5.4.
 
 
 
 
 
 
  
 
 
 
 
 
 


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Pregnancy Test (females of childbearing potential only)
•
Urine human chorionic gonadotropin (hCG)
•
Serum beta-hCG (at screening only)


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Specific procedures for sample collection, processing, storage, and shipment can be found in 
a separate Laboratory Manual provided to the sites.
4.3.6
Immunogenicity Evaluation
Serum samples to measure the presence of ADAs against MEDI2070 will be collected prior 
to administration of investigational product 
 
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate Laboratory Manual provided to the sites.
4.3.7
Biomarker Evaluation and Methods
Blood and stool samples will be collected and analyzed to evaluate protein, nucleic acid, and 
cellular biomarkers that relate to MEDI2070 treatment. All biomarker analyses will be 
conducted to generate hypotheses associated with the mechanisms of action of MEDI2070, 
identify subsets of subjects responsive to MEDI2070, and to characterize a gene signature.
Specific procedures for sample collection, processing, storage, and shipment can be found in 
a separate Laboratory Manual provided to the sites.
4.3.7.1
Blood Biomarker Evaluation
Whole blood samples will be collected in
 for total ribonucleic acid (RNA)
sample preparation. RNA may be used in the analyses of transcript expression using both 
 
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A second whole blood sample will be collected to evaluate, but will not be limited to the 
following cell populations:
. Blood serum and 
plasma samples will be collected for analysis of circulating soluble factors in relation to 
inflammatory cell activities. Factors to be analyzed may include, but are not limited to:
 
. Additional assays to 
evaluate levels of 
 
 may be conducted.
 
 
4.3.7.2
Stool Analysis of Fecal Calprotectin and Microbiome
Stool specimens from whole stools already being collected for quantitative determination of 
fecal calprotectin levels will be collected to support assessment of changes over time in the 
composition of the
 
 
. The clinical sites will collect the specimens from stool delivered to the 
sites by subjects, for processing, shipping, and subsequent testing. Detailed sample collection 
instructions and kits for the subjects, and specimen processing and shipping instructions and 
kits for the sites, will be provided through the central laboratory to support centralized testing 
for each exploratory objective. Stool specimens associated with any study visit at which an 
ileocolonoscopy is scheduled should be collected prior to the start of the bowel preparation 
for the ileocolonoscopy.
 
 
.
4.3.8
Pharmacogenomics
An additional optional blood sample collection is scheduled to support exploratory study of 
the relationships between pharmacodynamics and clinical responses in participants, and 
 and other pathways implicated in IBD 
pathogenesis using pharmacogenetic methods including but not limited to 
 


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 Samples will be collected, labeled, stored, and shipped as 
detailed in the Laboratory Manual.
 
 
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include but are not limited 
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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
If MedImmune determines that temporary suspension or 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
 
 
 
 
 
 
 


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4.5.1.1
Investigational Product Dose Preparation
The investigational product manager will select the kit assigned by the IVRS/IWRS to 
prepare the subject’s dose.
 
 
 
 
 
 
 
 
 
 
 
 


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IV = intravenous; OL = open-label; SC = subcutaneous
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Infections
If according to the investigator a subject shows signs of a clinically significant infection 
during the double-blind, placebo-controlled period, the subject will be withdrawn from the 
study. A clinically significant infection will be defined as:
•
An infection that meets criteria for a TESAE
•
An infection that is Grade 3 or higher severity
•
A mycobacterial infection
•
A systemic fungal infection
•
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•
A bacterial infection requiring IV antibiotics
During the open-label period, MEDI2070 should not be administered to a subject with a 
clinically significant active infection treated with oral or IV antimicrobials, antivirals, or 
antifungals until it is confirmed by the investigator that the infection has resolved. 
Abnormal Liver Function Test
Investigational product will not be administered to any subject with an ALT and/or AST of 
> 3.0 × ULN and concurrent elevated bilirubin > 2.0 × ULN.
Other Events
Investigational product will not be administered to a subject subsequent to an event that in 
the opinion of the investigator or the sponsor contraindicates further dosing or could result in 
complications.
4.5.1.7
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
            
    
      
      


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4.5.2
Additional Study Medications
No other study medications are required for use in this clinical study protocol.
4.5.3
Labeling……….
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. The label will fulfill GMP 
Annex 13 requirements for labeling. Label text will be translated into local languages, as 
required.
4.5.4
Storage……….
 
 
  
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor 
compliance. The administration of all investigational product should be recorded in the 
appropriate sections of the eCRF.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to 
MedImmune. All unused investigational product will be returned to a MedImmune-
authorized depot or disposed of upon authorization by MedImmune.
It is the investigator/institution’s responsibility to establish a system for handling 
investigational product to ensure that:
•
Deliveries of investigational product from the sponsor are correctly received by a 
responsible person (eg, a pharmacist)
•
Such deliveries are recorded
•
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•
Any unused investigational product is accounted for and returned to designated facility or 
the sponsor for destruction upon authorization by the sponsor. Certificates of destruction 
should be signed and filed.
At the end of the study, it must be possible to reconcile delivery records with records of 
usage and returned stocks. Any discrepancies must be accounted for. Certificates of delivery 
and return must be signed, preferably by the investigator or a pharmacist.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
For the double-blind induction and maintenance periods of the study, an IVRS/IWRS will be 
used to randomize subjects to a treatment arm, assign a unique randomization code, and 
assign investigational product kit numbers. A total of approximately 342 subjects will be 
randomized into 1 of 5 treatment groups:
•
Treatment Group 1: MEDI2070 – high (76 subjects)
•
Treatment Group 2: MEDI2070 – high-medium (76 subjects)
•
Treatment Group 3: MEDI2070 – low-medium (76 subjects)
•
Treatment Group 4: MEDI2070 – low (38 subjects)
•
Treatment Group 5: Placebo (76 subjects)
Subjects will be stratified based on the number of prior anti-TNFα agents that failed or were 
not tolerated (1 vs > 1). The randomization will be based on permutation block algorithm.
The maximum number of subjects within each stratum will not be set a priori.  
During the 24-week, open-label period of the study, all subjects will receive 210 mg SC 
MEDI2070.
A subject is considered randomized into the study when the investigator notifies the 
IVRS/IWRS that the subject meets eligibility criteria and the IVRS/IWRS provides the 
assignment of blinded investigational product kit numbers to the subject.
Investigational product (MEDI2070 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 
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4.6.2
Methods for Ensuring Blinding
This study includes double-blind induction and maintenance periods. Neither the subject 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 (International Conference 
on Harmonisation [ICH] E9; see Section 4.6.3.2 for unblinding related to planned analysis). 
Since MEDI2070 and placebo can be distinguished, investigational product will be handled 
by an unblinded investigational product manager and handed over to qualified site staff who
will administer the investigational product to subjects. An independent investigational 
product monitor will also be unblinded to perform investigational product accountability. In 
the event that the 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. If the treatment allocation for a subject needs to be known to treat an individual 
subject for an AE, the investigator must notify the sponsor immediately and, if possible, 
before unblinding the treatment allocation.
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 IVRS/IWRS manual. In general, 
unblinding should only occur if management of the medical emergency would be different 
based on the subject having received investigational product. In the majority of cases, the 
management of a medical emergency would be the same whether or not investigational 
product was received by the subject. If this was the case, the investigational product 
allocation should not be unblinded. 
MedImmune retains the right to unblind the treatment allocation for TESAEs that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. 
If a subject’s investigational product allocation is unblinded prior to that subject having 
completed the Week 28 visit and all its associated assessments, the subject should be 
discontinued from investigational product.
4.6.3.2
Unblinding for Planned Analysis Purposes 
An interim analysis may be performed, as described in in Section 4.8.10. The analysis would 
be conducted by a limited number of sponsor personnel who are not involved in the conduct 


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of the study. The study site personnel and sponsor personnel directly associated with the 
conduct of this study and the study subjects will remain blinded to the subject-specific 
treatment assignment and to the outcome of interim analysis until the completion of the 
28-week placebo-controlled, double-blind period. No changes to the conduct of this study or 
data analysis are planned based on the interim analysis.
The primary analysis will be performed when all subjects complete the initial 16-week,
induction period. A further analysis is planned when all subjects complete the 28-week,
maintenance period. At the time of the primary analysis, selected personnel from the sponsor 
will be unblinded to individual treatment assignments as will be outlined in an unblinding 
plan. The MedImmune clinical team, study subjects, site monitors, and investigators will 
remain blinded to subject-specific treatment assignments. The study will be formally 
unblinded when the last subject reaches the end of the maintenance period.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “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, antidiarrheals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines.
In addition, the following concomitant medications for CD are permitted during the study:
•
5-aminosalicylates, only if being taken at baseline 
•
Prednisone up to 20 mg/day or equivalent, only if being taken at baseline 
•
Budesonide up to 9 mg/day, only if being taken at baseline
•
Azathioprine, only if being taken at baseline
•
6-mercaptopurine, only if being taken at baseline
•
Methotrexate, only if being taken at baseline


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•
Oral antibiotics for CD (except for the treatment of acute illness), only if being taken at 
baseline
•
Probiotics (eg, Culturelle and Saccharomyces boulardii), only if being taken at baseline 
•
Antidiarrheals (eg, loperamide and diphenoxylate with atropine) for control of chronic 
diarrhea, only if being taken at baseline
The investigator may not increase the subject’s dose of the permitted concomitant 
medications listed above, and may not initiate treatment with any of these medications after 
the deadlines specified in the inclusion criteria, Section 4.1.2, criterion #6.
The dose of the medications listed above may not be reduced during the subject’s study 
participation before the Week 16 assessments, including ileocolonoscopy, have been 
completed, with the exception that antidiarrheal agents may be stopped if the subject has had 
no stools in 3 consecutive days. After any such stopping of antidiarrheal agents during the 
double-blind period, if any recurrence of loose stools occurs prior to Week 8, antidiarrheal 
use should be immediately resumed.  
Subjects receiving oral corticosteroids should initiate oral corticosteroid tapering as per local 
standard of care if, after Week 16, they have achieved both: 
•
SES-CD response (see Section 2.2), AND
•
PRO2 response (see Section 2.2)
For assessment of the SES-CD score for the purpose of tapering oral corticosteroid therapy, 
the investigators’ own scoring of these results may be used in place of central scoring.
In the event that the dose of any of the medications listed above must be reduced for the 
subject’s safety, investigational product must be withdrawn and an early termination visit 
must be completed.
Background CD medication is not regarded as investigational product, and will not be 
provided by the sponsor.
4.7.2
Prohibited Concomitant Medications
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.


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The following medications or interventions are considered exclusionary and are not 
permitted as specified below through Week 52 of the study. The sponsor must be notified if a 
subject receives any of these during the study:
•
Natalizumab (Tysabri®)
•
Anti-TNFα agents 
•
Vedolizumab
•
Any commercially available or experimental biologic agent, eg, ustekinumab 
•
Calcineurin inhibitors eg, cyclosporine (Neoral®) and tacrolimus (FK 506/Prograf®) 
•
Mycophenolate mofetil (CellCept®) 
•
Sirolimus (rapamycin) 
•
IV or intramuscular steroids 
•
Topical (rectal) aminosalicylic acid (eg, mesalamine) or topical (rectal) steroids
•
Thalidomide
•
Live attenuated vaccine 
•
Intra-abdominal surgery
•
Elemental diet
•
Any experimental product or device as specified in Section 4.1.3 (exclusion criterion 
#31)
In the event that a subject receives a treatment/intervention listed above, investigational 
product must be withdrawn and an Early Termination Visit must be completed (see Early 
Termination visit, Section 4.2.3).
4.8
Statistical Evaluation
4.8.1
General Considerations
Full details of statistical analyses will be described in the Statistical Analysis Plan (SAP), 
which will be finalized prior to unblinding.
All data will be provided in data listings sorted by treatment group and subject number. 
Tabular summaries will be presented by treatment group and by visit for all efficacy 
endpoints. Categorical data will be summarized by the number and percentage of subjects in 
each category. Continuous variables will be summarized by descriptive statistics, including 
number of observations, mean, standard deviation, median, minimum, and maximum. Day 1 
will be defined as the day of first investigational product administration.


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For the purpose of statistical analyses, the data from the placebo-controlled, double-blind 
period and open-label period will be analyzed separately. Unless otherwise stated, all 
efficacy analyses will be conducted with a two-sided test at a significance level of α = 0.10. 
Nominal p-values will be provided without multiplicity adjustment. 
Through the end of the double-blind period, missing data for dichotomous endpoints will be 
handled using the non-responder imputation method, and missing data for continuous 
endpoints will be handled using mixed effects repeated measures analysis assuming missing 
at random mechanism.
4.8.2
Sample Size and Power Calculation
With a total sample size of approximately 342 and a randomization ratio of 2:1:2:2:2, the 
sample sizes are 76, 38, 76, 76, and 76 for placebo and MEDI2070 low, low-medium, high-
medium, and high dose groups, respectively. A 10% dropout rate is assumed for each 
treatment group in the induction period.
Assuming a placebo CDAI clinical remission rate of 12% and MEDI2070 high dose CDAI 
clinical remission rate of 31% at Week 8 of the induction period, approximately 76 subjects 
per treatment group will provide at least 85% power to detect a 19% difference in CDAI 
clinical remission rates at Week 8 between MEDI2070 high dose versus placebo, using a 
two-sided test at a significance level of α = 0.10. The minimum detectable difference in 
CDAI clinical remission rates at Week 8 will be 11%. 
Assuming a 5% placebo SES-CD remission rate and 20% MEDI2070 high dose SES-CD 
remission rate at Week 16 of the induction period, the given sample size will provide at least 
81% power to detect a 15% difference in SES-CD remission rates at Week 16 between 
MEDI2070 high dose versus placebo using a two-sided test at a significance level of 
α = 0.10. The minimum detectable difference in SES-CD remission rates at Week 16 will be 
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4.8.3
Analysis Populations
Details of each population below and any additional population, if needed, will be described 
in the SAP.
4.8.3.1
Intent to Treat Population 
The ITT population includes all subjects who are randomized into the study and receive any 
dose of investigational product for the 28-week, placebo-controlled, double-blind period. 
Subjects will be analyzed according to their randomized treatment group, regardless of 
whether subjects receive an investigational product different from that they were randomized 
to. The ITT population will be used as the primary population for all efficacy analyses. 
Disposition summary, demographics, baseline characteristics, protocol deviation, and 
efficacy endpoints will utilize this analysis population.
4.8.3.2
As-treated Population
The as-treated population includes all subjects who receive any amount of investigational 
product. Subjects will be analyzed according to the actual treatment received during the 
placebo-controlled, double-blind period even if it is different from that the subject was 
randomized to. Analysis of safety endpoints and summary of investigational product 
administration from the placebo-controlled, double-blind period will utilize this analysis 
population.
4.8.3.3
Pharmacokinetics Population
The PK population includes all subjects who receive at least one dose of investigational 
product and have at least one PK sample containing detectable MEDI2070. The PK 
population will be used for the PK analysis of the serum PK samples and the evaluation of 
immunogenicity.
4.8.3.4
Open-label Population
The open-label population includes all subjects who are enrolled in the open-label period and 
receive at least one dose of open-label MEDI2070 210 mg SC. Both efficacy and safety 


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information from the open-label period will be reported based on this population. Data from 
the open-label period will be reported by double-blind treatment group and both combined.  
4.8.4
Efficacy……….
Efficacy data from the placebo-controlled, double-blind period and open-label period will be 
analyzed separately.
4.8.4.1
Primary Efficacy Analysis
The primary analysis will be conducted in the ITT population. The primary efficacy endpoint 
is CDAI remission at Week 8 of the induction period. The primary comparison of interest 
will be MEDI2070 high dose group versus placebo. The comparisons between MEDI2070 
high-medium dose group versus placebo, low-medium dose group versus placebo, and 
MEDI2070 low dose group versus placebo will also be conducted.  
Missing data will be handled using the non-responder imputation method through the end of 
the placebo-controlled, double-blind period; ie, any subject with missing information on the 
primary endpoint will be assumed as a non-responder. In addition, subjects with a clinically 
meaningful increase in steroid use will also be assumed to be non-responders for the primary 
analysis perspective. Clinical meaningful increase in steroid dose is defined as an increase of 
at least 5 mg/day for at least 3 days of prednisone, or equivalent, or an increase of at least 3 
mg/day for at least 3 days of budesonide.
The difference in CDAI clinical remission rates at Week 8 between MEDI2070 dose groups 
and placebo group and associated 90% confidence interval will be provided. P-values for 
comparisons between any MEDI2070 dose group and placebo will be obtained from a 
logistic regression model adjusting for the number of prior anti-TNFα agents that failed or 
were not tolerated (1 vs > 1). In the event the number of remissions is too small (ie, < 5), the 
exact logistic regression will be performed instead. The statistically significant treatment 
effect will be tested against two-sided alpha level of 0.10.
4.8.4.2
Additional Analyses of the Primary Endpoint
A sensitivity analysis for the primary efficacy endpoint will be performed by extending the 
logistic regression model planned above via adjusting for baseline CDAI score and/or other 
baseline covariates for subjects in the ITT population. The following baseline covariates may 
be assessed and the final model will only include the significant baseline covariates.
•
Age 


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•
Sex
•
Race
•
Region (USA, non-USA)
•
Baseline body mass index 
•
Disease duration
•
Baseline CDAI score 
•
Baseline CRP 
•
Baseline fecal calprotectin
•
Smoking status at baseline 
A stratified Cochran Mantel Haenszel test adjusting for the number of prior anti-TNFα agents 
that failed or were not tolerated (1 vs > 1), or stratified exact test in the event of a small 
number of remissions, may also be performed. Missing data will be handled using the non-
responder imputation method through the end of the double-blind induction and maintenance 
periods.
The dose-response trend for the double-blind induction period will be tested using a 
Cochran-Armitage trend test. Other dose-response models may be explored; ie, multiple 
comparison procedure modelling method. The details of the dose-response analysis will be 
described in the SAP.
The exposure-response trend for the placebo-controlled, double-blind, induction period will 
be tested. The details of the exposure-response analysis will be described in a separate 
document.
4.8.4.3
Secondary Efficacy Analyses
Double-blind Induction and Maintenance Periods 
The efficacy endpoints from the placebo-controlled, double-blind, induction and maintenance 
periods will be summarized descriptively and displayed graphically by visit and by treatment 
using the ITT population. The secondary efficacy endpoints with dichotomous outcomes 
from double-blind, induction and maintenance periods will be analyzed in a similar way to 
the primary efficacy endpoint. 


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The dose-response analysis may be repeated for secondary endpoints in the double-blind,
induction period, including but not limited to SES-CD remission and response at Week 16, 
PRO2 remission and response at Week 8 and Week 16, CDAI response at Week 8 and 
Week 16, and CDAI clinical remission at Week 16. 


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4.8.5
Safety……….
The analysis of safety endpoints will include TEAEs including TESAEs, AESIs, TEAEs 
resulting in permanent discontinuation of investigational product, laboratory values, vital 
signs, and ECGs. Safety data from the placebo-controlled, double-blind period will be 
analyzed using the as-treated population. Safety data from the open-label period will be 
analyzed using open-label population.
4.8.5.1
Analysis of Adverse Events
AEs will be monitored during the study and the data analyzed with respect to incidence 
within each treatment group as well as severity and potential relationship of the TEAEs to 
investigational product. The Medical Dictionary for Regulatory Activities (MedDRA) will be 
used to code all AEs. AEs with onset on or after the first dose of investigational product or 
with onset prior to the first dose of investigational product that increase in severity on, or 
after the first dose of investigational product will be considered treatment-emergent. TEAEs 
will be summarized by system organ class and preferred term. Tabular summaries of TEAEs 
will be provided as follows but not limited to: 
•
Incidence rate of TEAEs by treatment arm, system organ class, and preferred term


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•
Incidence rate of fatal TEAEs, TESAEs, TEAEs leading to permanent discontinuation of 
investigational product, treatment-related TESAEs, and AESIs will be provided
•
Incidence rate of treatment-emergent and infectious AEs occurring in at least 5% of the 
subjects in any treatment arm by preferred term in descending order of frequency
•
Incidence rate of TESAEs occurring in at least 1% of the subjects in any treatment arm
Analyses will also be performed for:
•
Systemic hypersensitivity events; specific analyses will be performed for anaphylactic 
reactions
•
Clinically significant infections; the frequency of serious infections, in particular 
GI infections, will be summarized for each treatment arm. For infections, whenever 
possible, the pathogen should be identified and recorded.
•
Malignancies: events of malignancy will also be summarized for each treatment arm
•
Infusion/injection-site reactions; the frequency of infusion/injection-site reactions will be 
summarized for each treatment arm
•
Major cardiac events, defined as myocardial infarction, stroke, or cardiovascular death
•
Ocular AEs, including cataracts; events of ocular AE, including cataracts, will be 
summarized for each treatment arm
•
Surgery for CD: the time to onset of surgery for CD complications will be summarized 
for each treatment arm
4.8.5.2
Analysis of Clinical Laboratory, Vital Sign, and ECG Parameters
Associated laboratory parameters such as hepatic profile, renal function, and hematology 
values will be grouped and presented together. For each laboratory test, individual subject 
values outside the standard reference range will be flagged and listed. Shift tables will be 
produced showing the frequency of shifts from baseline to the worst on-study value in and 
out of the normal range, as well as by visit. Changes from baseline to each visit for each 
laboratory parameter will also be summarized.
The change from baseline to each visit for each of the vital sign variables will be 
summarized. Abnormal vital sign values will be flagged and listed.
The overall interpretation of the ECG results (Normal; Abnormal, not Clinically Significant; 
and Abnormal, Clinically Significant) will be summarized by treatment groups and by visit.


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4.8.6
Patient-reported Outcomes 
The study will utilize several PRO instruments. Data from the PROs will be analyzed to 
achieve 2 key purposes: (1) identification of the best symptom definitions to meet the 
emerging requirement for a symptom-based endpoint in future pivotal studies involving 
patients with CD, and (2) development of data to assist in providing content validation for the 
symptom collection and reporting methods. The sequence in which scoring instruments that 
contain PRO components (CDAI) or PROs will be collected at a given study visit will be in 
this order:
1.
CDAI
4. PGIC-IBD (Visits 7 and 10 only)
5. Cognitive Patient Interview (selected subjects, Visit 10 or Early Termination Visit only)
The PRO endpoints will be summarized descriptively by treatment group and by visit. Data 
from the Cognitive patient interview will be analyzed and reported separately (ie, not in the 
Clinical Study Report).
4.8.7
Analysis of Immunogenicity/Pharmacokinetics
Descriptive statistics of serum MEDI2070 concentration data will be provided by visit. 
Individual and mean serum concentration-time profiles of MEDI2070 will be generated and 
included in the report. Pharmacokinetic data obtained in this study will be combined with all 
available PK data for MEDI2070 and analyzed using population PK methodology. For PK 
data analysis, time zero is defined as the beginning of infusion.
The presence of ADAs to MEDI2070 in serum will be assessed. Immunogenicity results 
(binding and, if positive, neutralizing) will be summarized by the number and percentage of 
subjects who develop detectable ADAs. If possible, the relationship between PK and ADA 
status will be summarized.
4.8.8
Additional Analyses
Data from 
 and mucosal biopsy analysis will be descriptive in nature and
will be presented in a separate report (ie, not in the clinical study report).


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4.8.9
Data Monitoring Committee
An external DMC will monitor and protect the safety of the subjects through review of safety 
data on a regular basis throughout the double-blind treatment period of the study, ie, until the 
last subject completes Week 28. The DMC members will be selected for their expertise. The 
voting members of the DMC will be comprised of external individuals including the DMC 
chair. Summaries of unblinded data will be prepared and provided to the DMC. To minimize 
the potential introduction of bias, DMC members will not have direct contact with the study 
site personnel or subjects. The data for review will be outlined in the DMC charter and will 
be agreed to in advance by the DMC members. 
The DMC will review safety data on a regular basis as set out in the DMC charter. Subject 
enrollment will continue during DMC review of safety data. The available unblinded safety 
data for the randomized subjects will be evaluated by the DMC. Safety and efficacy 
summaries will be prepared prior to each meeting.
The DMC will recommend modifications of the protocol to enhance subject safety and to 
recommend early termination of the study if there is strong evidence that MEDI2070 poses a 
safety concern to subjects with CD. In addition, the sponsor’s Safety Review Team (SRT) 
will review data on a regular basis throughout the course of the study. During the 
double-blind period, the SRT will remain blinded to the treatment assignments of the 
subjects. After the last subject has entered the open-label period of the study, the SRT will 
have access to unblinded data.
 
 
 
 
 
 
 
 
 
 


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5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for Good Clinical Practice 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


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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 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or serious adverse event (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 rapid communication by the 
investigator to the sponsor. An AESI may be serious or nonserious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.


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5.3.1
Hepatic Function Abnormality (Hy’s Law)
Hepatic function abnormality meeting the definition of Hy’s law is considered an AESI. See 
Section 5.6.2 for the definition and reporting of AESIs of hepatic function abnormality.
5.3.2
Infusion Reactions
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 MEDI2070, 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
and Food Allergy and Anaphylaxis Network guidance for anaphylaxis diagnosis is provided 
in Appendix 3.
AEs of infusion reactions (also termed infusion-related reactions) are of special interest to the 
sponsor. Instructions to the site on how to record in the eCRF and report these events to the 
sponsor are provided in Section 5.4.3.1 and Section 5.6.3.
5.3.3
Other Adverse Events of Special Interest
Other AESIs include malignancies, hypersensitivity reactions (eg, anaphylaxis), ocular AEs, 
including cataracts, and major cardiac events, defined as myocardial infarction, stroke, or 
cardiovascular death. Instructions to the site on how to record in the eCRF and report these 
events to the sponsor are provided in Section 5.4.3.2 and Section 5.6.
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 


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Section 5.2 for the definition of SAEs and Appendix 2 for guidelines for assessment of 
severity and relationship. If an AE evolves into a condition that meets the regulatory 
definition of “serious,” it will be reported as an SAE.
5.4.1
Time Period for Collection of Adverse Events
AEs will be collected from time that written informed consent is obtained until the end of 
subject participation in the study. New (nonserious) AEs that start after the reporting period 
has ended will not be collected. All AEs that start during the reporting period will be 
followed to resolution until the end of subject participation in the study.
All SAEs will be recorded from the time of informed consent.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. MedImmune retains the right to request 
additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
5.4.3
Recording of Adverse Events of Special Interest 
5.4.3.1
Infusion-related Reactions
Events of infusion-related reaction (as defined in Section 5.3.2) should be recorded according 
to the definitions of AE and SAE (Section 5.1 and Section 5.2, respectively). If reporting 
AE/SAE as a term “infusion reaction” or “infusion-related reaction” the site should also 
provide symptoms of the reaction. Whenever possible, time of the reaction should be 
provided.
5.4.3.2
Other Adverse Events of Special Interest
AESIs (as defined in Section 5.3.3) should be recorded according to the definitions of AE 
and SAE (Section 5.1 and Section 5.2, respectively). 
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.


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If any SAE occurs in the course of the study, then investigators 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 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 investigators or other site personnel indicate 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 
a 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.
An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on a MedImmune investigational product occurs in the course of the study, 
then the investigator or other site personnel inform 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.


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For overdoses associated with a 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 total bilirubin ≥ 2 × ULN may 
need to be reported as SAEs. Please refer to Appendix 4 for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.
5.6.3
Other Adverse Events of Special Interest
AESI (as defined in Section 5.3 and subsections) are required to be reported within 24 hours 
of knowledge of the event to MedImmune Patient Safety, even if the event is considered to 
be nonserious. 
5.6.4
Pregnancy……….
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.6.4.1
Maternal exposure
If a subject becomes pregnant during the course of the study she must not receive additional 
doses of investigational product but will not be withdrawn from the study. 
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 
handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed 
up and documented even if the subject was discontinued from the study.
If any pregnancy occurs during the study, 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 
information is provided to the sponsor’s patient safety data entry site within 1 or 5 calendar 
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.


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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.
5.6.4.2
Paternal exposure 
No data exist about the possible effects on pregnancy or the child resulting from a pregnancy 
induced by the sexual activity of a man exposed to MEDI2070. Male subjects should refrain 
from fathering a child or donating sperm during the study and for 26 weeks following the last 
dose. 
Pregnancy of the subject’s partner(s) is not considered to be an AE; however, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality), occurring from the date of the first dose until 26 weeks after 
the last dose should, if possible, be followed up and documented. Informed consent for 
gathering of information about the course and outcome of the pregnancy will be sought from 
the female partners of male subjects who become pregnant during the course of the study. 
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 
information is provided to the sponsor’s patient safety data entry site within 1 or 5 calendar 
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) 
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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.
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/the center should comply with all the terms, conditions, 
and obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of 
any inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, 
the terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and 
the treatment of subjects and in all other respects, not relating to study conduct or treatment 
of subjects, the terms of the Clinical Study Agreement shall prevail.


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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
6.3.1
Subject Completion
An individual subject who does not enter the 24-week, open-label period will be considered 
to have completed the double-blind period of the study if the subject was followed up 
through to the end of Week 28 of the study regardless of the number of doses of 
investigational product that was received. An individual subject who enters the open-label 
period will be considered to have completed the study if the subject was followed up through 
the end of Week 52 regardless of the number of doses of investigational product received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up, or the subject refuses to return for all follow-up visits (see 
Section 4.1.5 and Section 4.1.6).
Subject completion date will be recorded in the eCRF.
6.3.2
Site Completion
Site completion is defined as the date of the last protocol-specified visit/assessment for the 
last subject in the study at the given study site. All materials or supplies provided by the 
sponsor will be returned to the sponsor or designee upon site completion of the study, as
directed by the site monitor. The investigator will notify the IRB/IEC when the study has 
been completed at his/her site.
6.3.3
End of Study
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last subject in the study.
6.4
Data Management 
Data management will be performed according to the Data Management Plan. An EDC
system will be used for data collection and query handling. The investigator will ensure that 


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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/Good Clinical Practice (GCP), and 
applicable regulatory requirements.
7.2
Subject Data Protection
This study will have 3 separate ICFs, a main protocol ICF, a pharmacogenomics blood 
sample donation ICF, and a Cognitive Patient Interview (for subset of study subjects 
participating in these interviews). The main ICF will include a specific separate section with 
subject signature for consent to perform the optional intestinal mucosal biopsies. The ICF 
will incorporate (or, in some cases, be accompanied by a separate document incorporating) 
wording that complies with relevant data protection and privacy legislation.
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.


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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 
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 main
ICF, the pharmacogenomics blood sample ICF, the Cognitive Patient Interview 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 ICFs, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
Safety updates/reports, including suspected unexpected serious adverse reactions (SUSARs), 
where relevant, will be provided to Regulatory Authorities, IRBs/IECs, and investigators 
according to local requirements.
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 they are 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 provided
•
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study
•
Ensure the original, signed ICFs 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 approval, before implementation. Local requirements are to be 
followed for revised protocols.
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to IRB/IEC see Section 7.3.
If a protocol amendment requires a change to a site’s ICF, MedImmune and the site’s 
IRB/IEC are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC.


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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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9
CHANGES TO THE PROTOCOL
All changes described below have been incorporated into the current version of the protocol.
9.1
Protocol Amendment 1, 18Nov2015
This amendment has been implemented to meet the requirements of the regulatory agency. 
Text revisions have been incorporated into the body of Protocol Amendment 1 and changes
are summarized below.
1.
Section 4.1.2 (Inclusion Criteria): Inclusion criterion 9 was modified to state that the 
male condom plus spermicide method must be used in conjunction with another method 
specified in Table 
2.
Section 4.1.6 (Discontinuation of Investigational Product): Criterion 7 was revised to 
make it applicable to the entire study (formerly only applied to the 24-week, open-label 
period). Text was modified to clarify that recurrence of significant CD symptoms, that 
warrants escalation in therapy, according to investigator judgment, will result in 
discontinuation of the investigational product.
3.
Section 4.2.1 (Screening and Induction Periods): Text was modified to clarify that 
screening assessments may be carried out over more than one visit to the site. 
4.
Section 4.7.1 (Permitted Concomitant Medications): Text was modified to clarify that 
the investigators may use their own assessment of the SES-CD score to decide whether 
or not to begin oral glucocorticosteroid tapering after Week 16. 


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Appendix 1
Signatures


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Signature of Principal Investigator
A Phase 2b Double-blind, Multi-dose, Placebo-controlled Study to Evaluate the Efficacy and 
Safety of MEDI2070 in Subjects with Moderate to Severe Crohn’s Disease Who Have Failed 
or Are Intolerant to Anti-tumor Necrosis Factor-alpha Therapy
I, the undersigned, have reviewed this protocol and amendments, and I agree to conduct this 
protocol in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with the International Conference on Harmonisation (ICH) 
guidelines on Good Clinical Practice (GCP), any applicable laws and requirements, and any 
conditions required by a regulatory authority and/or Institutional Review Board/Independent 
Ethics Committee (IRB/IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:  
Address including postal code: 
  
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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Appendix 2
Additional Safety Guidance
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) V4.03 as provided in below. The 
determination of severity for all other events not listed in the CTCAE should be made by the 
investigator based upon medical judgment and the severity categories of Grade 1 to 5 as 
defined below.
Grade 1 (mild)
An event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not 
generally interfere with usual activities of daily living.
Grade 2 (moderate)
An event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Grade 3 (severe)
An event that requires intensive therapeutic intervention. The 
event interrupts usual activities of daily living, or significantly 
affects the clinical status of the subject.
Grade 4 (life threatening)
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death 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 (fatal)
Death (loss of life) as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE.


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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.
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:
•
An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related)
•
A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident)
•
A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event)
Individual AE/SAE reports will be considered “related” to use of the investigational product 
if the “not related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation).
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-
emergent SAEs. 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.


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Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).


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Appendix 3
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(2):391-7.
National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis 
Network 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 blood pressure (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)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c.
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. 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 
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Appendix 4
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law. 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 Hy’s Law (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 Hy’s Law (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 AE and SAE according to the outcome of the review and assessment in line with 
standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
AST or ALT ≥ 3 × ULN together with total bilirubin (TBL) ≥ 2 × ULN at any point during 
the study following the start of investigational product irrespective of an increase in ALP.
Hy’s Law (HL)
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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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
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
•
Promptly enter the laboratory data into the laboratory eCRF
Follow-up
Potential Hy’s Law Criteria Are Not Met
If the subject does not meet PHL criteria the investigator will:
•
Inform the sponsor representative that the subject has not met PHL criteria
•
Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol.
Potential Hy’s Law Criteria Are Met
If the subject does meet PHL criteria the investigator will notify the sponsor study 
representative who will then inform the central study team. The medical monitor contacts the 
investigator, to provide guidance, discuss and agree an approach for the study subject’s 
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 Study Physician. 


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•
Complete the Liver eCRF Modules as information becomes available 
•
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
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.  
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 a SAE:
•
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF
•
If the alternative explanation is an AE/SAE, record the AE/SAE in the eCRF accordingly 
and follow the sponsor 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 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:


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•
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
FDA 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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Statistical Analysis Plan for Protocol D5170C00002
MEDI2070_D517C000002
Amendment #1
CONFIDENTIAL AND PROPRIETARY
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Statistical Analysis Plan
A Phase 2b Double-blind, Multi-dose, Placebo-controlled Study to Evaluate 
the Efficacy and Safety of MEDI2070 in Subjects with Moderate to Severe 
Crohn’s Disease Who Have Failed or Are Intolerant to Anti-Tumor 
Necrosis Factor-alpha Therapy
Protocol Number:
D5170C00002
Final:
8 Dec 2015 
by MedImmune
Amendment #1:  
27 Mar 2018 by Allergan
Sponsor Name and Legal Registered Address:
Allergan Pharmaceuticals International Ltd., Clonshaugh Industrial Estate, Coolock,
Dublin 17, Ireland
US Agent: Allergan Sales, LLC
                   5 Giralda Farms, Madison, New Jersey 07940
                 2525 Dupont Drive, Irvine, California USA 292612 United States


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Table Of Contents
1
INTRODUCTION...........................................................................................................7
2
STUDY OVERVIEW .....................................................................................................7
2.1
Study Objectives...................................................................................................7
2.1.1
Primary Study Objective...........................................................................7
2.1.2
Secondary Study Objectives .....................................................................7
2.2
Study Design.........................................................................................................9
2.3
Treatment Assignment and Blinding..................................................................12
2.4
Sample Size.........................................................................................................13
3
STATISTICAL METHODS .........................................................................................13
3.1
General Considerations.......................................................................................13
3.2
Analysis Populations...........................................................................................14
3.3
Handling of Dropouts and Missing Data............................................................15
3.3.1
Missing and Incomplete Dates................................................................15
3.3.2
Missing Baseline Evaluation...................................................................15
3.3.3
Missing Efficacy Evaluations .................................................................16
3.4
Analysis Visit Windowing Rules........................................................................16
3.4.1
DB Treatment Period..............................................................................16
3.4.2
OL Treatment Period ..............................................................................18
3.5
Study Subjects.....................................................................................................18
3.5.1
Subject Disposition and Completion Status............................................18
3.5.2
Demographics and Baseline Characteristics...........................................19
3.5.3
Study Drug Exposure..............................................................................20
3.5.4
Prior and Concomitant Medications .......................................................20
3.5.5
CD History..............................................................................................21
3.5.6
Medical and Surgical History .................................................................21
3.5.7
Physical, Neurological and Visual Examination ....................................21
3.5.8
Protocol Deviations.................................................................................21
3.6
Efficacy Analyses ...............................................................................................21
3.6.1
Primary Efficacy Endpoint(s) and Analyses...........................................21
3.6.1.1 Primary Efficacy Endpoint .......................................................21
3.6.1.2 Primary Efficacy Analysis........................................................21
3.6.1.3 Additional Analyses of the Primary Efficacy Endpoint ...........21
3.6.2
Secondary Efficacy Endpoints and Analyses .........................................22
3.6.2.1 Secondary Efficacy Endpoints..................................................22
3.6.2.2 Secondary Efficacy Analyses ...................................................23
3.6.2.3 Predictive Biomarker Analyses.................................................23


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3.6.3 Exploratory Efficacy Endpoints and Analyses.........................................23
3.6.3.1
Exploratory Efficacy Endpoints................................................23
3.6.3.2
Analyses of Exploratory Endpoints ..........................................24
3.6.4.1
Dose-Response Analysis...........................................................24
3.6.4.2
Efficacy Analysis for OL Treatment Period.............................24
3.6.5 Subgroup Analysis ...................................................................................24
3.7
Patient Reported Outcomes ................................................................................25
3.7.1 CDAI score...............................................................................................25
3.8
Safety Analyses...................................................................................................27
3.8.1 Adverse Events and Serious Adverse Events...........................................27
3.8.1.1
Pre-treatment AEs.....................................................................27
3.8.1.2
Treatment-Emergent AEs during DB Treatment Period ..........27
3.8.1.3
TEAEs during OL Treatment Period........................................28
3.8.2 Deaths and Treatment Discontinuations due to Adverse Events .............28
3.8.4 Vital Signs ................................................................................................29
3.8.5 Electrocardiogram ....................................................................................29
3.9
Pharmacokinetics and Immunogenicity..............................................................29
4
INTERIM ANALYSIS..................................................................................................29
5
6
APPENDIX ...................................................................................................................31
6.1
CDAI Score.........................................................................................................31
6.2
6.3
Note to File .........................................................................................................35
List of In-Text Tables
Table 3-1
Analysis Populations..................................................................................... 14
Table 3-2
Missing Dates Imputation Rules ................................................................... 15
Table 3-3
General Analysis Visit Windows for DB Treatment Period ......................... 17
 
 


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Table 3-7
List of Secondary Endpoints ......................................................................... 23
Table 6-1
Items Included in CDAI and Their Weights ................................................. 32
List of In-Text Figures


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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
AE
Adverse Event
AESI
Adverse Event Of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
CD
Crohn’s Disease
CDAI
Crohn’s Disease Activity Index
CRP
C-reactive protein
CSP
Clinical Study Protocol
CSR
Clinical Study Report
DB
Double-Blind
ECG
Electrocardiogram
eCRF
electronic Case Report Form
IBD
Inflammatory Bowel Disease
IL
interleukin
ITT
Intent To Treat
IV
Intravenous
IVRS/IXRS
Interactive Voice/Web Response System
MACE
Major Adverse Cardiac Events
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
events
OL
Open-Label
PGIC-IBD
Patient Global Impression of Change-Inflammatory Bowel Disease
PK
Pharmacokinetic (s)
PT
Preferred Terms
PROs
Patient Reported Outcomes
PRO2
Patient-Reported Outcomes-2 score
Q4W
Every 4 Weeks
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SPP
Statistical Programming Plan
SC
Subcutaneous
SD
Standard Deviation
SES-CD
Simple Endoscopic Score for Crohn’s Disease
SMQ
Standardized MedDRA Query
SOC
System Organ Class
TEAE
Treatment-Emergent Adverse Event
TESAE
Treatment-Emergent Serious Adverse Event
TNFα
Tumor Necrosis Factor-alpha


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Abbreviation or 
Specialized Term
Definition
ULN
Upper Limit of Normal
WBC
White Blood Cell


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1
INTRODUCTION
This document describes the statistical analyses plan specified in the protocol D5170C00002. The 
scope of this plan addresses statistical analyses as they apply to safety and efficacy objectives, 
including the primary, intermediate and final analyses unless otherwise specified (e.g. analyses 
related to pharmacokinetic (PK) and translational science measurements will not be discussed in this 
document).  A separate statistical programming plan (SPP), containing table templates and 
specifications, will be created to be used in conjunction with this document.
The study, however, was early terminated; 29 subjects were randomized to one of the five treatment 
groups by the time of the study termination.
2
STUDY OVERVIEW
The following study objectives were copied from the original protocol. However, the study was 
early terminated; 29 subjects were randomized to one of five treatment groups by the time of the 
study termination. Due to the small number of subjects in the study, only descriptive statistics for 
limited efficacy endpoints are provided. However, all data will be listed.
2.1 Study Objectives
2.1.1 Primary Study Objective
To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission based on the CDAI 
score at Week 8 in subjects with moderate to severe Crohn’s Disease (CD) who have failed or are 
intolerant to anti-TNFα therapy.
2.1.2 Secondary Study Objectives
Induction Period Secondary Objectives: 
1. To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 16
based on the Simple Endoscopic Score for Crohn’s Disease (SES-CD)
2. To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 16
based on the SES-CD
3. To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 8
based on the Patient-reported Outcomes 2 score (PRO2)
4. To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 8 
based on the PRO2
5. To evaluate the efficacy of MEDI2070 versus placebo to induce clinical response at 
Week 8 based on the CDAI


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6. To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 16
based on the PRO2
7. To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 16
based on the PRO2
8. To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission at
Week 16 based on the CDAI
9. To evaluate the efficacy of MEDI2070 versus placebo to induce clinical response at 
Week 16 based on the CDAI
10. To demonstrate safety and tolerability of MEDI2070 therapy
11. To characterize the pharmacokinetics (PK) and immunogenicity of MEDI2070
12. To characterize the dose-response and exposure-response relationships
 
 
Maintenance Period Secondary Objectives: 
1. To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission 
based on CDAI score at Week 28
2. To evaluate the efficacy of MEDI2070 versus placebo on remission at Week 28 based 
on the SES-CD
3. To evaluate the efficacy of MEDI2070 versus placebo on remission at Week 28 based 
on the PRO2
4. To evaluate the efficacy of MEDI2070 versus placebo on modified sustained 
remission, defined as remission at both Week 16 and at Week 28 based on the SES-CD
5. To evaluate the efficacy of MEDI2070 versus placebo on modified sustained 
remission, defined as remission at both Week 8 and at Week 28 based on the PRO2
6. To evaluate the efficacy of MEDI2070 versus placebo on modified sustained clinical 
remission, defined as clinical remission at both Week 8 and at Week 28 based on the 
CDAI
7. To evaluate the efficacy of MEDI2070 versus placebo on response at Week 28 based 
on the SES-CD


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8. To evaluate the efficacy of MEDI2070 versus placebo on response at Week 28 based 
on the PRO2
9. To evaluate the efficacy of MEDI2070 versus placebo on clinical response at Week 28
based on the CDAI
10. To demonstrate safety and tolerability of MEDI2070 therapy
11. To characterize the PK and immunogenicity of MEDI2070
 
 
 
2.2 Study Design
This is a 3-part Phase 2b study comprising a 16-week, double-blind, placebo-controlled, induction 
period; a 12-week double-blind, placebo-controlled, maintenance period; and a 24-week, open-label 
period designed to evaluate the short-term efficacy and the short- and long- term safety of MEDI2070 
in subjects with moderate to severe, active CD who have failed or are intolerant to anti-TNFα therapy 
as determined by the investigator. Subjects will be stratified based on the number of prior anti-TNFα 
agents that they have failed (1 versus > 1). 


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Approximately 342 subjects at approximately 300 centers worldwide will be randomly assigned to 1 
of 5 treatment groups to receive intravenous (IV) and subcutaneous (SC) investigational product 
(MEDI2070 or placebo) once every 4 weeks (Q4W) during the double-blind, placebo-controlled 
induction and maintenance periods. Subjects who complete the double-blind, placebo controlled 
maintenance period (Week 28) will have the option to enter a 24-week, open-label period in which 
they will receive open-label MEDI2070 (210 mg SC) Q4W (Weeks 28 through 48). All subjects will 
be followed for safety at 3 visits over 28 weeks (Weeks 60, 70, and 80 for subjects completing the 
open-label period) after their last dose of investigational product.
The study, however, was early terminated; 29 patients were randomized to one of the five treatment 
groups by the time of the termination.


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Figure 2-1
Study Flow Diagram


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2.3 Treatment Assignment and Blinding
Subjects will receive investigational product (MEDI2070 or placebo) by IV infusion and/or SC 
injection at Week 0 (Day 1) then once Q4W during the 16-week, double-blind, placebo-controlled, 
induction period (i.e., Weeks 4, 8, and 12) and the 12-week double-blind, placebo-controlled, 
maintenance period (i.e., Weeks 16, 20, and 24). All subjects who complete the double-blind 
maintenance period will have the option to enter the 24-week open-label treatment period. All 
subjects entering the open-label period will receive open-label MEDI2070 (210 mg SC) once Q4W 
(i.e., Weeks 28, 32, 36, 40, 44, and 48). 
A total of approximately 342 subjects will be randomly assigned to one of five treatment groups:
Treatment 
Group
Double-blind Treatment Period
Open-label 
Period
Induction
Maintenance
Week 0
Week 4
Weeks 8, and 
12
Weeks 16, 20, 
and 24
Weeks 28, 32, 36, 
40, 44, and 48
Treatment 
Group 1 
High (n = 76)
700 mg 
MEDI2070 
IV + placebo 
SC
700 mg 
MEDI2070 IV + 
placebo SC
210 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
Treatment 
Group 2 
High-medium 
(n = 76)
280 mg 
MEDI2070 
IV + placebo 
SC 
210 mg 
MEDI2070 SC 
+ placebo IV 
210 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
Treatment 
Group 3 
Low-medium 
(n = 76)
210 mg 
MEDI2070 
SC + placebo 
IV 
105 mg 
MEDI2070 SC 
+ placebo IV 
105 mg 
MEDI2070 SC
105 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
Treatment 
Group 4 
Low (n = 38)
70 mg 
MEDI2070 
SC + placebo 
IV 
35 mg 
MEDI2070 SC 
+ placebo IV 
35 mg 
MEDI2070 SC
35 mg 
MEDI2070 SC
210 mg 
MEDI2070 SC
Treatment 
Group 5 
Placebo (n = 
76)
Placebo SC 
and IV
Placebo SC and 
IV
Placebo SC
Placebo SC
210 mg 
MEDI2070 SC
IV = intravenous; SC = subcutaneous
The study, however, was early terminated; 29 subjects were randomized to one of the five
treatment groups by the time of the study termination.


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2.4 Sample Size
With a total sample size of approximately 342 and a randomization ratio of 2:1:2:2:2, the sample sizes 
are 76, 38, 76, 76, and 76 for placebo and MEDI2070 low, low-medium, high-medium, and high dose 
groups, respectively. A 10% dropout rate is assumed for each treatment group during the induction 
period.
Assuming a placebo CDAI remission rate of 12% and MEDI2070 high dose CDAI remission rate of 
31% at Week 8 of the induction period, approximately 76 subjects per treatment group will provide at 
least 85% power to detect a 19% difference in CDAI remission rates at Week 8 between MEDI2070 
high dose versus placebo, using a two-sided test at a significance level of α = 0.10. The minimum 
detectable difference in CDAI remission rates at Week 8 will be 11%. 
Assuming a 5% placebo SES-CD remission rate and 20% MEDI2070 high dose SES-CD remission 
rate at Week 16 of the induction period, the given sample size will provide at least 81% power to 
detect a 15% difference in SES-CD remission rates at Week 16 between MEDI2070 high dose versus 
placebo using a two-sided test at a significance level of α = 0.10. The minimum detectable difference 
in SES-CD remission rates at Week 16 will be 10%.  
 
 
 
 
 
 
 
 
 
The study, however, was early terminated; 29 subjects were randomized to one of the five
treatment groups by the time of the study termination.
3
Statistical Methods
3.1 General Considerations
All data will be provided in data listings. Tabular summaries for limited efficacy and safety 
parameters in the double-blind treatment period will be presented by treatment group.  
All efficacy data will be summarized using the analysis visits. The analysis visit windowing rules 
will be defined based on study days of post-baseline. The details of analysis visit windowing rules 
will be described in Section 3.4.
Day 1 will be defined as the day of first investigational product administration.  For any variable, 
unless otherwise defined, the baseline value is the last non-missing assessment taken prior to the first 


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investigation product administration. 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.
The following conventions will be applied to all data presentations and summary.

For continuous endpoints, arithmetic mean, and median will be formatted to one more 
decimal place than the measured value.  SD will be formatted to two more decimal place than 
the measured value.  Minimum and maximum values will be presented with the same number 
of decimal places as the measured value. 

For categorical variables, the count and percentage of responses will be presented in the form 
XX (XX.X%) where the percentage is in the parentheses. 

Data analyses will be conducted using SAS® version 9.4 (SAS Institute Inc., Cary, 
NC) or higher.
3.2 Analysis Populations
The analysis populations are defined in Table 3-1.
Table 3-1
Analysis Populations
Population
Description
Intent-to-treat 
(ITT) population
The Intent-to-Treat (ITT) Population includes all subjects who are randomized into the 
study and receive at least one whole dose of investigational product for the 28-week, 
double-blind, placebo-controlled treatment period.  Subjects will be analysed according to 
their randomized treatment group, regardless of whether they receive an investigational 
product that is different from what they were randomized to.
Safety population
The Safety Population includes all subjects who receive at least one dose of
investigational product. Subjects will be analyzed according to the actual treatment 
received during the placebo-controlled, double-blind treatment period even if it is 
different from what the subject is randomized to.  
Open-label
population
Open-label population includes all subjects who are enrolled in the open-label treatment 
period and have at least one dose of open-label MEDI2070 210 mg SC treatment.  
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 
MEDI2070.  


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3.3 Handling of Dropouts and Missing Data 
Subjects may be missing specific data points for a variety of causes. In general, data may be missing 
due to a subject’s early withdrawal from study, a missed visit, or inability to evaluate an endpoint at a 
particular point in time. The general procedures outlined below describe what will be done when a 
data point is missing. Missing safety endpoints will not be imputed.
3.3.1 Missing and Incomplete Dates
For any listings, missing or incomplete dates will be listed as is.
In the case where the start or stop date of an event or medication is missing or incomplete, the 
following rules will be applied in the analysis:
Table 3-2
Missing Dates Imputation Rules
Missing
Imputation
Exception
Start date
(Adverse Events
and concomitant 
medication)
Day
01
Default to Study Day 1 if an event starts 
the same year and month as Study Day 
1 and Stop date is after Study Day 1
Day/Month
01JAN
Default to Study Day 1 if an event 
started the same year as Day 1 and Stop
date is after Study Day 1
Day/Month/Year
No imputation
Stop date 
(concomitant 
medication)
Day
Last day of the month
Default to the End of Study Date or the 
primary analysis cut-off date for 
ongoing subjects if the concomitant 
medication stopped the same year and 
month as the End of Study Date or 
primary analysis cut-off date
Day/Month
31DEC
Default to the End of Study Date or the 
primary analysis cut-off date for 
ongoing subjects if the concomitant 
medication stopped the same year as the 
End of Study Date or primary analysis 
cut-off date
Day/Month/Year
No imputation
3.3.2 Missing Baseline Evaluation
For any endpoint, unless otherwise defined, the baseline value is the last non-missing assessment 
taken prior to the first investigational product administration. If the baseline is still missing following 
above definition, the baseline evaluation will not be imputed and will be considered as missing.


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3.3.3 Missing Efficacy Evaluations 
Through the end of the DB period (induction and maintenance periods), the missing efficacy data will 
be handled as described below:

Missing data for dichotomous endpoints will be handled using the non-responder 
imputation method, i.e. any subject with missing information on the endpoint will be 
assumed as a non-responder.

Missing data for continuous measures will not be imputed. 

Missing data for PRO components (e.g. IBDQ, CD-PRO) will be handled according to 
the scoring algorithm as described in corresponding sections. If the score is still missing, 
no further imputation will be done.
3.4 Analysis Visit Windowing Rules
The actual visit for a subject may not exactly coincide with their targeted visit date. The actual visit 
date will be mapped to the study visit following the analysis visit windowing rules below. Unless 
specified otherwise, all efficacy and safety analyses will be based on the analysis visits. If there are 
multiple records fall within the same defined analysis visit window, the non-missing record closest to 
the target day will be considered for the analysis. 
If two non-missing assessment actual dates are equidistant from the target day, the later visit will be 
considered for analysis. 
Composite endpoints (e.g. CDAI score) will be calculated for each date at which individual 
components are being measured before applying the analysis visit windows rather than to calculate 
visit window based individual component.
3.4.1 DB Treatment Period
DB Period Study Day 1 is defined as the first day of DB IP administration. For subjects who are 
randomized but not dosed after randomization, the Day 1 is defined as the date of randomization. 
DB Period Study Day is defined as the number of days from the Double-blind Treatment Period
Study Day 1.
•
Before DB Period Study Day 1:
Double-blind Treatment Period Study Day = (Date of Interest – Date of DB Period Study Day 1)
•
On or After DB Period Study Day 1:
DB Period Study Day = (Date of Interest – Date of DB Period Study Day 1) + 1


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Unless otherwise specified, all efficacy analysis will apply the analysis visit window rules as defined 
in 
 


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3.4.2 OL Treatment Period
OL Period Study Day 1 is defined as the first day of OL IP administration. OL Period Study Day is 
defined as the number of days from OL Period Study Day 1.
•
Before OL Period Study Day 1:
Open-Label Period Study Day = (Date of Interest – Date of OL Period Study Day 1)
•
On or After OL Period Study Day 1:
OL Period Study Day = (Date of Interest – Date of OL Period Study Day 1) + 1.
3.5 Study Subjects
3.5.1 Subject Disposition and Completion Status
A summary of subject disposition throughout the study with respect to completion of 
double-blind induction and maintenance periods and open-label period will be provided.  The 
number and percentage will be provided by treatment groups and overall using the
randomized subjects as the denominator. The timing of and reasons for early withdrawal 
from treatment and from study will be tabulated and listed.


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3.5.2 Demographics and Baseline Characteristics
Subject demographics and baseline characteristics will be listed for each subject. Following 
demographics and baseline characteristics will be summarized by treatment groups and overall using 
the ITT population.  A summary of baseline disease characteristics may include, but not be limited to:

Age 

Age (< 40 years, ≥ 40 years)

Sex (Male, Female)

Race (White, Black/African American, Asian, Other)

Race (White, Non-white)

Region (US, Non-US)

Disease duration of CD (years)

Disease duration (< 5 years, ≥ 5 years)

Ethnic group (Hispanic or Latino, Other)

Height (cm)

Weight (kg)

BMI (kg/m2)

Baseline disease location (ileum, not colon; colon, not ileum; or ileo-colonic, as 
observed at baseline ileocolonoscopy)

Baseline CDAI score

Baseline weekly abdominal pain score

Baseline weekly loose/liquid stool count

Baseline SES-CD score

Baseline SES-CD score by baseline disease location subgroup (per subgroup of 
subjects with ileum, not colon; colon, not ileum; or ileo-colonic disease)

Baseline CRP (mg/L)

Baseline CRP (< 5 mg/L, ≥ 5 mg/L)

Baseline fecal calprotectin (μg/g)

Baseline fecal calprotectin (< 250 μg/g, ≥ 250 μg/g)

Baseline fecal calprotectin (< 200 μg/g, ≥ 200 μg/g)


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
Baseline IBDQ score

Alcohol status (Never, Current and Former)

Number of prior use of anti-TNF agents (1, > 1)

Number of prior use of anti-TNFα agents (1, 2, ≥3)

Prior use of vedolizumab (Yes, No)

Use of 5-aminosalicylatesat baseline (Yes, No)

Use of corticosteroids at baseline (Yes, No)

Use of immunomodulators at baseline (Yes, No)

Smoking status at baseline (Never, Current, Former)
3.5.3 Study Drug Exposure
Descriptive statistics for extent of exposure (in days) will be presented for the safety population and 
the OL population during the specified treatment period. 
For DB period, the following summaries will be provided using for the safety population: 

Duration of exposure in the DB period
For OL period, the following summaries will be provided using the OL population:

Duration of exposure in the OL period
Additionally, descriptive statistics for the cumulative exposure for overall MEDI2070 will be 
provided. If a subject entered both the DB period and OL period, the subject will be considered as the 
same subject and the exposure data will be combined from both periods.
3.5.4 Prior and Concomitant Medications
Prior medication refers to all medications that were started prior to the start of the first dose of 
investigational product. 
Concomitant medication refers to all medications taken during the treatment period of the DB period
and the OL period. Concomitant medications include medications continued from pre-treatment. 
Medications with missing start and stop dates will be counted as concomitant medications. 
Medications with partial start or stop dates will be handled as described in Section 3.3.1. Medications 
with start and stop dates which bracket the first dose date will be flagged as both prior and 
concomitant medications.
All prior and concomitant medications data will be coded by World Health Organization Drug 
Dictionary, version March 2017 or newer and listed for each subject by treatment groups.  


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3.5.5 CD History
The CD history will be listed using the safety population. 
3.5.6 Medical and Surgical History
Abnormalities in subjects’ medical and surgical histories will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), version 20.1 or newer.  Preferred Term (PT) in the medical 
history and surgical history will be listed using the safety population.
3.5.7 Physical, Neurological and Visual Examination
All data related to physical, neurological and visual examination will be listed for each subject. 
3.5.8 Protocol Deviations
Protocol deviations will be recorded and are classified as critical, major, and minor deviation. Listing 
of critical and major protocol deviations will be provided by treatment group. 
3.6 Efficacy Analyses
Efficacy data from the DB treatment period will be summarized descriptively by treatment 
group. 
3.6.1 Primary Efficacy Endpoint(s) and Analyses
3.6.1.1 Primary Efficacy Endpoint
The primary efficacy endpoint is Crohn’s Disease Activity Index (CDAI) remission at Week 8.  
CDAI remission is defined as a CDAI score of < 150.  Refer to Appendix 6.1 for detail on CDAI 
score. 
3.6.1.2 Primary Efficacy Analysis
The primary analysis will be conducted in the ITT population.  The primary efficacy 
endpoint is CDAI remission at Week 8 of the induction period will be descriptively 
summarized.  
3.6.1.3 Additional Analyses of the Primary Efficacy Endpoint
No sensitivity analyses of the primary efficacy endpoint will be performed. 


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3.6.2 Secondary Efficacy Endpoints and Analyses
3.6.2.1 Secondary Efficacy Endpoints
Remission and response will be assessed by both clinical and patient reported outcomes (PRO)
measures. The following definitions will be used to define the secondary efficacy endpoints:
•
CDAI clinical response: Decrease from baseline in the CDAI of ≥ 100 points
•
SES-CD remission: Total SES-CD score ≤ 4, with:
o
No subscore > 2, and
o
Segments scored at baseline that cannot be observed on a subsequent examination will be 
scored with an imputed value unchanged from baseline 
•
SES-CD response: Decrease from baseline in SES-CD ≥ 50%; segments scored at 
baseline that cannot be observed on a subsequent examination will be scored with an 
imputed value unchanged from baseline. 
•
PRO2 remission (loose/liquid stool frequency/abdominal pain): Remission achieved for 
both abdominal pain and loose/liquid stool frequency
•
PRO2 response: (loose/liquid stool frequency/abdominal pain): Remission or response in 
one symptom (either abdominal pain or stool frequency) plus response in the other
o
Abdominal pain remission: On an 11-point (0 to 10) pain scale: During 1 week, no daily 
score > 2
o
Abdominal pain response: On an 11-point (0 to 10) pain scale: ≥ 30% reduction in weekly 
pain score from baseline
o
Loose/liquid stool frequency remission: Counting stools identified as Type 6 or 7 on Bristol 
Stool Form Scale, during 1 week, each daily loose loose/liquid stool count ≤ 3
o
Loose/liquid stool frequency response: Counting stools identified as Type 6 or 7 on Bristol 
Stool Form Scale, ≥ 30% reduction in weekly loose/liquid stool count compared to baseline
Please note that hematocrit results from hematology central lab testing during the study were required 
to calculate the CDAI scores for a given visit.  It was discovered post-sponsor-transition in August 
2017 that central labs for hematology were not required to be taken per protocol during study visits 
V8 (W20/D141), V9 (W24/D169), V11 (W32/D225), V12 (W36/D253), V14 (W44/D309) and V15 
(W48/D337); therefore, the hematocrit item scores and subsequent CDAI total scores could not be 
calculated for these study visits.  It was therefore agreed that any CDAI scores obtained from the 
study database for the above 6 visits will not be included in any study analyses. Refer to Note to File 
in Appendix 6.3 for detail. 
Refer to Appendix 6.1 and Appendix 6.2 for details on CDAI score and SES-CD score.


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Table 3-7
List of Secondary Endpoints
Secondary Efficacy Endpoints
Induction Period
Week 8
PRO2 Remission 
Abdominal pain remission 
Loose/liquid stool frequency remission 
PRO2 Response
Abdominal pain response
Loose/liquid stool frequency response
CDAI clinical Response
Week 16
SES-CD Remission 
PRO2 Remission 
CDAI clinical remission
Abdominal pain remission 
Loose/liquid stool frequency remission 
SES-CD Response
PRO2 Response
CDAI clinical response
Abdominal pain response
Loose/liquid stool frequency response
Maintenance Period
Week 28
CDAI clinical remission 
SES-CD Remission 
PRO2 Remission 
Abdominal pain remission  
Loose/liquid stool frequency remission 
CDAI clinical response
SES-CD Response
PRO2 Response
Abdominal pain response
Loose/liquid stool frequency response
3.6.2.2 Secondary Efficacy Analyses
The efficacy data from the DB induction and maintenance periods will be summarized descriptively 
by treatment group and by visit using the ITT Population. 
The secondary efficacy endpoints with dichotomous outcomes will be summarized similarly as the 
primary analysis of the primary efficacy endpoint using the ITT population.
3.6.2.3 Predictive Biomarker Analyses
Due to a small number of subjects in the study, the predictive biomarker analyses will not 
be performed.
3.6.3 Exploratory Efficacy Endpoints and Analyses
3.6.3.1 Exploratory Efficacy Endpoints
Induction Period Exploratory endpoints: 


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3.6.3.2 Analyses of Exploratory Endpoints
Patient reported outcomes endpoints (e.g. change from baseline in IBDQ, change from baseline in 
newly developed PRO scores) will be described in Section 3.6.
The exploratory efficacy endpoints with continuous or ordinal outcomes (e.g. change from baseline in 
CRP and change from baseline in FCP) will be summarized descriptively.  
3.6.4 Other Efficacy Analyses
3.6.4.1 Dose-Response Analysis
Due to a small number of subjects in the study, no dose-response analysis will be performed.
3.6.4.2 Efficacy Analysis for OL Treatment Period
Due to a small number of the subjects in the study, no efficacy analysis for OL Treatment 
Period will be performed.
3.6.5 Subgroup Analysis
Due to a small number of subjects in the study, no subgroup analysis will be performed.


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3.7 Patient Reported Outcomes
The study will utilize several PRO instruments. The sequence in which scoring instruments that 
contain PRO components (CDAI) or PROs will be collected at a given study visit will be the 
following order:
•
CDAI
•
Crohn’s Disease Patient Reported Outcomes (CD-PRO)
•
Inflammatory Bowel Disease Questionnaire (IBDQ)
•
PGIC-IBD (Visits 7 and 10 only)
•
Cognitive Patient Interview (selected subjects, Visit 10 or Early Termination Visit only)
Data from PGIC-IBD will be analyzed and reported separately (i.e. not in the clinical study report).
Data from cognitive patient interviews was not available on account of early study termination.  
The PRO data will be explored. A separate (supplementary) psychometric analysis plan (PAP) to 
explore the performance of the PRO instruments and to potentially develop new domain or total 
scores to inform endpoint development (including responder & remitter definitions) was developed 
by QuintilesIMS and the associated results will be reported separately in a psychometric analysis 
report (i.e. not in the clinical study report).
3.7.1 CDAI score
The two items from CDAI, “total number of liquid or very soft stools over past week” and “total 
abdominal pain score over past week”, will be descriptively summarized over time.  


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3.8 Safety Analyses
The analysis of safety endpoints will include TEAEs, laboratory values, vital signs, and ECG.  Only 
TEAEs and clinical laboratory evaluation from the 28-week placebo-controlled DB treatment period
will be summarized using the safety population.   All other safety endpoints will be listed.  No 
statistical comparisons will be performed for the safety data.
3.8.1 Adverse Events and Serious Adverse Events
Adverse events (AE) will be coded by MedDRA and the type incidence, severity and relationship to 
study investigational product will be summarized. Specific adverse events will be counted once for 
each subject for calculating percentages. In addition, if the same adverse event occurs multiple times 
within a particular subject, the highest severity and level of relationship observed will be reported. All 
AEs and SAEs collected in the database (including those starting prior to first dose of study drug) will 
be listed.  Any other information collected (e.g. relatedness to study drug, action taken etc.) will be 
listed as appropriate.
3.8.1.1 Pre-treatment AEs
The AEs with onset prior to the administration of the first dose of investigational product (MEDI2070 
or placebo) will be considered as pre-treatment AEs for the DB treatment period.  Pre-treatment AEs 
will be listed with a flag. 
3.8.1.2 Treatment-Emergent AEs during DB Treatment Period
For subjects entering the OL treatment period, the TEAE will be defined as any AE with onset on or 
after the administration of the first dose of blinded investigational product up to the day prior to 
administration of the first OL SC dose. For subjects not entering the OL treatment period, the TEAE
will be defined as any AE with onset on or after the administration of the first dose of blinded 
investigational product up to and including 28 weeks post last blinded dose.
All TEAEs including TESAEs, Adverse Event of Special Interest (AESIs), and TEAEs leading to 
permanent discontinuation of investigational product will be summarized overall. The TEAEs with 
severity grades will be summarized by grades assigned by National Cancer Institute Common 
Terminology Criteria for AEs (NCI CTCAE) V4.0. Tabular summaries of the TEAEs during the DB 
treatment period will be provided as follows:
•
Incidence rate of TEAEs by SOC and PT
•
Incidence rate of TEAEs by SOC, PT, and severity 
•
Incidence rate of related TEAE by SOC and PT
•
Incidence rate of TESIs by SOC and PT


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3.8.1.3 TEAEs during OL Treatment Period 
TEAE for the OL treatment period will be defined as any AE with onset on or after the administration 
of the first open-label SC dose of MEDI2070 up to and including 28 weeks post-last dose. Incidence 
rate of TEAEs during OL treatment period will be summarized by SOC and PT using the OL 
population.
3.8.2 Deaths and Treatment Discontinuations due to Adverse Events
Deaths and treatment discontinuation due to AEs will be listed by treatment groups.


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3.8.4 Vital Signs
Vital signs parameters, including blood pressure, temperature, pulse rate and respiration rate, will be 
obtained according to study schedule procedures.  All vital signs parameters (blood pressure, 
temperature, pulse rate, and respiration rate) will be listed. Abnormal vital sign values will be flagged.
3.8.5 Electrocardiogram
12-lead Electrocardiogram (ECG) measurements will be performed according to the study schedule.  
The ECG data will be listed. The overall interpretation of the ECG results (Normal; Abnormal, not 
Clinically Significant; and Abnormal, Clinically Significant) will be listed.  
3.9 Pharmacokinetics and Immunogenicity
The SAP for pharmacokinetics and immunogenicity will be presented separately.
4
Interim Analysis
Not applicable.


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6
Appendix
6.1 CDAI Score
The CDAI is the oldest and most widely used of several multi-item instruments that have been 
developed and is validated for use in clinical studies to measure disease activity in CD
(Best et al, 1976; Sands et al, 2005).  The CDAI measures the severity of active disease using 
symptom scores that are monitored over the previous week and includes subject-reported symptoms, 
physician-assessed signs, and laboratory markers. 
The CDAI score is calculated by summing weighted scores for subjective items (number of liquid or 
very soft stools, the degree of abdominal pain over a week (on a scale of 0-3, mild to severe) and 
general well-being (on scale of 1-4, “Generally well” to “Terrible”) recorded by a diary during a 
1-week period, and objective items (associated symptoms, taking antidiarrheal such as 
loperamide/opiates, abdominal mass, hematocrit, daily morning temperature, and body weight). The 
CDAI scores range approximately from 0 to 600, with higher scores indicating greater disease activity 
(See Table 6-1 for details). 
The CDAI will be calculated at the site in order to determine the eligibility for the study. For 
statistical analysis, CDAI for all visits will be also calculated based on the data entered in the eCRF.


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Table 6-1
Items Included in CDAI and Their Weights
Item
× Weight
Total
Total number of liquid or very soft stools over past week
×2
X1
Total abdominal pain score  (rating: 0-3) over past week (range: 0-21)
×5
X2
Total general well-being score (rating: 1-4) over past week (range: 1-28)
×7
X3
Sum of presence of following clinical signs over past week: 
1.
Arthritis/Arthralgia (1=yes, 0=no)
2.
Iritis/ uveitis(1=yes, 0=no)
3.
Erythema Nodosum/Pyoderma Gangrenosum/Aphthous Stomatitis 
(1=yes, 0=no)
4.
Anal Fissure, Fistula or Abscess (1=yes, 0=no)
5.
Other Fistula (1=yes, 0=no)
6.
Fever >37.8 C During Past Week(1=yes, 0=no)
×20
X4
Antidiarrheal use (Eg, Diphenoxylate hydrochloride) (0=none, 1=yes)
×30
X5
Abdominal mass (none=0, equivocal=2, present=5)
×10
X6
Deviation of Hematocrit levels (minimum value = 0)
      47 - hematocrit (males) 
      42 - hematocrit (females)  
×6
X7
(if value<0, 
enter 0)
Weight ratio
      100×(1-[Current body weight /  standard weight])
      Minimum = -10 for overweight subject
      Maximum = 10 for underweight subject
×1
X8
(if value<-10, 
enter -10,
if value >10, 
enter 10)
CDAI score


8
1
i
i
X
In addition, following set of rules will be applied:
For items 1, 2 and 3, if information is available only for ≤ 3 days, then CDAI score 
will be set to missing. Otherwise, the sub score for each of these three items will 
be calculated as mean value of item from available days × 7. 
For all items, if a subject doesn’t have score for any of the sub categories, CDAI 
score will be set to missing. 
Any total CDAI score < 0 will be considered as 0 in the analysis.


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Subjects with scores of < 150, 150 to 219, and 220 to 450 represent remission, mild disease, and 
moderate to severe disease, respectively; whereas subjects with scores of > 450 have very severe 
disease (Buxton et al, 2007).


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6.3 Note to File


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Statistical Analysis Plan 
 
A Phase 2b Double-blind, Multi-dose, Placebo-controlled Study to Evaluate 
the Efficacy and Safety of MEDI2070 in Subjects with Moderate to Severe 
Crohn’s Disease Who Have Failed or Are Intolerant to Anti-Tumor 
Necrosis Factor-alpha Therapy 
 
Protocol Number: D5170C00002 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION ...........................................................................................................7 
2 
STUDY OVERVIEW .....................................................................................................7 
2.1 
Study Objectives ...................................................................................................7 
2.1.1Primary Study Objective(s) ..........................................................................7 
2.1.2Secondary Study Objectives .........................................................................7 
 
2.2 
Study Design .........................................................................................................9 
2.3 
Treatment Assignment and Blinding ..................................................................11 
2.4 
Sample Size.........................................................................................................12 
3 
STATISTICAL METHODS .........................................................................................13 
3.1 
General Considerations .......................................................................................13 
3.2 
Analysis Populations...........................................................................................14 
3.3 
Handling of Dropouts and Missing Data ............................................................15 
3.3.1Missing and Incomplete Dates ....................................................................15 
3.3.2Missing Baseline Evaluation ......................................................................16 
3.3.3Missing Efficacy Evaluations .....................................................................16 
3.4 
Analysis Visit Windowing Rules ........................................................................17 
3.4.1DB Treatment Period ..................................................................................18 
3.4.2OL Treatment Period ..................................................................................19 
3.5 
Study Subjects.....................................................................................................20 
3.5.1Subject Disposition and Completion Status ...............................................20 
3.5.2Demographics and Baseline Characteristics ...............................................20 
3.5.3Study Drug Exposure ..................................................................................21 
3.5.4Prior and Concomitant Medications ...........................................................22 
3.5.5CD History ..................................................................................................23 
3.5.6Medical and Surgical History .....................................................................24 
3.5.7Physical, Neurological and Visual Examination ........................................24 
3.5.8Protocol Deviations.....................................................................................24 
3.6 
Efficacy Analyses ...............................................................................................25 
3.6.1Primary Efficacy Endpoint(s) and Analyses ...............................................25 
3.6.1.1 
Primary Efficacy Endpoint(s) ...................................................25 
3.6.1.2 
Primary Efficacy Analysis ........................................................25 
3.6.1.3 
Additional Analyses of the Primary Efficacy Endpoint ...........26 
3.6.2Secondary Efficacy Endpoint(s) and Analyses ...........................................27 
3.6.2.1 
Secondary Efficacy Endpoint(s) ...............................................27 
3.6.2.2 
Secondary Efficacy Analyses ...................................................29 
3.6.2.3 
Predictive Biomarker Analyses.................................................30 


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3.6.3Exploratory Efficacy Endpoint(s) and Analyses ........................................32 
3.6.3.1 
Exploratory Efficacy Endpoint(s) .............................................32 
3.6.3.2 
Analyses of Exploratory Endpoints ..........................................33 
 
3.6.4.1 
Dose-Response Analysis ...........................................................34 
3.6.4.2 
Efficacy Analysis for OL Treatment Period .............................36 
3.6.5Subgroup Analysis ......................................................................................36 
3.7 
Patient Reported Outcomes ................................................................................38 
3.7.1CDAI score .................................................................................................38 
 
 
3.8 
Summary of Analyses .........................................................................................40 
3.9 
Safety Analyses...................................................................................................42 
3.9.1Adverse Events and Serious Adverse Events .............................................43 
3.9.1.1 
Pre-treatment AEs .....................................................................43 
3.9.1.2 
Treatment-Emergent AEs during DB Treatment Period ..........43 
3.9.1.3 
TEAEs during OL Treatment Period ........................................44 
3.9.2Adverse Events of Special Interest (AESI).................................................44 
3.9.3Deaths and Treatment Discontinuations due to Adverse Events ................45 
 
3.9.4.1 
Vital Signs .................................................................................46 
3.9.4.2 
Electrocardiogram .....................................................................47 
3.10 Pharmacokinetics and Immunogenicity ..............................................................47 
4 
INTERIM ANALYSIS..................................................................................................47 
 
 
6 
APPENDIX ...................................................................................................................49 
6.1 
CDAI Score.........................................................................................................49 
6.2 
 
6.3 
 
6.4 
 
 
LIST OF IN-TEXT TABLES 
Table 3.2-1 
Analysis Populations ............................................................................15 
Table 3.3.1-1  
Missing Dates Imputation Rules ..........................................................16 
Table 3.4.2-1  
General Analysis Visit Windows for DB Treatment Period ................18 
  
 
  
 
 


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Table 3.6.2.1-1  
List of Secondary Endpoints ................................................................28 
Table 3.6.2.3-1  
List of Efficacy Endpoints for Predictive Biomarker Analyses ...........30 
  
 
Table 3.6.4.1-1  
Candidate Dose-response Models ........................................................35 
Table 3.6.5-1  
List of Efficacy Endpoints for Subgroup Analysis ..............................37 
Table 3.6.5-2  
List of Subgroups of Interest................................................................37 
Table 3.8-1   
Summary of Efficacy Endpoints and Analyses ...................................40 
Table 3.9.2-1 
AESIs Categories .................................................................................44 
 
 
Table 6.1-1  
Items Included in CDAI and Their Weights ........................................50 
 
 
  
 
   
 
   
 
 


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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event Of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the serum concentration-time Cure 
CI 
Confidence Interval 
CD 
Crohn’s Disease 
CDAI 
Crohn’s Disease Activity Index 
 
 
CRP 
C-reactive protein 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
DB 
Double-Blind 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
e-diary 
Electronic diary 
EOS 
End of Study 
IBD 
Inflammatory Bowel Disease 
 
 
IL 
interleukin 
IM 
Immunogenicity 
ITT 
Intent To Treat 
IV 
Intravenous 
IVRS/IXRS 
Interactive Voice/Web Response System 
 
 
LLOQ 
Lower Limit of Quantification 
MACE 
Major Adverse Cardiac Events 


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Abbreviation or 
Specialized Term 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP-Mod 
Multiple Comparison Procedure - Modelling 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse events 
OL 
Open-Label 
PGIC-IBD 
Patient Global Impression of Change-Inflammatory Bowel Disease 
PK 
Pharmacokinetic (s) 
PT 
Preferred Terms 
PROs 
Patient Reported Outcomes 
PRO2 
Patient-Reported Outcomes-2 score 
Q4W 
Every 4 Weeks 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SPP 
Statistical Programming Plan 
SC 
Subcutaneous 
 
SD 
Standard Deviation 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SIDES 
Subgroup Identification based on Differential Effect Search 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
STEPP 
Subpopulation Treatment Effect Pattern Plot 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TNFα 
Tumor Necrosis Factor-alpha 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
 
 


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1 
INTRODUCTION 
This document describes the statistical analyses plan specified in the protocol D5170C00002.  
The scope of this plan addresses statistical analyses as they apply to safety and efficacy 
objectives, including the primary, intermediate and final analyses unless otherwise specified 
(e.g. analyses related to pharmacokinetic (PK) and translational science measurements will 
not be discussed in this document).  A separate statistical programming plan (SPP), 
containing table templates and specifications, will be created to be used in conjunction with 
this document. 
 
 
2 
STUDY OVERVIEW 
2.1 
Study Objectives 
2.1.1 
Primary Study Objective(s) 
To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission based on 
the CDAI score at Week 8 in subjects with moderate to severe Crohn’s Disease (CD) who 
have failed or are intolerant to anti-TNFα therapy. 
 
2.1.2 
Secondary Study Objectives 
Induction Period Secondary Objectives:  
1.  To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 16
 
based on the Simple Endoscopic Score for Crohn’s Disease (SES-CD) 
2.  To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 16
 
based on the SES-CD 
3.  To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 8
 
based on the Patient-reported Outcomes 2 score (PRO2) 
4.  To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 8 
 
based on the PRO2 
5.  To evaluate the efficacy of MEDI2070 versus placebo to induce clinical response at 
 
Week 8 based on the CDAI 
6.  To evaluate the efficacy of MEDI2070 versus placebo to induce remission at Week 16
 
based on the PRO2 
7.  To evaluate the efficacy of MEDI2070 versus placebo to induce response at Week 16
 
based on the PRO2 
8.  To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission at
 
Week 16 based on the CDAI 


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9.  To evaluate the efficacy of MEDI2070 versus placebo to induce clinical response at 
 
Week 16 based on the CDAI 
10. To demonstrate safety and tolerability of MEDI2070 therapy 
11. To characterize the pharmacokinetics (PK) and immunogenicity of MEDI2070 
12. To characterize the dose-response and exposure-response relationships 
 
 
 
 
Maintenance Period Secondary Objectives:  
1.  To evaluate the efficacy of MEDI2070 versus placebo to induce clinical remission based
 
on CDAI score at Week 28 
2.  To evaluate the efficacy of MEDI2070 versus placebo on remission at Week 28 based on
 
the SES-CD 
3.  To evaluate the efficacy of MEDI2070 versus placebo on remission at Week 28 based on
 
the PRO2 
4.  To evaluate the efficacy of MEDI2070 versus placebo on modified sustained remission,
 
defined as remission at both Week 16 and at Week 28 based on the SES-CD 
5.  To evaluate the efficacy of MEDI2070 versus placebo on modified sustained remission,
 
defined as remission at both Week 8 and at Week 28 based on the PRO2 
6.  To evaluate the efficacy of MEDI2070 versus placebo on modified sustained clinical 
 
remission, defined as clinical remission at both Week 8 and at Week 28 based on the 
 
CDAI 
7.  To evaluate the efficacy of MEDI2070 versus placebo on response at Week 28 based on 
 
the SES-CD 
8.  To evaluate the efficacy of MEDI2070 versus placebo on response at Week 28 based on
 
the PRO2 
9.  To evaluate the efficacy of MEDI2070 versus placebo on clinical response at Week 28
 
based on the CDAI 
10. To demonstrate safety and tolerability of MEDI2070 therapy 
11. To characterize the PK and immunogenicity of MEDI2070 
 
 
 
 
 
 
 
  
 
  
 
 


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2.2 
Study Design 
This is a 3-part Phase 2b study comprising a 16-week, double-blind, placebo-controlled, 
induction period; a 12-week double-blind, placebo-controlled, maintenance period; and a 24-
week, open-label period designed to evaluate the short-term efficacy and the short- and long- 
term safety of MEDI2070 in subjects with moderate to severe, active CD who have failed or 
are intolerant to anti-TNFα therapy as determined by the investigator. Subjects will be 
stratified based on the number of prior anti-TNFα agents that they have failed (1 versus > 1).  
Approximately 342 subjects at approximately 300 centers worldwide will be randomly 
assigned to 1 of 5 treatment groups to receive intravenous (IV) and subcutaneous (SC) 
investigational product (MEDI2070 or placebo) once every 4 weeks (Q4W) during the 
double-blind, placebo-controlled induction and maintenance periods. Subjects who complete 
the double-blind, placebo controlled maintenance period (Week 28) will have the option to 
enter a 24-week, open-label period in which they will receive open-label MEDI2070 (210 mg 
SC) Q4W (Weeks 28 through 48). All subjects will be followed for safety at 3 visits over 28 
weeks (Weeks 60, 70, and 80 for subjects completing the open-label period) after their last 
dose of investigational product. 


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2.3 
Treatment Assignment and Blinding 
Subjects will receive investigational product (MEDI2070 or placebo) by IV infusion and/or 
SC injection at Week 0 (Day 1) then once Q4W during the 16-week, double-blind, placebo-
controlled, induction period (ie, Weeks 4, 8, and 12) and the 12-week double-blind, placebo-
controlled, maintenance period (ie, Weeks 16, 20, and 24). All subjects who complete the 
double-blind maintenance period will have the option to enter the 24-week open-label 
treatment period. All subjects entering the open-label period will receive open-label 
MEDI2070 (210 mg SC) once Q4W (ie, Weeks 28, 32, 36, 40, 44, and 48).  
A total of approximately 342 subjects will be randomly assigned to one of five treatment 
groups: 


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Treatment 
Group 
 
Double-blind Period 
Open-label 
Period 
Induction 
Maintenance 
Week 0 
Week 4 
Weeks 8, and 
12 
Weeks 16, 20, 
and 24 
Weeks 28, 32, 36, 
40, 44, and 48 
Treatment 
Group 1  
High (n = 
76) 
700 mg 
MEDI2070 IV + 
placebo SC 
700 mg 
MEDI2070 IV + 
placebo SC 
210 mg 
MEDI2070 SC 
210 mg 
MEDI2070 SC 
210 mg 
MEDI2070 SC 
Treatment 
Group 2  
High-
medium (n 
= 76) 
280 mg 
MEDI2070 IV + 
placebo SC  
210 mg 
MEDI2070 SC 
+ placebo IV  
210 mg 
MEDI2070 SC 
210 mg 
MEDI2070 SC 
210 mg 
MEDI2070 SC 
Treatment 
Group 3  
Low-
medium (n 
= 76) 
210 mg 
MEDI2070 SC 
+ placebo IV  
105 mg 
MEDI2070 SC 
+ placebo IV  
105 mg 
MEDI2070 SC 
105 mg 
MEDI2070 SC 
210 mg 
MEDI2070 SC 
Treatment 
Group 4  
Low (n = 
38) 
70 mg 
MEDI2070 SC 
+ placebo IV  
35 mg 
MEDI2070 SC 
+ placebo IV  
35 mg 
MEDI2070 SC 
35 mg 
MEDI2070 SC 
210 mg 
MEDI2070 SC 
Treatment 
Group 5  
Placebo (n 
= 76) 
Placebo SC and 
IV 
Placebo SC and 
IV 
Placebo SC 
Placebo SC 
210 mg 
MEDI2070 SC 
IV = intravenous; SC = subcutaneous 
 
 
 
2.4 
Sample Size 
With a total sample size of approximately 342 and a randomization ratio of 2:1:2:2:2, the 
sample sizes are 76, 38, 76, 76, and 76 for placebo and MEDI2070 low, low-medium, high-
medium, and high dose groups, respectively. A 10% dropout rate is assumed for each 
treatment group during the induction period. 
Assuming a placebo CDAI remission rate of 12% and MEDI2070 high dose CDAI remission 
rate of 31% at Week 8 of the induction period, approximately 76 subjects per treatment group 
will provide at least 85% power to detect a 19% difference in CDAI remission rates at Week 


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8 between MEDI2070 high dose versus placebo, using a two-sided test at a significance level 
of α = 0.10. The minimum detectable difference in CDAI remission rates at Week 8 will be 
11%.  
Assuming a 5% placebo SES-CD remission rate and 20% MEDI2070 high dose SES-CD 
remission rate at Week 16 of the induction period, the given sample size will provide at least 
81% power to detect a 15% difference in SES-CD remission rates at Week 16 between 
MEDI2070 high dose versus placebo using a two-sided test at a significance level of α = 
0.10. The minimum detectable difference in SES-CD remission rates at Week 16 will be 
10%.   
 
 
 
 
 
 
 
 
 
 
 
   
 
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.  Data from OL period will be summarized by 
DB treatment group in additional to overall column.  
All efficacy data will be analyzed using the analysis visits. The analysis visit windowing rules 
will be defined based on study days of post-baseline. The details of analysis visit windowing 
rules will be described in Section 3.4.  
Day 1 will be defined as the day of first investigational product administration.  For any 
variable, unless otherwise defined, the baseline value is the last non-missing assessment 


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taken prior to the first investigation product administration. 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. 
For the purpose of statistical analyses, the data from DB treatment period (induction and 
maintenance periods) and OL treatment period will be analyzed separately.  Unless otherwise 
stated, all efficacy analyses will be conducted with a two-sided test at a significance level of 
α = 0.10.  Nominal p-values will be provided without multiplicity adjustment.     
In addition, the following conventions will be applied to all data presentations and analyses. 
 For continuous endpoints, arithmetic mean, and median will be formatted to one more 
decimal place than the measured value.  SD will be formatted to two more decimal 
place than the measured value.  Minimum and maximum values will be presented 
with the same number of decimal places as the measured value.  Confidence limits 
will be presented to the same decimal places as the point estimate. 
 For categorical variables, the count and percentage of responses will be presented in 
the form XX (XX.X%) where the percentage is in the parentheses.  
 Nominal p-values will be rounded to three decimal places using the following 
algorithm.  If the fourth digit of the p-value is less than or equal to 4 the p-value will 
be rounded down. If the fourth digit of the p-value is greater than or equal to 5, the p-
value will be rounded up.  All p-values rounded to 0.000 will be presented as 
“<0.001” and p-values rounded to 1.000 will be presented as “>0.999”.   
 Data analyses will be conducted using SAS® version 9.3 (SAS Institute Inc., Cary, 
NC) or higher in UNIX platform. 
3.2 
Analysis Populations 
The analysis populations are defined in Table 3.2-1. 


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Table 3.2-1 
Analysis Populations 
Population 
Description 
Intent-to-treat 
(ITT) population 
The Intent-to-Treat (ITT) Population includes all subjects who are randomized into the 
study and receive at least one dose of investigational product for the 28-week, double-
blind, placebo-controlled treatment period.  Subjects will be analysed according to their 
randomized treatment group, regardless of whether they receive an investigational 
product that is different from what they were randomized to. 
As-treated 
population 
The As-treated Population includes all subjects who receive at least one dose of 
investigational product.  Subjects will be analyzed according to the actual treatment 
received during the placebo-controlled, double-blind treatment period even if it is 
different from what the subject is randomized to.   
Open-label 
population 
Open-label population includes all subjects who are enrolled in the open-label treatment 
period and have at least one dose of open-label MEDI2070 210 mg SC treatment.   
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 
MEDI2070.   
 
 
3.3 Handling of Dropouts and Missing Data  
Subjects may be missing specific data points for a variety of causes. In general, data may be 
missing due to a subject’s early withdrawal from study, a missed visit, or inability to evaluate 
an endpoint at a particular point in time. The general procedures outlined below describe 
what will be done when a data point is missing. Missing safety endpoints will not be 
imputed. 
3.3.1 
 Missing and Incomplete Dates 
For any listings, missing or incomplete dates will be listed as is.  
In the case where the start or stop date of an event or medication is missing or incomplete, 
the following rules will be applied in the analysis: 


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Table 3.3.1-1  
Missing Dates Imputation Rules 
Missing 
Imputation 
Exception 
Start date 
(Medical 
History, Adverse 
Events, 
concomitant 
medication) 
Day 
01 
Default to Study Day 1 if an event 
starts the same year and month as 
Study Day 1 and Stop date is after 
Study Day 1 
Day/Month 
01JAN 
Default to Study Day 1 if an event 
started the same year as Day 1 and 
Stop date is after Study Day 1 
Day/Month/Year 
No imputation 
Stop date 
(concomitant 
medication) 
Day 
Last day of the month 
Default to the End of Study Date or 
the primary analysis cut-off date for 
ongoing subjects if the concomitant 
medication stopped the same year and 
month as the End of Study Date or 
primary analysis cut-off date 
Day/Month 
31DEC 
Default to the End of Study Date or 
the primary analysis cut-off date for 
ongoing subjects if the concomitant 
medication stopped the same year as 
the End of Study Date or primary 
analysis cut-off date 
Day/Month/Year 
No imputation 
 
3.3.2 
Missing Baseline Evaluation 
For any endpoint, unless otherwise defined, the baseline value is the last non-missing 
assessment taken prior to the first investigational product administration. If the baseline is 
still missing following above definition, the baseline evaluation will not be imputed and will 
be considered as missing. 
3.3.3 
Missing Efficacy Evaluations  
Through the end of the DB period (induction and maintenance periods), the missing efficacy 
data will be handled as described below: 
 Missing data for dichotomous endpoints will be handled using the non-responder 
imputation method, i.e. any subject with missing information on the endpoint will be 
assumed as a non-responder.  In addition, subjects with a clinically meaningful 
increase in steroid use will also be assumed to be a non-responder for the primary 


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analysis perspective.  Clinical meaningful increase in steroid dose is defined as an 
increase of at least 5 mg/day for at least 3 days of prednisone, or equivalent, or an 
increase of at least 3mg/day for at least 3 days of budesonide. 
 Missing data for continuous measures will not be imputed. The continuous measures 
will be analyzed using the repeated measure mixed effects model adjusting for prior 
anti-TNFα agent use and baseline covariate, assuming the missing at random 
mechanism. Other missing data imputation method (e.g. multiple imputation) may be 
explored.  
 Missing data for PRO components (e.g. IBDQ, CD-PRO) will be handled according 
to the scoring algorithm as described in corresponding sections. If the score is still 
missing, no further imputation will be done. 
 
Through the end of the OL period, the missing efficacy data will be handled as described 
below: 
• Missing data for dichotomous endpoints will be handled using the non-responder 
 
imputation method in a similar way of the DB period.   
• Missing data for continuous measures will not be imputed and will be summarized as 
 
observed. 
• Missing data for PRO components (e.g. IBDQ, CD-PRO) will be handled in the 
 
same way as the DB period.  
 
3.4 
Analysis Visit Windowing Rules 
The actual visit for a subject may not exactly coincide with their targeted visit date. The 
actual visit date will be mapped to the study visit following the analysis visit windowing 
rules below. Unless specified otherwise, all efficacy and safety analyses will be based on the 
analysis visits. If there are multiple records fall within the same defined analysis visit 
window, the non-missing record closest to the target day will be considered for the analysis.  
If two non-missing assessment actual dates are equidistant from the target day, the later visit 
will be considered for analysis.  
Composite endpoints (e.g. CDAI score) will be calculated for each date  at which individual 
components are being measured before applying the analysis visit windows rather than to 
calculate visit window based individual component. 


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3.4.1 
DB Treatment Period 
DB Period Study Day 1 is defined as the first day of DB IP administration. For subjects who 
are randomized but not dosed after randomization, the Day 1 is defined as the date of 
randomization.  
DB Period Study Day is defined as the number of days from the Double-Blind Period Study 
Day 1. 
• Before DB Period Study Day 1: 
Double-Blind Period Study Day = (Date of Interest – Date of DB Period Study Day 1) 
• On or After DB Period Study Day 1: 
DB Period Study Day = (Date of Interest – Date of DB Period Study Day 1) + 1 
Unless otherwise specified, all efficacy analysis will apply the analysis visit window rules as 
defined in 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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3.4.2 
OL Treatment Period 
OL Period Study Day 1 is defined as the first day of OL IP administration. OL Period Study 
Day is defined as the number of days from OL Period Study Day 1. 
• Before OL Period Study Day 1: 
Open-Label Period Study Day = (Date of Interest – Date of OL Period Study Day 1) 
• On or After OL Period Study Day 1: 
OL Period Study Day = (Date of Interest – Date of OL Period Study Day 1) + 1. 


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3.5 
Study Subjects 
3.5.1 
Subject Disposition and Completion Status 
A summary of subject disposition throughout the study with respect to completion of double-
blind induction and maintenance periods and open-label period will be provided.  The 
number and percentage will be provided by treatment groups and overall using the ITT 
population and OL population, respectively. The timing of and reasons for early withdrawal 
from treatment and from study will be tabulated and listed. 
3.5.2 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be listed for each subject. Following 
demographics and baseline characteristics will be summarized by treatment groups and 
overall using the ITT population and OL population, respectively.  A summary of baseline 
disease characteristics may include, but not be limited to: 
 Age  
 Age (< 40 years, ≥ 40 years) 
 Sex (Male, Female) 
 Race (White, Black/African American, Asian, Other) 
 Race (White, Non-white) 
 Region (US, Non-US) 
 Disease duration of CD (years) 
 Disease duration (< 2 years, ≥ 2 years ) 
 Disease duration (< 5 years, ≥ 5 years ) 
 Ethnic group (Hispanic or Latino, Other) 
 Height (cm) 
 Weight (kg) 
 BMI (kg/m2) 


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 Baseline disease location (ileum, not colon; colon, not ileum; or ileo-colonic, as 
observed at baseline ileocolonoscopy) 
 Baseline CDAI score 
 Baseline weekly abdominal pain score 
 Baseline weekly loose/liquid stool count 
 Baseline SES-CD score 
 Baseline SES-CD score by baseline disease location subgroup (per subgroup of 
subjects with ileum, not colon; colon, not ileum; or ileo-colonic disease) 
 Baseline CRP (mg/L) 
 Baseline CRP (< 5 mg/L, ≥ 5 mg/L) 
 Baseline fecal calprotectin (μg/g) 
 Baseline fecal calprotectin (< 250 μg/g,  ≥ 250 μg/g) 
 Baseline fecal calprotectin (< 200 μg/g, ≥ 200 μg/g) 
 Baseline IL22 (unit) 
 
 
 Baseline IBDQ score 
 Alcohol status(Never, Current and Former) 
 Number of prior use of anti-TNF agents (1, > 1) 
 Number of prior use of anti-TNFα agents (1, 2,  ≥ 3) 
 Prior use of vedolizumab (Yes, No) 
 Use of 5-aminosalicylatesat baseline (Yes, No) 
 Use of corticosteroids at baseline (Yes, No) 
 Use of immunomodulators at baseline (Yes, No) 
 Smoking status at baseline (Never, Current, Former) 
3.5.3 
Study Drug Exposure 
Descriptive statistics for extent of exposure (in days) will be presented for the as-treated 
population and the OL population during the specified treatment period.  
For DB period, the following summaries will be provided using for the as-treated population:  
 Duration of exposure in the DB period 


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 Number of doses received 
 Number and percentage of subjects received the entire dose 
For OL period, the following summaries will be provided using the OL population: 
 Duration of exposure in the OL period 
 Number of doses received  
 Number and percentage of subjects received the entire dose by visit 
Additionally, descriptive statistics for the cumulative exposure for overall MEDI2070 will be 
provided. If a subject entered both the DB period and OL period, the subject will be considered 
as the same subject and the exposure data will be combined from both periods. 
3.5.4 
Prior and Concomitant Medications 
Prior medication refers to all medications that were started prior to the start of the first dose 
of investigational product.  
Concomitant medication refers to all medications taken during the treatment period of the 
DB period and the OL period.  Concomitant medications include medications continued from 
pre-treatment. Medications with missing start and stop dates will be counted as concomitant 
medications. Medications with partial start or stop dates will be handled as described in 
Section 3.3.1.  Medications with start and stop dates which bracket the first dose date will be 
summarized as both prior and concomitant medications. 
All prior and concomitant medications data will be coded by Medimmune approved drug 
dictionary (AstraZeneca Drug Dictionary or WHODrug) and listed for each subject by 
treatment groups.  The number and percentage of subjects taking at least one prior or 
concomitant medication will be presented by Preferred Term (PT) and treatment group for 
the DB and OL treatment periods using the ITT population and the OL population, 
respectively.  The following summary tables will be provided for the prior and concomitant 
medications: 
 Prior disease related treatments 
 Concomitant medication taken for CD 
 Concomitant medications for reason other than CD 
 Disallowed concomitant medications 
 


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In addition, the number and percentage of subjects receiving the following selected 
medications: 5- aminosalicylates, prednisone, and immunomodulators (e.g. methotrexate, 
azathioprine, and 6-mercaptopurine) will be summarized for each treatment group as coded.  
The dose level of oral corticosteroid will be summarized by visit.  
3.5.5 
CD History 
The CD history will be summarized descriptively using the ITT population. In particular,  
 Summary of Crohn’s location by category for current, at the original diagnosis, and at 
any past time. The Crohn’s location categories include Colon, not ileum; Ileocolonic 
(ileum and colon); Ileum, not colon; Extra-intestinal. 
 Summary of subjects with anti-TNF use 
 
Number and percentage of subjects with anti-TNF use 
 
Number and percentage of subjects with prior use of following anti-TNF: 
Infliximab, Adalimumab, Certolizumab pegol, Golimumab. 
 
Descriptive summary of time since first use of anti-TNF by type of anti-TNF 
 
Number and percentage of subjects by primary reason for stopping prior anti-
TNF: Primary failure, Secondary failure, Intolerance, Not applicable, Other 
 Summary of subjects with biologics agents other than anti-TNF agents  
 
Number and percentage of subjects with biologics agents other than anti- 
 
TNF agents 
 
Number and percentage of subjects with prior use of Vedolizumab 
 
Number and percentage of subjects by primary reason for stopping prior 
Vedolizumab: Primary failure, Secondary failure, Intolerance, Not applicable, 
Other 
 Summary of subjects with immunomodulator 
 
Number and percentage of subjects with prior immunomodulator 
 
Number and percentage of subjects with prior use of following 
immunomodulator: Methotrexate, Azathioprine, 6-mercaptopurine,Other 
 
Descriptive summary of time since first use of immunomodulator 
 Summary of subjects with fistula and stricture/obstruction 
 
Number and percentage of subjects with history of fistula 
 
Number and percentage of subjects with fistula at baseline 
 
Number and percentage of subjects with stricture/obstruction 


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3.5.6 
Medical and Surgical History 
The MedDRA Preferred Term (PT) in the medical history and surgical history will be 
summarized by the number and percentage of subjects for each treatment group and overall 
using the ITT population. 
3.5.7 
Physical, Neurological and Visual Examination 
All data related to physical, neurological and visual examination will be listed for each 
subject.  
The physical and neurological examination will be summarized by visit and treatment groups 
using the ITT population and the OL population respectively. Frequency count and 
percentages will be presented. 
The visual examination will include following parameters: 
 Best corrected near vision (Right eye, Left eye) 
 Best corrected distance vision (Right eye, Left eye)  
Summary statistics of best corrected near and distance vision for both eyes will be presented 
using the decimal format of the acuity notation.  The visual acuity notation conversions can 
be found in Appendix. Change from baseline will be calculated and categorized as < 0 
(worsened vision), 0 (no change) and > 0 (improved vision). Frequency count and 
percentages based on the defined categories will be presented. 
3.5.8 
Protocol Deviations 
Protocol deviations (PDs), will be recorded and are classified as major and minor deviation 
under following categories: 
 Did not fulfil eligibility criteria   
 Developed discontinuation criteria but continued IP treatment  
 Received incorrect investigational treatment/dose  
 Received prohibited concomitant medication  
 Protocol-required procedure not adhered to 
 Other 


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Tabulation of major protocol deviations by category will be provided by treatment group. 
The number of percentage of subjects who had at least one major protocol violation or 
deviation will be summarized in total and by treatment group. A supporting data listing will 
be provided as well. 
 
3.6 
Efficacy Analyses 
Efficacy data from the DB treatment period and the OL treatment period will be analyzed 
separately.  All efficacy endpoints will be summarized by treatment group.  
3.6.1 
Primary Efficacy Endpoint(s) and Analyses 
3.6.1.1 
Primary Efficacy Endpoint(s) 
The primary efficacy endpoint is Crohn’s Disease Activity Index (CDAI) remission at Week 
8.  CDAI remission is defined as a CDAI score of < 150.  Refer to Appendix 6.1 for detail on 
CDAI score.  
3.6.1.2 
Primary Efficacy Analysis 
The primary analysis will be conducted in the ITT population.  The primary efficacy 
endpoint is CDAI remission at Week 8 of the induction period.  The null and alternative 
hypotheses for the primary endpoint are: 
H0: There is no difference between the proportions of CDAI remission in MEDI2070 high 
dose group and placebo at Week 8 for subjects with moderate to severe CD who have failed 
or are intolerant to anti-TNFα therapy. 
versus 
H1: There is difference between the proportion of CDAI remission in MEDI2070 high dose 
group and placebo at Week 8 for subjects with moderate to severe CD who have failed or are 
intolerant to anti-TNFα therapy. 
The primary comparison of interest will be MEDI2070 high-dose group versus placebo.  The 
comparisons between MEDI2070 high-medium dose group versus placebo, low-medium 
dose group versus placebo, and MEDI2070 low dose group versus placebo will also be 
conducted. Nominal p-values will be presented without multiplicity adjustment.  
P-values for comparisons between any MEDI2070 dose group and placebo will be obtained 
from a logistic regression model adjusting for prior anti-TNFα use (1 versus >1).  In the 


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event the number of remissions is too small (i.e. < 5), the exact logistic regression will be 
performed instead.  The statistical significant treatment effect will be tested against 2-sided 
alpha level of 0.10. The odds ratio and associated 90% confidence interval from the 
aforementioned logistic regression model will be presented.  
In addition, the difference in CDAI remission rates at Week 8 between MEDI2070 dose 
groups and placebo group and associated 90% confidence interval will be provided using the 
logistic regression with delta method approach (Ge et al, 2011). In the event the number of 
remission is too small (i.e. < 5), the unconditional exact confidence interval for the difference 
in CDAI remission at Week 8 between MEDI2070 dose groups and placebo group will be 
provided using Agresti and Ming (2001)’s approach via STATXACT. The pseudo SAS code 
can be found in the SPP. 
3.6.1.3 
Additional Analyses of the Primary Efficacy Endpoint 
The following sensitivity analyses will be performed for the primary efficacy endpoints in 
the ITT population using the non-responder imputation: 
1.   A sensitivity analysis for the primary efficacy endpoint will be performed by extending 
the logistic regression model planned above via adjusting for baseline CDAI score. The 
odds ratio between each MEDI2070 dose group and placebo and associated 90% 
confidence interval will be presented. 
2.  A stratified Cochran-Mantel-Haenszel (CMH) row mean score test adjusting for prior 
 
anti-TNFα use (1 versus > 1) will be conducted for the primary efficacy endpoint using 
 
the ITT population. In the event of small number of remissions (i.e. < 5), the stratified 
 
conditional exact test will be performed via STATXACT.  P-value, point estimate of 
 
common odds ratio and associated 90% mid-p corrected exact confidence interval will be 
 
presented.  
3.   Other baseline covariates will be explored by extending the logistic regression model via 
adjusting for baseline CDAI score and/or other baseline covariates. The following 
baseline covariates may be assessed and the final model will only include the significant 
baseline covariates (p < 0.10). The odds ratio between each MEDI2070 dose group and 
placebo and associated 90% confidence interval from the logistic regression model will 
be presented.  
 Region (US, Non-US) 
 Disease duration 


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 Baseline CDAI score  
 Baseline IL22 
 
 
 Baseline CRP  
 Baseline weekly abdominal pain score 
 Baseline weekly loose/liquid stool count  
 Baseline SES-CD score 
 Baseline fecal calprotectin 
 Smoking status at baseline  
 
3.6.2 
Secondary Efficacy Endpoint(s) and Analyses 
3.6.2.1 
Secondary Efficacy Endpoint(s) 
Remission and response will be assessed by both clinical and patient reported outcomes 
(PRO) measures. The following definitions will be used to define the secondary efficacy 
endpoints: 
• CDAI clinical response: Decrease from baseline in the CDAI of ≥ 100 points 
• SES-CD remission: Total SES-CD score ≤ 4, with: 
◦ 
No subscore > 2, and 
◦ 
Segments scored at baseline that cannot be observed on a subsequent examination 
will be scored with an imputed value unchanged from baseline  
• SES-CD response: Decrease from baseline in SES-CD ≥ 50%; segments scored at 
baseline that cannot be observed on a subsequent examination will be scored with an 
imputed value unchanged from baseline.  
• PRO2 remission (loose/liquid stool frequency/abdominal pain): Remission achieved for 
both abdominal pain and loose/liquid stool frequency 
• PRO2 response: (loose/liquid stool frequency/abdominal pain): Remission or response in 
one symptom (either abdominal pain or stool frequency) plus response in the other 
◦ 
Abdominal pain remission: On an 11-point (0 to 10) pain scale: During 1 week, no 
daily score > 2 
◦ 
Abdominal pain response: On an 11-point (0 to 10) pain scale: ≥ 30% reduction in 
weekly pain score from baseline 


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◦ 
Loose/liquid stool frequency remission: Counting stools identified as Type 6 or 7 on 
Bristol Stool Scale, during 1 week, each daily loose loose/liquid stool count ≤ 3 
◦ 
Loose/liquid stool frequency response: Counting stools identified as Type 6 or 7 on 
Bristol Stool Scale, ≥ 30% reduction in weekly loose/liquid stool count compared to 
baseline 
Refer to Appendix 6.1 and Appendix 6.2 for details on CDAI score and SES-CD score. 
Table 3.6.2.1-1  
List of Secondary Endpoints 
 
Secondary Efficacy Endpoints 
Induction Period 
Week 8 
PRO2 Remission  
Abdominal pain remission  
Loose/liquid stool frequency remission  
 
 
 
 
 
 
PRO2 Response 
Abdominal pain response 
Loose/liquid stool frequency response 
CDAI clinical Response 
 
Week 16 
SES-CD Remission  
PRO2 Remission  
CDAI clinical  remission 
Abdominal pain remission  
Loose/liquid stool frequency remission  
SES-CD Response 
PRO2 Response 
CDAI clinical response 
Abdominal pain response 
Loose/liquid stool frequency response 
Maintenance Period 
Week 28 
CDAI clinical remission  
SES-CD Remission  
PRO2 Remission  
Abdominal pain remission   
Loose/liquid stool frequency remission  
CDAI clinical response 
SES-CD Response 
PRO2 Response 
Abdominal pain response 
Loose/liquid stool frequency response 
Other 
CDAI Modified sustained clinical remission at Week 8 and 28 
 
 
 


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3.6.2.2 
Secondary Efficacy Analyses 
The efficacy data from the DB induction and maintenance treatment periods will be 
summarized descriptively and displayed graphically by treatment group and by visit using the 
ITT Population.  
The secondary efficacy endpoints with dichotomous outcomes will be analyzed similarly as 
the primary analysis of the primary efficacy endpoint using the ITT population.   The 
following sensitivity analysis will be performed for the selected secondary endpoints (e.g. 
SES-CD and PRO2 endpoints, CDAI remission) in the DB induction period: 
1.   A logistic regression model with treatment, randomization stratification factor and 
corresponding baseline score (e.g., baseline SES-CD score, baseline CDAI score, 
baseline weekly abdominal pain score, baseline weekly loose/liquid stool count) will be 
performed. 
2.  A stratified Cochran-Mantel-Haenszel (CMH) row mean score test adjusting for prior 
anti-TNFα use (1 versus > 1) will be conducted. In the event of small number of 
remissions (i.e. < 5), the stratified conditional exact test will be performed via 
STATXACT.   
3.   Other baseline covariates will be explored by extending the logistic regression model via 
adjusting for baseline CDAI score and/or other baseline covariates. The following 
baseline covariates may be assessed and the final model will only include the significant 
baseline covariates (p < 0.10).  
 Region (US, Non-US) 
 Disease duration 
 Baseline CDAI score  
 Baseline IL22 
 
 
 Baseline CRP  
 Baseline weekly abdominal pain score 
 Baseline weekly loose/liquid stool count 
 Baseline SES-CD score 
 Baseline fecal calprotectin 
 Smoking status at baseline  


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3.6.2.3 
Predictive Biomarker Analyses 
To evaluate the predictive biomarkers, serum IL-22 and serum 
 for their value in 
predicting MEDI2070’s efficacy for induction and maintenance of response and remission, 
two types of the analyses will be performed for the following efficacy endpoints at the DB 
treatment period.  
Table 3.6.2.3-1  
List of Efficacy Endpoints for Predictive Biomarker 
Analyses 
DB Treatment Period 
Efficacy Endpoints 
Induction  
CDAI clinical remission at Week 8 
CDAI clinical remission at Week 16 
SES-CD remission at Week 16, SES-CD response at Week 16 
PRO2 remission at Week 8, PRO2 response at Week 8  
PRO2 remission at Week 16, PRO2 response at Week 16 
Maintenance 
SES-CD remission at Week 28, SES-CD response at Week 28 
CDAI modified sustained clinical remission at Week 8 and Week 28 
 
 
 
 
 
 
 
  
 
 
 


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Figure 3.6.2.3-1 
Effective Dose Determination Diagram 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
SES-CD 
effective? 
Yes 
Dose X 
PRO2 effective? 
SES-CD 
effective? 
No 
Not Effective 
No 
Yes 
Effective 
No 
Undefined  
Assess further  
Yes 


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3.6.3 
Exploratory Efficacy Endpoint(s) and Analyses 
3.6.3.1 
Exploratory Efficacy Endpoint(s) 
Induction Period Exploratory endpoints:  
Table 3.6.3.1-1  
List of Exploratory Efficacy Endpoints  
DB Treatment Period 
Efficacy Endpoints 
Induction  
Change from baseline in IL-22 at 
 Week 16 
 
 
 
 


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DB Treatment Period 
Efficacy Endpoints 
 
 
 
 
 
 
 
Maintenance 
Change from baseline in IL-22 at Week 28 
 
 
 
 
 
 
 
 
3.6.3.2 
Analyses of Exploratory Endpoints 
Serum IL-22 and 
 concentrations will be summarized by treatment group and by visit. 
Efficacy data over time during the DB induction and maintenance periods will be 
summarized and plotted by visit and by treatment.  
Patient reported outcomes endpoints 
 
 will be described in Section 3.6. 
The exploratory efficacy endpoints with continuous or ordinal outcomes 
 
 
 
 will be analyzed using a mixed effects repeated measures model with 
fixed terms for treatment group, visit, treatment-by-visit interaction, stratification factor of 
prior anti-TNFα use (1 versus >1), and corresponding baseline values, and subject as a 
random effect with unstructured covariance structure for the observed data up to Week 28.  
Comparisons between any MEDI2070 dose group and placebo will be performed by visit. 
Point estimate of the difference between each MEDI2070 dose group and placebo and 
associated 90% CI will be provided. 


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Distributional assumptions underlying the model will be assessed by visual inspection of 
residual plots. The assumption of normality will be assessed by examination of the normal 
probability plot. The assumption of homogeneity of variance will be assessed by plotting the 
residuals versus the predicted values from the model. If assumptions appear to be grossly 
violated, the data will be log-transformed or alternative analyses such as Wilcoxon rank-sum 
test will be performed. 
 
 
 
  
 
 
  
 
  
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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Table 3.6.4.1-1  
Candidate Dose-response Models 
Model 
𝒇(𝒅, 𝜽) = 𝜽𝟎+ 𝜽𝟏𝒇𝟎(𝒅,  𝜽𝟎) 
𝒇𝟎(𝒅,  𝜽𝟎) 
Pre-specified 𝜽𝟎 
Linear log-
dose 
𝐸0 + 𝛿 log⁡(𝑑+ 𝑐) 
log⁡(𝑑+ 𝑐) 
NA 
EMax 
𝐸0 + 𝐸𝑚𝑎𝑥𝑑/[ 𝐸𝐷50 + 𝑑] 
𝑑/[ 𝐸𝐷50 + 𝑑] 
𝐸𝐷50 =105, 210 
Sigmoid 
EMax 
𝐸0 + 𝐸𝑚𝑎𝑥𝑑ℎ/ [ 𝐸𝐷50
ℎ+ 𝑑ℎ] 
𝑑ℎ/ [ 𝐸𝐷50
ℎ+ 𝑑ℎ] 
𝐸𝐷50 =105, 210 
ℎ=0.5 


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Model 
𝒇(𝒅, 𝜽) = 𝜽𝟎+ 𝜽𝟏𝒇𝟎(𝒅,  𝜽𝟎) 
𝒇𝟎(𝒅,  𝜽𝟎) 
Pre-specified 𝜽𝟎 
Logistic 
𝐸0 + 𝐸𝑚𝑎𝑥/{1 + exp⁡[(𝐸𝐷50 −𝑑)/𝛿]} 
1/{1 + exp⁡[(𝐸𝐷50 −𝑑)/𝛿]} 𝐸𝐷50 =105, 210 
𝛿=45 
 
 
Figure 3.6.4.1-1  
Dose-response Shape for the Selected Candidate Models 
 
3.6.4.2 
Efficacy Analysis for OL Treatment Period 
The efficacy data from the OL treatment period will be summarized descriptively by 
randomized treatment group in the DB period and by visit using the OL population.  The 
efficacy data from the DB treatment and OL treatment period will be combined and 
displayed graphically by visit and by the randomized treatment group in DB treatment period 
using the OL population. 
3.6.5 
Subgroup Analysis 
This section applies to the following selected efficacy endpoints outlined in Table 3.6.5-1. 
The subgroup analyses will be focusing on the effective dose(s) only. If there is more than 
one effective dose, the effective doses may be combined for the purpose of subgroup 
analysis. 


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Table 3.6.5-1  
List of Efficacy Endpoints for Subgroup Analysis 
DB Treatment Period 
Efficacy Endpoints 
Induction  
CDAI clinical remission at Week 8 
CDAI clinical remission at Week 16 
SES-CD remission at Week 16 
PRO2 remission at Week 8  
PRO2 remission at Week 16 
Maintenance 
CDAI clinical remission at Week 28 
SES-CD remission at Week 28 
PRO2 remission at Week 28 
 
Table 3.6.5-2  
List of Subgroups of Interest 
Subgroups of Interest 
Subgroup Categories 
Prior anti-TNF failure reason  
intolerance, primary or secondary failure 
Prior anti-TNF failure reason  
intolerance,  primary failure, secondary failure 
Prior Vedolizumab failure reason  
intolerance, primary or secondary failure 
Prior Vedolizumab failure reason  
intolerance,  primary failure, secondary failure 
Number of prior use of anti-TNFα agents  
1 versus > 1 
Region  
USA, Non-USA 
Disease duration  
< 5 years, ≥ 5 years 
Disease duration  
< 2 years, ≥ 2 years 
Baseline CRP  
< 5 mg/L, ≥ 5 mg/L 
Baseline FCP  
< 200 μg/g, ≥ 200 μg/g 
  
 
 
 
 
 
  
 
 
 
 
 
 
Difference in proportions between MEDI2070 dose groups and placebo and associated 90% 
confidence interval will be provided for each subgroup. The results will be tabulated and the 
corresponding forest plots for the subgroup analyses will be presented as well. In addition, 
the interaction effect between treatment group and subgroups may be explored.  SIDES may 


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be used for the subgroups with differential treatment effect. SIDES may also be applied to 
search for differential subgroups for baseline disease duration, CRP, and FCP.  
3.7 
Patient Reported Outcomes 
The study will utilize several PRO instruments. The sequence in which scoring instruments 
that contain PRO components (CDAI) or PROs will be collected at a given study visit will be 
the following order: 
• CDAI 
 
 
 
 
• PGIC-IBD (Visits 7 and 10 only) 
• Cognitive Patient Interview (selected subjects, Visit 10 or Early Termination Visit only) 
Data from PGIC-IBD and cognitive patient interview will be analyzed and reported 
separately (i.e. not in the clinical study report).  
The PRO data may be further explored. A separate (supplementary) SAP for the endpoint 
development process and responder remitter definitions may be developed by Quintiles and 
the associated results will be reported separately (i.e. not in the clinical study report). 
 
3.7.1 
CDAI score 
The two items from CDAI, “total number of liquid or very soft stools over past week” and 
“total abdominal pain score over past week”, will be descriptively summarized and plotted 
over time.  Further explorations on the 2-item CDAI data may be described in the 
supplementary SAP and reported separately.  
 
 
 
 
 
 
 
 
  


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3.8 
Summary of Analyses 
In summary, the primary, secondary and exploratory endpoints in the DB induction and 
maintenance treatment periods will be analyzed using the methods specified in Table 3.8-1. 
Table 3.8-1   
Summary of Efficacy Endpoints and Analyses 
Endpoints 
Primary Analysis 
Secondary/Sensitivity Analyses  
Primary Efficacy Endpoint 
CDAI Clinical Remission at 
Week 8 
1. Summary statistics using non-
responder imputation 
 
2. Logistic regression (or exact 
logistic regression) with treatment 
and prior anti-TNFα use as 
covariates using non-responder 
imputation  
1. Logistic regression model adjusting 
for baseline CDAI score 
2. CMH test or exact stratified test 
3. Logistic regression model adjusting 
other baseline covariates 
4. Predictive biomarker analysis 
5. Cochran-Armitage trend test 
6. MCP-Mod analysis 
Secondary Efficacy Endpoints for DB induction period 
SES-CD remission at Week 16 
PRO2 remission at Week 8 
PRO2 remission at Week 16 
 
 
 
1. Summary statistics using non-
responder imputation 
 
2. Logistic regression (or exact 
logistic regression) with treatment 
and prior anti-TNFα use as 
covariates using non-responder 
imputation  
1. Logistic regression model adjusting 
for baseline SES-CD or PRO2 score   
2. CMH test or exact stratified test 
3. Logistic regression model adjusting 
other baseline covariates. 
4. Predictive biomarker analysis 
5. Cochran-Armitage trend test 
6. MCP-Mod analysis 


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Endpoints 
Primary Analysis 
Secondary/Sensitivity Analyses  
SES-CD response at Week 16 
PRO2 response at Week 8 
PRO2 response at Week 16 
CDAI clinical remission at 
Week 16 
1. Summary statistics using non-
responder imputation 
 
2. Logistic regression (or exact 
logistic regression) with treatment 
and prior anti-TNFα use as 
covariates using non-responder 
imputation  
1. Logistic regression model adjusting 
for baseline CDAI, SES-CD or PRO2 
score 
2. CMH test or exact stratified test 
3. Logistic regression model adjusting 
other baseline covariates 
4. Predictive biomarker analysis 
5. Cochran-Armitage trend test 
CDAI clinical response at 
Week 8 
1. Summary statistics using non-
responder imputation 
 
2. Logistic regression (or exact 
logistic regression) with treatment 
and prior anti-TNFα use as 
covariates using non-responder 
imputation 
1. Logistic regression model adjusting 
for baseline CDAI, SES-CD or PRO2 
score 
2. CMH test or exact stratified test 
3. Logistic regression model adjusting 
other baseline covariates 
4. Cochran-Armitage trend test 
CDAI clinical response at 
Week 16 
Abdominal pain remission at 
Week 8 
Abdominal pain response at 
Week 8 
Abdominal pain remission at 
Week 16 
Abdominal pain response at 
Week 16 
1. Summary statistics using non-
responder imputation 
 
2. Logistic regression (or exact 
logistic regression) with treatment 
and prior anti-TNFα use as 
covariates using non-responder 
imputation  
1. Logistic regression model adjusting 
for baseline CDAI or PRO2 score  
2. CMH test or exact stratified test 
3. Logistic regression model adjusting 
other baseline covariates. 
 
Secondary efficacy endpoints for DB maintenance period 
SES-CD remission at Week 28 
SES-CD response at Week 28 
CDAI modified sustained 
remission  
SES-CD modified sustained 
remission  
PRO2 modified sustained 
remission  
1. Summary statistics using non-
responder imputation 
 
2. Logistic regression (or exact 
logistic regression) with treatment 
and prior anti-TNFα use as 
covariates using non-responder 
imputation  
1. Predictive biomarker analysis 
 
CDAI clinical remission at 
Week 28 
1. Summary statistics using non-
responder imputation 
 


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Endpoints 
Primary Analysis 
Secondary/Sensitivity Analyses  
CDAI clinical response at 
Week 28 
PRO2 remission at Week 28 
PRO2 response at Week 28 
Abdominal pain remission at 
Week 28 
Abdominal pain response at 
Week 28 
Loose/liquid stool frequency 
remission at Week 28 
Loose/liquid stool frequency 
response at Week 28 
 
2. Logistic regression (or exact 
logistic regression) with treatment 
and prior anti-TNFα use as 
covariates using non-responder 
imputation 
Exploratory Efficacy Endpoints 
Change from Baseline in IL22 
 
 
 
 
 
 
1. Summary statistics by visit 
 
2. Repeated measures analysis using 
observed data only (up to Week 28)  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
3.9 
Safety Analyses 
The analysis of safety endpoints will include TEAEs, laboratory values, vital signs, and 
ECG.  Safety data from the 28-week placebo-controlled, DB treatment period will be 
analyzed using the as-treated population with the actual treatment received.  Safety data from 


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the OL treatment period will be analyzed in a similar way using the OL population. No 
statistical comparisons will be performed for the safety data. 
3.9.1 
Adverse Events and Serious Adverse Events 
Adverse events (AE) will be coded by MedDRA version (17.0 or higher) and the type 
incidence, severity and relationship to study investigational product will be summarized. 
Specific adverse events will be counted once for each subject for calculating percentages. In 
addition, if the same adverse event occurs multiple times within a particular subject, the 
highest severity and level of relationship observed will be reported. If any associations of 
interest between adverse events and baseline characteristics are observed, additional stratified 
results may be presented. All AEs and SAEs collected in the database (including those 
starting prior to first dose of study drug) will be listed.  Any other information collected (e.g. 
relatedness to study drug, action taken etc.) will be listed as appropriate. 
3.9.1.1 
Pre-treatment AEs 
The AEs with onset prior to the administration of the first dose of investigational product 
(MEDI2070 or placebo) will be considered as pre-treatment AEs for the DB treatment 
period.  Pre-treatment AEs will be summarized with number of subjects and percentages by 
SOC and PT for each treatment group.  
3.9.1.2 
Treatment-Emergent AEs during DB Treatment Period 
For subjects entering the OL treatment period, the TEAE will be defined as any AE with 
onset on or after the administration of the first dose of blinded investigational product up to 
the day prior to administration of the first OL SC dose. For subjects not entering the OL 
treatment period, the TEAE will be defined as any AE with onset on or after the 
administration of the first dose of blinded investigational product up to and including 28 
weeks post last blinded dose. 
All TEAEs including TESAEs, AESIs, and TEAEs leading to permanent discontinuation of 
investigational product will be summarized overall as well as categorized by MedDRA 
System Organ Class (SOC) and Preferred Term (PT). The TEAEs with severity grades will 
be summarized by grades assigned by National Cancer Institute Common Terminology 
Criteria for AEs (NCI CTCAE) V4.0.  Tabular summaries of the TEAEs during the DB 
treatment period will be provided as follows: 
• Incidence rate of TEAEs by SOC and PT 
• Incidence rate of TEAEs by severity and relationship to the investigational product 


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• Incidence rate of fatal TEAEs, TESIs, TESAEs, TEAEs leading to permanent 
discontinuation of investigational product, treatment-related TESAEs by SOC and PT 
• Incidence rate of TEAE and infectious TEAEs occurring in at least 5% of the subjects in 
any treatment group by PT in descending order of frequency 
• Incidence rate of TESAEs occurring in at least 1% of the subjects in any treatment group 
 
3.9.1.3 
TEAEs during OL Treatment Period  
TEAE for the OL treatment period will be defined as any AE with onset on or after the 
administration of the first open-label SC dose of MEDI2070 up to and including 28 weeks 
post-last dose. Similar tabular summaries will be prepared for the OL treatment period using 
the OL population.  
3.9.2 
Adverse Events of Special Interest (AESI) 
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and requires close monitoring and rapid communication by the 
investigator to the sponsor.  An AESI may be serious or non-serious. Identification of TESIs 
through search criteria (Standardized MedDRA Query (SMQ) etc.) will be an ongoing task 
throughout the study and latest convention will be used to summarize by SOC and PT in each 
category. In particular, the time to onset of surgery for CD complications will be summarized 
for each treatment group. 
Table 3.9.2-1 
AESIs Categories 
AESI Category  
Description 
Hepatic Function 
Abnormality (Hy’s Law) 
The Hy’s law is defined in the protocol Section5.6.2. AEs meeting the Hy’s 
law criteria will be identified using MedDRA SMQ. 
Infusion/injection site 
Reactions 
AEs with PT “infusion reaction” will be captured under this category. 
Infections 
An event recorded on the AEs eCRF that is coded to the MedDRA SOC of 
“Infections and Infestations.” 
Systemic Hypersensitivity  
e.g. anaphylaxis 
Malignancies 
 
Major Cardiac Events 
(MACE) 
AEs defined as myocardial infarction, stroke, or cardiovascular death 
Ocular AEs 
Including cataracts 
 
 


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3.9.3 
Deaths and Treatment Discontinuations due to Adverse Events 
Deaths and treatment discontinuation due to AEs will be listed and summarized by treatment 
groups. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.9.4.1 
Vital Signs 
Vital signs parameters, including blood pressure, temperature, pulse rate and respiration rate, 
will be obtained according to study schedule procedures.  All vital signs parameters (blood 
pressure, temperature, pulse rate, and respiration rate) will be listed. Abnormal vital sign 
values will be flagged. 
Vital signs parameter values will be collected before, during, and after completion of the IV 
administration and before and after the completion of the SC administration at each visit. 
Change from baseline for each vital signs parameter to each scheduled visit will be 
summarized by treatment group using descriptive statistics. For vital sign assessments 
collected on the dosing day, the vital sign data will be summarized by time points of interest 
as well.  The time points of interest are as follows:   
• pre-dose assessment,  
• the 1st set of assessment after dosing, and  
• the last set of assessment before discharge from site.  
The results for the DB treatment period and the OL treatment period will be presented using 
the as-treated population and OL population respectively.  


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3.9.4.2 
Electrocardiogram 
12-lead Electrocardiogram (ECG) measurements will be performed according to the study 
schedule.  The ECG data will be listed. 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.  The 
results for the DB treatment period and the OL treatment period will be presented separately 
using the as-treated population and the OL population respectively. 
3.10 Pharmacokinetics and Immunogenicity 
Serum MEDI2070 concentration data will be summarized descriptively by visit using the PK 
population.  Individual and mean serum concentration-time profiles of MEDI2070 will be 
generated. PK data obtained in this study will be combined with all available PK data for 
MEDI2070 and analyzed using population PK methodology and will be reported separately 
from the CSR for this study. 
In addition, the presence of anti-drug antibodies (ADA) to MEDI2070 in serum will be 
assessed and reported. Immunogenicity results (binding and, if positive, neutralizing) will be 
summarized by the number and percentage of subjects who develop detectable ADAs. If 
possible, the relationship between PK and ADA status will be summarized. 
 
4 
INTERIM ANALYSIS 
An interim analysis may be conducted when at least 75% of the total planned number of 
subjects has completed the Week 16 visit or withdrawn prior to the Week 16 visit. Data for 
the primary and secondary endpoints through Week 16 will be analyzed as part of the interim 
analysis for internal decision making purposes. To ensure the blinding of each subject’s 
treatment assignment throughout the 28-week placebo-controlled, double-blind period, the 
interim analysis will be conducted by a limited number of sponsor personnel who are not 
involved in the conduct of the study. Study site personnel and sponsor personnel directly 
associated with the conduct of this study and the study subjects will remain blinded to the 
treatment assignment for individual subjects and to the outcome of interim analysis until the 
completion of the 28-week placebo-controlled, double-blind period. 
Since this is a Phase 2b study, the interim analysis is intended to assist internal decision 
making and does not include a possibility to stop the study for efficacy or futility. Thus, there 
will be no alpha level adjustment for the final analysis. Should the sponsor choose to perform 


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such an interim analysis, the details would be described in an interim unblinding analysis 
plan prior to unblinding. 
The primary analysis will be performed when all subjects complete the initial 16-week 
induction period. All the data available by the time of primary analysis database snapshot 
will be included in the analysis, including available data through Week 28 and the open-label 
period for a certain proportion of subjects. At the time of the primary analysis, selected 
personnel from the sponsor will be unblinded to individual treatment assignments as will be 
outlined in an unblinding plan. Study team members who are unblinded to conduct and 
review the results from the primary analysis will be removed from the blinded study team 
and the associated study responsibilities. 
A further analysis is planned when all subjects complete the maintenance period, at Week 28. 
The study will be blinded to all subjects, investigators, and sponsor study team through the 
end of the maintenance period. 
The final analysis for the study, including all study periods and all data, will be performed at 
the end of the study.   
Independent Data Monitoring Committee (IDMC) analysis will be performed for the safety 
data on a regular basis throughout the DB treatment period of the study as set out in the 
IDMC charter, i.e. until the last subject completes Week 28. A separate IDMC SAP and/or 
SPP will be prepared. 
 


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6 
APPENDIX 
6.1 
CDAI Score 
The CDAI is the oldest and most widely used of several multi-item instruments that have 
been developed and is validated for use in clinical studies to measure disease activity in 
CD (Best et al, 1976; Sands et al, 2005).  The CDAI measures the severity of active disease 
using symptom scores that are monitored over the previous week and includes subject-
reported symptoms, physician-assessed signs, and laboratory markers.  
The CDAI score is calculated by summing weighted scores for subjective items (number of 
liquid or very soft stools, the degree of abdominal pain over a week (on a scale of 0-3, mild 


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to severe)  and general well-being (on scale of 1-4, “Generally well” to “Terrible”) recorded 
by a diary during a 1-week period, and objective items (associated symptoms, taking 
antidiarrheal such as loperamide/opiates, abdominal mass, hematocrit, daily morning 
temperature, and body weight).  The CDAI scores range approximately from 0 to 600, with 
higher scores indicating greater disease activity (See Table 3.4.1.1-1 for details).  
The CDAI will be calculated at the site in order to determine the eligibility for the study. For 
statistical analysis, CDAI for all visits will be also calculated based on the data entered in the 
eCRF. 
Table 6.1-1  
Items Included in CDAI and Their Weights 
Item 
× Weight 
Total 
Total number of liquid or very soft stools over past week 
×2 
X1 
Total abdominal pain score  (rating: 0-3) over past week (range: 0-21) 
×5 
X2 
Total general well-being score (rating: 1-4) over past week (range: 1-28) 
×7 
X3 
Sum of presence of following clinical signs over past week:  
1. Arthritis/Arthralgia (1=yes, 0=no) 
2. Iritis/ uveitis(1=yes, 0=no) 
3. Erythema Nodosum/Pyoderma Gangrenosum/Aphthous Stomatitis 
(1=yes, 0=no) 
4. Anal Fissure, Fistula or Abscess (1=yes, 0=no) 
5. Other Fistula (1=yes, 0=no) 
6. Fever >37.8 C During Past Week(1=yes, 0=no) 
×20 
X4 
Antidiarrheal use (Eg, Diphenoxylate hydrochloride) (0=none, 1=yes) 
×30 
X5 
Abdominal mass (none=0, equivocal=2, present=5) 
×10 
X6 
Deviation of Hematocrit levels (minimum value = 0) 
      47 - hematocrit (males)  
      42 - hematocrit (females)   
×6 
X7 
(if value<0,  
enter 0) 
Weight ratio 
      100×(1-[Current body weight /  standard weight]) 
      Minimum = -10 for overweight subject 
      Maximum = 10 for underweight subject 
×1 
X8 
(if value<-10,  
enter -10, 
if value >10, 
enter 10) 
CDAI score 
 


8
1
i
i
X  
 


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In addition, following set of rules will be applied: 
 For items 1, 2 and 3, if information is available only for ≤ 3 days, then CDAI score 
will be set to missing. Otherwise, the sub score for each of these three items will 
be calculated as mean value of item from available days × 7.  
 For all items, if a subject doesn’t have score for any of the sub categories, CDAI 
score will be set to missing.  
 Any total CDAI score < 0 will be considered as 0 in the analysis. 
Subjects with scores of < 150, 150 to 219, and 220 to 450 represent remission, mild disease, 
and moderate to severe disease, respectively; whereas subjects with scores of > 450 have 
very severe disease (Buxton et al, 2007). 


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6.3 
Covariate-adjusted difference of proportion using logistic 
regression 
The fitted logistic regression model is used to predict the response rate for every subject in 
the study as if they had received the treatment or the control intervention, and the 
difference in the average of the treated and control rates is computed. The delta method is 
used to calculate a standard error for the difference and an associated CI. Regarding the 
strata (covariate) values in the trial as a population distribution (e.g. regarding strata 
frequencies as fixed, which is also implicit in the weighted mean risk difference 
estimators), the LR estimator is the maximum likelihood estimator of the risk difference 
under the logistic model (See the SPP for pseudo SAS codes). 
6.4 
Visual acuity notation conversions 
The visual acuity notation routinely used at different sites may vary. Each site should convert 
the acuity notation to decimal format to enter onto the electronic case report form (eCRF). 
 
 


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