Clinical trial NCT03235050
Conditions: Diabetes Mellitus, Type 2
Sponsor: AstraZeneca
Start date: 2017-08-02; Completion date: 2019-06-14
Enrollment: 834 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the dose range for MEDI0382 with respect to blood glucose control and weight loss effects, as well as to further explore the safety profile of MEDI0382

Detailed description:

Arms: arm 1: Drug: MEDI0382 low dose Drug: Metformin tablets, total daily dose of ≥1500 mg (unless only tolerated at a lower dose) arm 2: Drug: MEDI0382 mid dose Drug: Metformin tablets, total daily dose of ≥1500 mg (unless only tolerated at a lower dose) arm 3: Drug: MEDI0382 high dose Drug: Metformin tablets, total daily dose of ≥1500 mg (unless only tolerated at a lower dose) arm 4: Drug: Placebo Drug: Metformin tablets, total daily dose of ≥1500 mg (unless only tolerated at a lower dose) arm 5: Drug: Liraglutide Drug: Metformin tablets, total daily dose of ≥1500 mg (unless only tolerated at a lower dose)
Interventions: intervention 1: MEDI0382 low dose intervention 2: MEDI0382 mid dose intervention 3: MEDI0382 high dose intervention 4: Placebo intervention 5: Liraglutide
Intervention descriptions: intervention 1: Pharmaceutical form: solution Route of administration: subcutaneous intervention 2: Pharmaceutical form: solution Route of administration: subcutaneous intervention 3: Pharmaceutical form: solution Route of administration: subcutaneous intervention 4: Pharmaceutical form: solution Route of administration: subcutaneous intervention 5: Pharmaceutical form: solution Route of administration: subcutaneous

Protocol documents:
Prot_002.pdf: 
Clinical Study Protocol
Drug Substance
MEDI0382
Study Code
D5670C00004
Version
5.0
Date
04 December 2018 
A Phase IIb, Randomised, Parallel, Double-Blind Placebo-Controlled and 
Open-Label Active Comparator Study to Evaluate the Efficacy and Safety of 
MEDI0382 in the Treatment of Overweight and Obese Subjects with Type 2 
Diabetes Mellitus
Sponsor:  AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
2 (111)
VERSION HISTORY
Version 5.0, 04 Dec 2018
Changes to the protocol are summarised below.
Synopsis and Sections 1 through 8 were modified to reduce the length of the treatment 
extension period from 92 to 40 weeks. Week 54 (Visit 14) will be the minimum required 
time point for treatment comparisons. Study duration will now be a minimum of 62 weeks, 
including a 2-week screening period, a 2-week run-in period, a 14-week treatment period, a 
minimum 40-week treatment extension, and a 4-week follow-up. The rationale for this 
change is to allow subjects adequate time to transition to other therapies and allow 
continued collection of safety and efficacy data to inform further decisions regarding 
MEDI0382 doses.
Figure 1 was modified to reduce the length of the treatment extension period from 92 to a 
minimum of 40 weeks. 
Table 2 and Table 3 were modified to reduce the length of the treatment extension period 
from 92 to a minimum of 40 weeks. All subjects must complete an end of treatment
schedule of assessments.
Appendix D was modified to be consistent with the updated potential Hy’s Law/ Hy’s Law 
reporting process.
Version 4.0, 20 Apr 2018
Changes to the protocol are summarised below.
Synopsis, section 3.7 (Methods for unblinding), section 8.1 (Statistical considerations): 
These sections were modified to include an analysis when all subject reach 26 weeks 
treatment. The rationale for introducing the 26 week analysis is to inform about efficacy at 
6 months and guide the selection process of the optimal dose regimen because the impact of 
weight loss on improved insulin sensitivity and glucose control may not be adequately 
captured at 14 weeks.
Table 2, Table 3 and section 4.2.1.5 (Rescue visit): These tables and the rescue visit 
description were modified to remove the requirement of bringing used/unused IP to the 
rescue visit. Subjects should continue receiving IP while receiving rescue therapy.
Section 4.3 (Last dose of investigational product follow-up visit): PK sample collection was 
added to the visit description to keep consistency with Table 2 and Table 3.


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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Section 6.3.9 (Pancreatitis): This section was modified to indicate more detailed 
information to be collected for events of pancreatitis.
Section 6.3.10 (Pancreatic carcinoma) was added to include collection of specific 
information for events of pancreatic carcinoma. Section 6.4 (Clinical Event Adjudication) 
was updated to include pancreatic carcinoma and thyroid neoplasm to the list of adjudicated 
events. Given the controversy of whether GLP-1–based therapy increases the risk for 
specific malignant disease like pancreatic carcinoma and thyroid cancer, we plan to 
adjudicate pancreatic carcinoma and thyroid cancer in the phase IIb study.
Version 3.0, 05 Feb 2018
Changes to the protocol are summarised below.
Synopsis, section 1.4 (Study design), section 3.5 (Methods for assigning treatment groups), 
section 3.7 (Methods for unblinding), section 8.1 (Statistical considerations) and section 
8.5.4 (Interim analysis): These sections were modified to exclude the interim analysis and 
the analysis associated with the 26 week data. Due to fast enrolment to the study, timing for 
the primary analysis advanced so there is no longer a need for the interim analysis. 
Similarly, the separate analysis associated with the 26 week data is removed because fast 
enrolment leads to an insufficient number of subjects reaching 26 weeks at the time of the 
primary analysis to provide satisfactory statistical power. 
Version 2.0, 09 Oct 2017
Changes to the protocol are summarised below.
Section 1.2.3.1 (Recruitment of subjects with T2DM and a body mass index ≥25 kg/m2), 
section 3.1 (Inclusion criteria): This section and inclusion criterion 3 were modified to 
remove the upper BMI limit for the study. The rationale is to improve rate of enrolment and 
to increase ability to demonstrate significant weight loss when including subjects with very 
high BMI.
Section 1.4 (Study design): The number of countries and participating sites was updated.
Study flow diagram: The diagram was corrected to reflect that MEDI0382 and liraglutide 
dosing does not depend on the time of day.
Section 3.1 (Inclusion criteria): The metformin monotherapy inclusion criterion (#5) was 
modified to allow use of another glucose-lowering medication for up to 2 weeks in the 2 
months prior to screening. The rationale is to improve rate of enrolment and still include 
subjects on Metformin monotherapy who may have been offered another glucose-lowering 


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
4 (111)
agent on top of metformin but only took it briefly for less than 2 weeks. Additionally the 
birth control criterion for women of childbearing potential was clarified to require at least 
one appropriate birth control method in effect prior to receiving the first IP dose and to 
include total sexual abstinence as an appropriate birth control method based on Best 
Practice Reference Guideline: Human Exposure Limits Committee (HELC) Guideline for 
Information Required Before Inclusion of Women in AstraZeneca/MedImmune Clinical 
Trials
Section 3.2 (Exclusion criteria): Exclusion criterion number 5 was modified to allow daily 
SC insulin treatment for up to 2 weeks within 90 days prior to screening. Exclusion 
criterion number 13 was updated to present basal calcitonin values in pg/ml. Exclusion 
criterion number 18 was clarified to restrict enrolment of subjects with any history of 
psychosis or bipolar disorder; subjects with a history of major depressive disorder within 
the past year with the subject being clinically unstable.
Section 3.8 (Restrictions): Fasting requirement was modified to include all study site visits 
except for Visits 2, 12, 13, 15, 16, 17 and 18. These visits do not require weight 
measurement or fasting laboratory sampling. Restriction to withhold tobacco and caffeine 
24 hours prior to each study site visit was removed.
Section 3.9 (Discontinuation of investigational product) and section 3.9.1 (Procedures for 
discontinuation of a subject from investigational product): These sections were corrected to 
refer only to discontinuation from the IP. Additional options for visits after the IP 
discontinuation were added.
Section 3.10.1 (Screen failures): Screening was clarified to refer to a period instead of 
window. 
Section 3.10.2 (Withdrawal of informed consent): This section was modified to include 
collection of subjects vital status at the end of study.
Section 4 (Study plan and timing of procedures): Table 1 was modified to remove the visit 
window from Screening. Fasting requirement was clarified to include Visit 1. IVRS/IXRS 
contact was removed from FU visit. Provision of the subject diary and instructions was 
clarified to include further study visits, if needed. As requested by the FDA, 
Immunogenicity blood sampling was added to Visits 4 and 6. Table 3 was modified to 
include IVRS/IXRS contact at applicable study visits. 
 
The arrow covering 
the 4-weekly interval IP supply visits was corrected to span the period between Visit 12 and 
Visit 19. In addition, the requirement to collect adverse events and concomitant medication 
changes at IP supply visits was removed.
Section 4.1.1 (Visit 1 assessments – Screening): These section was updated to refer to a 2 
week period. Restrictions for tobacco and caffeine us for 24 hours prior to the visit was 
removed and additional options for re-testing laboratory results was added.  


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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Section 4.1.3 (Visit 2 assessments – 2-week run in period): This section was updated to 
clarify the screening period and visit window for Visit 2. Tobacco and caffeine restrictions 
in addition to the fasting requirement were removed. 
Section 4.2 (Treatment period): This section was updated to remove the tobacco and 
caffeine restriction for 24 hours prior to scheduled visits.
Section 4.2.1.1 (Visit 3 assessments – Baseline): The visit window for Visit 3 was corrected 
to a maximum of 2 days upon completion of the run-in period, to keep consistency with 
Table 1. Fundoscopy was clarified to refer to dilated funduscopic examination. 
Section 4.2.1.2 (Visit 4 to 5 assessments – Up-titration) and section 4.2.1.3 (Visit 6 to 8 
assessments – maintenance period) were updated to include immunogenicity laboratory 
sampling at Visits 4 and 6.
Section 4.2.1.4 (Initiation of rescue medication (14 week treatment period) was corrected to 
include the period from Week 0 to the criteria for initiation of rescue medication, as
described in Table 4. Note on rescue medication not being provided by the sponsor was 
removed.
Section 4.2.2 (92-week extension period): This section was modified to remove the 
requirement of adverse event collection, concomitant medication review, vital signs 
collection and brief physical examination during the IP resupply visits. Clarification on 
urine collection for urinalysis was added.
Section 4.2.3 (Resupply of investigational product visits): Section clarified to include need 
for collection, review and resupply of IP and IFU. 
Section 4.2.5 (Early termination): This section was updated to refer to discontinuation from 
IP. Additional clarification of return for visit no later than 7 days post last IP dose was 
added.  
Section 5.2.1.4 (Serum calcitonin): This section was updated to include the calcitonin level 
of clinical concern.
Section 5.2.1.6 (Urinalysis): Section referring to recording and analysis of lab samples by 
the central laboratory moved to section 5.2.1 (Laboratory safety assessments).
Section 5.2.1.8 (Immunogenicity) Added clarification that ADA samples will be collected 
for subjects in MEDI0382/Placebo arm.
Section 5.2.4.1 (Pulse and blood pressure): This section was updated with additional 
guidance on pulse collection by a semi-automatic device or manual measurement. 
Clarification on the same time of day, with a two hour window was added.


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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Section 5.3.2.3 (Retinal assessment): Fundoscopy was clarified to refer to dilated 
funduscopic examination.
Section 6.4 (Clinical Event Adjudication): Term pancreatitis as one of the adjudicated 
events was updated to pancreatic disease.
Section 6.9.1 (Tolerability): This section was updated to allow for metformin withhold 
during persistent symptoms of nausea and vomiting.
Section 7.7.1 (Permitted concomitant medications):  Section updated to keep consistency 
with Inclusion criterion #5. Additional clarifications added on use of anti-emetic therapy. 
5HT-3 antagonist treatment recommendation removed from the text.  
Section 8.1 (Statistical considerations) and section 8.5.4 (Interim analysis): Sample size 
updated to allow a margin for any low-quality or untestable samples.
Section 8.3.3 (PK analysis set): Clarification added on PK population to refer to MEDI0382 
treated subjects only.
Clinical Study Protocol Synopsis: Modifications and clarifications from the Clinical Study 
Protocol have also been included in the Synopsis. A clarification has been added on the use 
of liraglutide in patients with congestive heart failure New York Heart Association (NYHA) 
class III and label updates with the data from the LEADER trial.
 
Version 1.0, 16 May 2017
Initial creation


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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CLINICAL STUDY PROTOCOL SYNOPSIS
A Phase IIb, Randomised, Parallel, Double-Blind Placebo-Controlled and 
Open-Label Active Comparator Study to Evaluate the Efficacy and Safety 
of MEDI0382 in the Treatment of Overweight and Obese Subjects with 
Type 2 Diabetes Mellitus
International Co-ordinating Investigators
Study site(s) and number of subjects planned
This will be a global, multicentre study conducted at approximately 150 sites in 8 countries.  It 
is planned that approximately 750 subjects will be enrolled (approximately 5 subjects per 
centre), and that approximately 542 subjects will complete the study, taking into account a 
projected annual study drop-out rate of 15%.  
Phase of development IIb
Study design
This is a randomised, parallel, double-blind, placebo-controlled study with an open-label 
active comparator (liraglutide) arm designed to evaluate 100 μg, 200 μg, and 300 μg of 
MEDI0382 in overweight and obese subjects with type 2 diabetes mellitus (T2DM) and an 
haemoglobin A1c (HbA1c) of 7.0% to 10.5%, who are concurrently treated with metformin.  


Clinical Study Protocol Synopsis
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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The study has a run-in period of 2 weeks, and following randomisation, a 14-week treatment 
period for the primary analysis, followed by a minimum 40-week treatment extension.  
Objectives
Primary objective:
Outcome measure:
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on haemoglobin A1c 
(HbA1c) and body weight versus placebo 
Change in HbA1c from baseline to 14 weeks  
Percent change in body weight from baseline to 
14 weeks
Secondary objective:
Outcome measure:
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on additional measures 
of glycaemic control and body weight versus 
placebo
Change in HbA1c from baseline to 26 weeks, and 
54 weeks 
Percentage of subjects achieving an HbA1c target 
< 7.0% after 14 weeks, 26 weeks, and 54 weeks
Percent change in body weight from baseline to 
26 weeks, and 54 weeks
Absolute change in body weight from baseline to 
14 weeks, 26 weeks, and 54 weeks
Percentage of subjects achieving weight loss of ≥5% 
and ≥10% after 14 weeks, 26 weeks, and 54 weeks
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on the requirement for 
additional blood glucose lowering therapies 
versus placebo 
Proportion of subjects rescued or discontinued for 
lack of glycaemic control at 14 weeks, 26 weeks, and 
54 weeks
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on weight versus 
liraglutide 1.8 mg once daily 
Percent and absolute change in body weight from 
baseline to 14 weeks, 26 weeks, and 54 weeks
To characterise the pharmacokinetic (PK) 
profile and immunogenicity of 100 μg, 200 μg, 
and 300 μg of MEDI0382 
PK endpoints (trough plasma concentration, Cmin) 
Development of antidrug antibodies and titre (if 
positive) during dosing and follow-up


Clinical Study Protocol Synopsis
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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Safety objective:
Outcome measure:
To characterise the safety profile, and 
tolerability of 100 μg, 200 μg and 300 μg of 
MEDI0382 
Measures of safety and tolerability [(vital signs, 
laboratory test results, adverse events (AEs)] during 
treatment and follow-up
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol Synopsis
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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Target subject population
Male or female subjects aged ≥18 years of age, with body mass index (BMI) ≥25 kg/m2, a 
diagnosis of T2DM and inadequate blood glucose control as defined by an HbA1c of 7.0 to 
10.5% who are on metformin monotherapy.
Duration of treatment
Study duration will be a minimum of 62 weeks, including a 2-week screening period, a 2-
week run-in period, a 14-week treatment period, a minimum 40-week treatment extension, and 
a 4-week follow-up.
Dosage and mode of administration – investigational product, oral antidiabetic agents, 
and rescue therapy
Investigational product
Investigational product (IP) in this clinical study protocol (CSP) refers to either MEDI0382, 
placebo, or liraglutide.  
MEDI0382 and placebo:
All IP will be packed into kits with supplies for 1 week treatment (8 syringes – 7 day supply 
and one spare syringe).  MEDI0382 or placebo will be administered by subcutaneous (SC) 
injection once daily for the 14-week treatment period and a minimum 40-week treatment 
extension.
Liraglutide: 
Liraglutide (6.0 mg/mL, open label) as active drug will be administered by SC injection once 
daily for the 14-week treatment period and a minimum 40-week treatment extension using a 
3 mL pen-injector.  Liraglutide should be administered and stored according to product-
specific and country-specific labelling. We recognise that in some markets the liraglutide label 
has not been updated with the data from the LEADER trial, as so is currently not 
recommended in patients with congestive heart failure New York Heart Association (NYHA) 
class III. However, based on recent data and updates to the EU summary of product 
characteristics, which was submitted with the CTA, we plan to include patients with 
congestive heart failure NYHA class III in our study.
Oral antidiabetic agents:
Throughout the study, subjects should continue to administer the same type and dose of 
metformin therapy that they were using at study entry.  Metformin should be administered and 
stored according to product-specific and country-specific labelling.
Rescue therapy:
Subjects who require rescue therapy will receive open-label insulin as a preferred option.  
Subjects should continue receiving IP while receiving rescue therapy.


Clinical Study Protocol Synopsis
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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Statistical methods
Populations for analyses
The Intent-to-treat (ITT) analysis set for the efficacy evaluation will be the primary analysis 
set and will include subjects who received at least one dose of IP, and will be analysed 
according to their randomised treatment group.  
The Per Protocol (PP) analysis set will include only treatment completers and exclude those 
with important protocol violation(s).  Important protocol violations are those that have the 
potential to affect the result of the primary analysis.
The Safety analysis set, which includes all subjects receiving at least one dose of any study IP, 
will be analysed according to the treatment they actually receive.  
The Pharmacokinetic (PK) population includes all subjects who received at least one dose of 
MEDI0382 and had at least one post-baseline MEDI0382 PK sample taken that is above the 
lower limit of quantification.
 
 
 
 
 
Statistical analysis methods
The co-primary efficacy endpoints of HbA1c change and weight change from baseline to 
14 weeks will be compared between MEDI0382 and placebo arms.  For these endpoints, an 
analysis of covariance (ANCOVA) model with last-observation-carried-forward (LOCF) 
approach to handle missing data will be used and adjusted for treatment and measurement at 
baseline.  For weight loss, the strata of screening HbA1c (≤8% or >8%) will be added into the 
model as a covariate.  Analyses will be based on the ITT population, which includes all 
randomised subjects who received at least one dose of IP.  The analysis will include the post 
IP-discontinuation data and post-rescue data for those subjects who discontinue from study 
treatments or are rescued, but are still followed up for their scheduled visits.
Secondary efficacy endpoints of body weight and HbA1c change at 26 weeks and 54 weeks 
will be analysed by ANCOVA model with LOCF.  For the secondary proportion-related 
endpoints, a logistic regression model will be used.  These analyses will be performed for the 
ITT population.  Anti-drug antibody incidence rate and titre will be tabulated for each 
treatment.  Individual MEDI0382 plasma concentrations will be summarised by treatment and 
visit.


Clinical Study Protocol Synopsis
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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All safety [(vital signs, laboratory test results, adverse events (including cardiovascular
events)] and tolerability variables will be summarised descriptively for each treatment group 
for the Safety population.  Details on the safety analyses will be provided in the statistical 
analysis plan.  
 
A primary analysis when all subjects reach 14 weeks treatment, an analysis when all subjects 
reach 26 weeks treatment, and a final analysis at the end of the study are planned.  


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS ....................................................8
TABLE OF CONTENTS................................................................................... 14
1.
INTRODUCTION ............................................................................................. 23
1.1
........................................... 23
1.2
.......................................... 24
1.2.1
....................................................................... 24
1.2.1.1
................................................................ 24
1.2.1.2
................... 25
1.2.1.3
.......................... 25
1.2.1.4
................. 25
1.2.2
............................................................................. 26
1.2.3
........................................................................... 28
1.2.3.1
.............. 28
1.2.3.2
................................................................ 28
1.2.3.3
................................. 28
1.2.3.4
.............................. 28
1.3
Benefit/risk and ethical assessment .................................................................... 29
1.4
Study design ...................................................................................................... 29
1.5
Study governance and oversight......................................................................... 32
1.5.1
Steering Committee – Not Applicable ................................................................ 32
1.5.2
Data Monitoring Committee – Not Applicable ................................................... 32
1.5.3
Scientific Advisory Committee – Not Applicable............................................... 32
1.5.4
Clinical Event Adjudication Committee ............................................................. 32
2.
STUDY OBJECTIVES...................................................................................... 32
2.1
Primary objective............................................................................................... 32
2.2
Secondary objectives.......................................................................................... 32
2.3
Safety objectives................................................................................................ 33
2.4
33
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 34
3.1
Inclusion criteria ................................................................................................ 34


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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3.2
Exclusion criteria ............................................................................................... 35
3.3
Subject enrolment and randomisation................................................................. 37
3.4
Procedures for handling incorrectly enrolled or randomised subjects.................. 37
3.5
Methods for assigning treatment groups............................................................. 37
3.6
Methods for ensuring blinding ........................................................................... 38
3.7
Methods for unblinding...................................................................................... 38
3.8
Restrictions........................................................................................................ 39
3.9
Discontinuation of investigational product ......................................................... 40
3.9.1
Procedures for discontinuation of a subject from investigational product............ 41
3.10
Criteria for withdrawal....................................................................................... 42
3.10.1
Screen failures ................................................................................................... 42
3.10.2
Withdrawal of the informed consent................................................................... 42
3.11
Discontinuation of the study............................................................................... 42
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 43
4.1
Screening/Enrolment period............................................................................... 52
4.1.1
Visit 1 assessments - Screening.......................................................................... 52
4.1.2
Re-screening ...................................................................................................... 53
4.1.3
Visit 2 assessments - 2-week run-in period......................................................... 53
4.2
Treatment period................................................................................................ 54
4.2.1
14-week treatment period................................................................................... 55
4.2.1.1
Visit 3 assessments - Baseline ............................................................................ 55
4.2.1.2
Visits 4 to 5 assessments – Up-titration .............................................................. 56
4.2.1.3
Visits 6 to 8 assessments - maintenance period................................................... 57
4.2.1.4
Initiation of rescue medication (14-week treatment period) ................................ 57
4.2.1.5
Rescue visit........................................................................................................ 58
4.2.2
A minimum 40-week extension period............................................................... 59
4.2.2.1
Initiation of rescue medication (minimum 40-week treatment extension) ...........60
4.2.3
Resupply of investigational product visits .......................................................... 61
4.2.4
Unscheduled visits ............................................................................................. 61
4.2.5
Early termination ............................................................................................... 61
4.3
Last dose of investigational product follow-up visit............................................ 62
5.
STUDY ASSESSMENTS.................................................................................. 62
5.1
Efficacy assessments.......................................................................................... 62
5.1.1
HbA1c ............................................................................................................... 62
5.1.2
Body weight....................................................................................................... 62
5.2
Safety assessments............................................................................................. 63
5.2.1
Laboratory safety assessments............................................................................ 63
5.2.1.1
Haematology...................................................................................................... 63
5.2.1.2
Serum clinical chemistry.................................................................................... 63


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Study Code D5670C00004
Version 5.0
Date 04 December 2018
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5.2.1.3
Serum amylase and lipase .................................................................................. 63
5.2.1.4
Serum calcitonin ................................................................................................ 64
5.2.1.5
Fasting plasma glucose ...................................................................................... 64
5.2.1.6
Urinalysis........................................................................................................... 64
5.2.1.7
Coagulation panel .............................................................................................. 65
5.2.1.8
Other clinical laboratory evaluations .................................................................. 65
5.2.2
Physical examination ......................................................................................... 66
5.2.3
Resting 12-lead ECG ......................................................................................... 66
5.2.4
Vital signs.......................................................................................................... 66
5.2.4.1
Pulse and blood pressure.................................................................................... 66
5.2.4.2
Orthostatic blood pressure.................................................................................. 67
5.2.5
Other safety assessments.................................................................................... 67
5.2.5.1
Drug-induced liver injury................................................................................... 67
5.3
Other assessments.............................................................................................. 68
5.3.1
Glucose measurements....................................................................................... 68
5.3.2
Clinical outcome assessments ............................................................................ 68
5.3.2.1
Calculation of BMI ............................................................................................ 68
5.3.2.2
Waist circumference .......................................................................................... 68
5.3.2.3
Retinal assessment ............................................................................................. 69
5.3.3
.................................................................................. 69
5.3.3.1
................................................... 70
5.3.3.2
............................................................... 70
5.3.3.3
....................................................................................................... 70
5.3.4
 
......................................................................................... 71
5.3.5
Calculation of eGFR .......................................................................................... 71
5.3.6
Serology ............................................................................................................ 71
5.4
Pharmacokinetics ............................................................................................... 71
5.4.1
Collection of samples......................................................................................... 71
5.4.2
Determination of drug concentration.................................................................. 71
5.4.3
Storage and destruction of pharmacokinetic samples.......................................... 72
5.5
Pharmacodynamics - Not Applicable ................................................................. 72
5.6
............................................................................................................ 72
5.6.1
................................ 72
5.6.2
........................................................ 72
5.7
Biomarker analysis............................................................................................. 72
5.7.1
Storage, re-use, and destruction of biological samples........................................ 73
5.7.2
Labelling and shipment of biological samples .................................................... 73
5.7.3
Chain of custody of biological samples .............................................................. 73
5.7.4
Withdrawal of informed consent for donated biological samples........................ 74
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 74
6.1
Definition of adverse events............................................................................... 74


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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6.2
Definitions of serious adverse event ................................................................... 75
6.3
Recording of adverse events............................................................................... 75
6.3.1
Time period for collection of adverse events ...................................................... 75
6.3.2
Follow-up of unresolved adverse events............................................................. 75
6.3.3
Variables............................................................................................................ 75
6.3.4
Causality collection............................................................................................ 76
6.3.5
Adverse events based on signs and symptoms.................................................... 77
6.3.6
Adverse events based on examinations and tests ................................................ 77
6.3.7
Hy’s Law ........................................................................................................... 77
6.3.8
Hypoglycaemia .................................................................................................. 77
6.3.9
Pancreatitis ........................................................................................................ 78
6.3.10
Pancreatic carcinoma ......................................................................................... 78
6.3.11
Thyroid neoplasm .............................................................................................. 78
6.3.12
Clinical events for adjudication.......................................................................... 78
6.3.13
Injection site adverse events............................................................................... 79
6.3.14
Disease under study – Not Applicable................................................................ 79
6.4
Clinical Event Adjudication ............................................................................... 79
6.5
Reporting of serious adverse events ................................................................... 80
6.6
Overdose............................................................................................................ 80
6.7
Pregnancy .......................................................................................................... 81
6.7.1
Maternal exposure.............................................................................................. 81
6.8
Medication error ................................................................................................ 81
6.9
Management of investigational product-related toxicities (Dose reductions)....... 83
6.9.1
Tolerability ........................................................................................................ 83
6.9.2
Renal impairment............................................................................................... 83
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 83
7.1
Identity of investigational product(s).................................................................. 83
7.2
Dose and treatment regimens ............................................................................. 84
7.3
Labelling............................................................................................................ 86
7.4
Storage............................................................................................................... 86
7.5
Compliance........................................................................................................ 86
7.6
Accountability.................................................................................................... 86
7.7
Concomitant medication and other treatments.................................................... 86
7.7.1
Permitted concomitant medications.................................................................... 87
7.7.2
Prohibited concomitant medications................................................................... 87
7.7.3
Rescue therapy for hyperglycaemia.................................................................... 88
7.7.4
Other concomitant treatment .............................................................................. 88
7.7.4.1
Anti-hypertensive drug dose reduction............................................................... 88
7.8
Post study access to study treatment – Not Applicable........................................ 88


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8.
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 88
8.1
Statistical considerations .................................................................................... 88
8.2
.......................................................................................... 89
8.3
Definitions of analysis sets................................................................................. 89
8.3.1
Efficacy analysis set........................................................................................... 89
8.3.2
Safety analysis set.............................................................................................. 89
8.3.3
PK analysis set................................................................................................... 89
8.3.4
Other analysis sets.............................................................................................. 90
8.3.4.1
Per Protocol analysis set..................................................................................... 90
8.4
Outcome measures for analyses.......................................................................... 90
8.4.1
Primary efficacy endpoint .................................................................................. 90
8.4.2
Secondary efficacy endpoints............................................................................. 90
8.5
Methods for statistical analyses.......................................................................... 90
8.5.1
Analysis of primary variable (s) ......................................................................... 90
8.5.2
Analysis of secondary variable(s)....................................................................... 91
8.5.2.1
Efficacy ............................................................................................................. 91
8.5.2.2
Safety................................................................................................................. 91
8.5.2.3
Pharmacokinetics and immunogenicity .............................................................. 91
8.5.3
Subgroup analysis.............................................................................................. 91
8.5.4
Interim analysis – Not Applicable ...................................................................... 92
8.5.5
Sensitivity analysis............................................................................................. 92
8.5.6
92
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 92
9.1
Training of study site staff.................................................................................. 92
9.2
Monitoring of the study...................................................................................... 92
9.2.1
Source data ........................................................................................................ 93
9.2.2
Study agreements............................................................................................... 93
9.2.3
Archiving of study documents............................................................................ 93
9.3
Study timetable and end of study........................................................................ 93
9.4
Data management by AstraZeneca ..................................................................... 93
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 94
10.1
Ethical conduct of the study ............................................................................... 94
10.2
Subject data protection....................................................................................... 94
10.3
Ethics and regulatory review .............................................................................. 94
10.4
Informed consent ............................................................................................... 95
10.5
Changes to the Clinical Study Protocol and Informed Consent Form.................. 96
10.6
Audits and inspections ....................................................................................... 96
11.
LIST OF REFERENCES ................................................................................... 96


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LIST OF TABLES
Table 1
Proposed study doses and predicted safety margins based on safety 
data from the cynomolgus monkey........................................................26
Table 2
Study plan (screening, run-in, and 14-week treatment period) ...............44
Table 3
Study plan (minimum 40-week treatment extension period and 
follow-up).............................................................................................49
Table 4
Criteria for initiation of rescue medication (14-week treatment 
period) ..................................................................................................58
Table 5
Criteria for initiation of rescue medication (minimum 40-week 
treatment extension)..............................................................................61
Table 6
Permitted and prohibited rescue therapies..............................................88
LIST OF FIGURES
Figure 1
Study flow diagram...............................................................................31
LIST OF APPENDICES
Appendix A
Additional Safety Information............................................................. 100
Appendix B
International Airline Transportation Association 6.2 Guidance 
Document ........................................................................................... 102
Appendix C
................................................................................ 103
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ...................................................................... 106
Appendix E
......................................... 111
Appendix F
......................................................... 111
Appendix G
............................ 111


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibodies
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
AST
Aspartate transaminase
AUC
Area under concentration-time curve
BMI
Body mass index
BP
Blood pressure
CKD-EPI
Chronic kidney disease epidemiology collaboration
CEA
Clinical Event Adjudication
CK-MB
Creatine kinase (muscle and brain)
CI
Confidence interval
Cmax
Maximum observed concentration
Cmin
Minimum plasma concentration
CPK
Creatine phosphokinase
CRF
Case Report Form
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CV
Cardiovascular
DILI
Drug induced liver injury
DPP4
Dipeptidyl peptidase-4
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
EoT
End of treatment 


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Abbreviation or 
special term
Explanation
FPG
Fasting plasma glucose
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GI
Gastrointestinal
GLP-1
Glucagon-like peptide-1
HbA1c
Haemoglobin A1c
HIV
Human immunodeficiency virus
HL
Hy’s Law
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council on Harmonisation
IFU
Instructions for use
IP
Investigational product 
ITT
Intent-to-treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LOCF
Last-observation-carried-forward
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
NOAEL
No-observed-adverse-effect level
PHL
Potential Hy’s Law
PK
Pharmacokinetic(s)
PP
Per Protocol
PRO
Patient Reported Outcomes
SAE
Serious adverse event 
SAP
Statistical analysis plan
SC
Subcutaneous(ly)
T2DM
Type 2 diabetes mellitus
TBL
Total bilirubin level


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Abbreviation or 
special term
Explanation
TIA
Transient ischaemic attack
ULN
Upper limit of normal
WBDC
Web Based Data Capture


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1.
INTRODUCTION
1.1
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 


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1.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
1.2.1
 
1.2.1.1
 
 
 
 
 


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1.2.1.2
 
 
 
 
  
 
 
  
 
 
1.2.1.3
 
 
 
 
  
1.2.1.4
 
 
 
 
 
 
 
 
 
  
 
 
  


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1.2.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.3
  
1.2.3.1
 
 
  
 
 
 
 
 
 
1.2.3.2
 
 
 
 
 
  
 
 
  
 
 
1.2.3.3
 
 
 
 
.
1.2.3.4
 
 
 


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1.3
Benefit/risk and ethical assessment
This study will provide efficacy and safety information for 3 doses of MEDI0382 compared 
with placebo and liraglutide in subjects with T2DM who are taking metformin.  All subjects 
will be monitored throughout the study to ensure adequate glycaemic control.  Refer to the 
current IB for information on the potential benefits of MEDI0382, and an assessment of the 
potential and known risks.  Refer to the prescribing information for the potential benefits of 
liraglutide, and an assessment of the potential and known risks.
1.4
Study design
This is a randomised, double-blind, placebo-controlled study with an open-label active 
comparator (liraglutide) arm, designed to evaluate the efficacy and safety of MEDI0382 in 
overweight and obese subjects with T2DM.  This study will enrol male and female subjects 
aged ≥18 years, with a BMI ≥25 kg/m2.  Subjects will have a diagnosis of T2DM, and 
inadequate blood glucose control as defined by an HbA1c of 7.0% to 10.5%, and are on 
metformin monotherapy.  Approximately 750 subjects will be randomised at approximately 
150 sites in approximately 8 countries, and it is anticipated that approximately 542 subjects 
will complete the study, taking into account a projected annual study drop-out rate of 15%.  
The study has a run-in period of 2 weeks, a 14-week treatment period, followed by a 
minimum 40-week treatment extension.  
Prior to the run-in period, subjects will be consented and screened for suitability.  During the 
run-in period, subjects will refrain from taking prohibited medications (see Section 7.7 for 
details of prohibited medications), but will continue to take their prescribed stable dose of 
metformin for the remainder of the study.  After completion of run-in, subjects who are still 
eligible will be randomised within 1 week.  Diet and exercise counselling will be provided 
from the beginning and throughout the duration of the study.  Only subjects who are treated 
with metformin monotherapy will be enrolled; this will ensure that subjects with an early 
stage of T2DM are treated in this study.
To achieve the enrolment goal for the initially planned interim analysis (see previous versions 
of the protocol), subjects will be randomly assigned with a ratio of 2:2:2:1:1 to 1 of 5 
treatment arms to receive MEDI0382 at dose level of 300 μg, 200 μg, or 100 μg, placebo or 
liraglutide respectively.  After approximately the first 400 subjects have been enrolled, the 
randomisation ratio will be changed to 5:5:0:2:2 to fully enrol the remaining 350 subjects. 
Analysis will be stratified with respect to screening HbA1c (≤8% or >8%).  
For subjects randomised to MEDI0382 or placebo, MEDI0382 will be initiated at 100 μg, and 
dose increments may occur in 100 μg steps every week until the predefined maintenance dose 
is reached.  Subjects and Investigators will be advised that there may be dose increments.  
During the 14-week treatment period, open-label liraglutide will be initiated at 0.6 mg and up 
titrated by an additional 0.6 mg weekly until a stable daily dose of 1.8 mg is reached. After the 


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14-week treatment period, subjects will continue with the allocated treatment for a further 
minimum of 40 weeks of extension treatment, after which study treatment will end.
Subjects receiving study treatment who have completed more than 40 weeks of extension 
treatment will end study treatment as soon as possible, preferably at the next scheduled visit
(including IP-supply visits), but in no case longer than 4 weeks beyond the next scheduled 
visit.   
An Early Termination visit will be performed for subjects who discontinue treatment 
prematurely at any time and for any reason as soon as possible, but not later than 7 days from 
last IP dose.  A follow-up visit will be performed for final safety assessments 4 weeks after 
the last dose of IP.
See Figure 1 for a summary of the study design.  Details of assessments at each visit are 
summarised in Table 2 and Table 3.


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Figure 1
Study flow diagram
40c week treatment extension
14 week dosing a,b
MEDI0382 300µg
MEDI0382 200µg
MEDI0382 100µg
Placebo
Liraglutide 1.8mg
MEDI0382 300µg
MEDI0382 200µg
MEDI0382 100µg
Placebo
Liraglutide 1.8mg
2 week run in on 
stable 
background 
metformin for 
main study
14 week primary analysis
Co-primary end points:
-
Change in HbA1c from 
baseline to week 14 
vs. placebo
-
Change in weight 
from baseline to week 
14 vs. placebo
ᵃMEDI0382 dosing will be initiated at 100 µg once daily in the morning in each cohort, 
and where required up-titration at 100 µg dose steps will occur at weekly intervals. The 
study will be double-blinded for subjects receiving MEDI0382 and placebo.
ᵇLiraglutide will be initiated at 0.6 mg daily in the morning, and up-titrated at 0.6 mg 
dose steps over 2 weeks then a stable dose of 1.8 mg will be maintained. The study will 
be open-labeled for the subjects receiving liraglutide.
cTreatment extension will be a minimum of 40 weeks.
Subjects will remain on background stable metformin throughout the study.
Screening
Run in
Treatment period
Treatment extension
Follow-up
2 weeks
2 weeks
14 weeks
Minimum 40 weeks
28 days post 
last dose


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1.5
Study governance and oversight
1.5.1
Steering Committee – Not Applicable
1.5.2
Data Monitoring Committee – Not Applicable
1.5.3
Scientific Advisory Committee – Not Applicable
1.5.4
Clinical Event Adjudication Committee
A Clinical Event Adjudication (CEA) Committee, blinded to the treatment of the subject, will 
independently adjudicate certain clinical events including CV AEs, and it will operate in 
accordance with a CEA Charter and Event Handling Manual for Sites and Monitors.  For 
details, see Section 6.4.  
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary objective:
Outcome measure:
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on haemoglobin A1c 
(HbA1c) and body weight versus placebo 
Change in HbA1c from baseline to 14 weeks  
Percent change in body weight from baseline to 
14 weeks
2.2
Secondary objectives
Secondary objective:
Outcome measure:
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on additional measures 
of glycaemic control and body weight versus 
placebo 
Change in HbA1c from baseline to 26 weeks and
54 weeks
Percentage of subjects achieving an HbA1c target of 
<7.0% at 14 weeks, 26 weeks, and 54 weeks
Percent change in body weight from baseline to 
26 weeks, and 54 weeks
Absolute change in body weight from baseline to 
14 weeks, 26 weeks, and 54 weeks
Percentage of subjects achieving weight loss of ≥5% 
and ≥10% after 14 weeks, 26 weeks, and 54 weeks
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on the requirement for 
additional blood glucose lowering therapies 
versus placebo 
Proportion of subjects rescued or discontinued
for lack of glycaemic control at 14 weeks, 26 weeks, 
and 54 weeks
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on weight versus 
liraglutide 1.8 mg once daily 
Percent and absolute change in body weight from 
baseline to 14 weeks, 26 weeks, and 54 weeks


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Secondary objective:
Outcome measure:
To characterise the PK profile and 
immunogenicity of 100 μg, 200 μg and 300 μg 
of MEDI0382 
PK endpoints (trough plasma concentration, Cmin
Development of anti-drug antibodies and titre (if 
positive) during dosing and follow-up
2.3
Safety objectives
Safety objective:
Outcome measure:
To characterise the safety profile, and 
tolerability of 100 μg, 200 μg and 300 μg of 
MEDI0382
Measures of safety and tolerability [(vital signs, 
laboratory test results, adverse events] during 
treatment and follow-up
2.4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.  The subjects may be 
recruited from primary or specialist care, or any systems for referral or advertisements.
3.1
Inclusion criteria
For inclusion in the study, subjects should fulfil the following criteria:
1.
Provision of informed consent prior to any study-specific procedures
2.
Male and female subjects aged ≥ 18 years at screening
3.
Body mass index ≥ 25 kg/m2 at screening
4.
HbA1c range of 7.0% to 10.5% (inclusive) at screening
5.
Diagnosed with T2DM with glucose control managed with metformin monotherapy 
where no significant dose change (increase or decrease ≥500 mg/day) has occurred 
in at least the 2 months prior to screening and the total daily dose of metformin is 
≥1500 mg unless metformin is only tolerated at a lower dose.  Use of another 
glucose-lowering medication for up to 2 weeks in the 2 months prior to screening is 
acceptable (a GLP-1 receptor agonist containing preparation cannot be used within 
the last 30 days or 5 half-lives of the drug, whichever is longer, at the time of 
screening)
6.
For women of childbearing potential:

Must be using appropriate birth control to avoid pregnancy throughout the 
study and for up to 4 weeks after the last dose of IP.  Appropriate birth control 
is defined as a method which results in a low failure rate, ie, less than 1% per 
year, when used consistently and correctly, such as implants, injectables, 
hormonal contraceptives [pills, vaginal rings, or patches], some intrauterine 


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contraceptive devices (levonorgestrel-releasing or copper-T), tubal ligation or 
occlusion, total sexual abstinence that is in line with the preferred and usual 
lifestyle choice of the subject, or a vasectomized partner during the entire 
duration of the study.  As applicable, at least one method must be in effect prior 
to receiving the first dose of IP

Must have a negative serum or urine pregnancy test within 72 hours prior to the 
start of IP

Must not be breastfeeding
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1.
History of, or any existing condition that, in the opinion of the Investigator, would 
interfere with evaluation of the IP, put the subject at risk, influence the subject’s 
ability to participate or affect the interpretation of the results of the study and/or any 
subject unable or unwilling to follow study procedures during the run-in period
2.
Any subject who has received another IP as part of a clinical study or a GLP-1 
receptor agonist containing preparation within the last 30 days or 5 half-lives of the 
drug (whichever is longer) at the time of screening
3.
Concurrent participation in another interventional study of any kind and repeat 
randomisation in this study is prohibited
4.
Severe allergy/hypersensitivity to any of the proposed study treatments or 
excipients
5.
Symptoms of acutely decompensated blood glucose control, a history of type 1 
diabetes mellitus or diabetic ketoacidosis, or if the subject has been treated with 
daily SC insulin for a period longer than 2 weeks within 90 days prior to screening
6.
Acute or chronic pancreatitis.  Subjects with serum triglyceride concentrations 
above 1000 mg/dL (11 mmol/L) at screening as this can precipitate acute 
pancreatitis
7.
Significant inflammatory bowel disease or other severe disease or surgery affecting 
the upper GI tract (including weight-reducing surgery and procedures) which may 
affect gastric emptying or could affect the interpretation of safety and tolerability 
data
8.
Significant hepatic disease (except for non-alcoholic steatohepatitis or 
non-alcoholic fatty liver disease without portal hypertension or cirrhosis) and/or 
subjects with any of the following results at screening: 


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
Aspartate transaminase (AST) ≥3 × upper limit of normal (ULN) 

Alanine transaminase (ALT) ≥3 × ULN 

Total bilirubin (TBL) ≥2 × ULN
9.
Impaired renal function defined as estimated glomerular filtration rate (eGFR) 
≤30 mL/minute/1.73m2 at screening (GFR estimated according to chronic kidney 
disease epidemiology collaboration [CKD-EPI]).  For more details see Section 
5.3.5.
10.
Severely uncontrolled hypertension defined as systolic BP ≥180 mm Hg and/or 
diastolic BP ≥110 mm Hg on the average of two seated measurements after being at 
rest for at least 5 minutes
11.
Unstable angina pectoris, myocardial infarction (MI), transient ischaemic attack 
(TIA), or stroke within 3 months prior to screening, or subjects who have 
undergone percutaneous coronary intervention or a coronary artery bypass graft 
within the past 6 months or who are due to undergo these procedures at the time of 
screening
12.
Severe congestive heart failure (New York Heart Association Class IV)
13.
Basal calcitonin level >50 ng/L or pg/mL at screening or history/family history of 
medullary thyroid carcinoma or multiple endocrine neoplasia
14.
Haemoglobinopathy, haemolytic anaemia, or chronic anaemia (haemoglobin 
concentration <11.5 g/dL [115 g/L] for males, <10.5 g/dL [105 g/L] for females) at 
screening or any other condition known to interfere with interpretation of HbA1c 
measurement
15.
History of neoplastic disease within 5 years prior to screening, except for 
adequately treated basal cell, squamous cell skin cancer, or in situ cervical cancer
16.
Any positive results for serum hepatitis B surface antigen, hepatitis C antibody, and 
human immunodeficiency virus (HIV) antibody
17.
Substance dependence likely to impact subject safety or compliance with study 
procedures
18.
History of psychosis or bipolar disorder. History of major depressive disorder 
within the past year with the subject being clinically unstable, or any history of 
suicide attempt or history of suicidal ideation within the past year
19.
Involvement of any AstraZeneca, MedImmune, the contract research organization, 
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Subjects may be rescreened once, if in the opinion of the Investigator there is a reason to 
believe they may be eligible.  Subjects should continue to meet all inclusion and none of the 
exclusion criteria to qualify for re-screening.  
For the procedures for withdrawal of incorrectly enrolled subjects, see Section 3.4.
3.3
Subject enrolment and randomisation
Investigator(s) should keep a record, the subject screening log, of subjects who entered study 
screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject before any study-specific 
procedures are performed.
2.
Assign potential subject a unique enrolment number, beginning with ‘E#’.
3.
Determine subject eligibility.  See Section 3.1 and 3.2.
4.
Assign eligible subject unique randomisation code.
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
Randomisation codes will be generated by screening HbA1c (≤8% or >8%) strata and regions 
(Europe, US/Canada, Russia, Mexico).  Specific information concerning the use of interactive 
voice/web response system (IVRS/IWRS) will be provided in a separate manual.  Randomised 
subjects who discontinue from IP administration will not be replaced.
3.4
Procedures for handling incorrectly enrolled or randomised 
subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive IP.  There can be no exceptions to this rule.  Subjects who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be randomised or initiated 
on treatment, and must be withdrawn from the study.
3.5
Methods for assigning treatment groups
Assignment to treatment groups will be determined by a computer-generated random 
sequence using an IVRS/IWRS.  To achieve the enrolment goal for the initially planned 
interim analysis (see previous versions of the protocol), subjects will be randomly assigned 
with a ratio of 2:2:2:1:1 to 1 of 5 treatment arms to receive MEDI0382 at dose level of 300 μg, 
200 μg, or 100 μg, placebo or liraglutide respectively.  After approximately the first 400 
subjects have been enrolled, the randomisation ratio will be changed to 5:5:0:2:2 to fully enrol 
the remaining 350 subjects.  


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3.6
Methods for ensuring blinding
The study will be conducted in a double-blind fashion for MEDI0382 and placebo.  Pre-filled 
syringes of MEDI0382 three different doses and placebo are visually distinct from one 
another.  Clear, colourless solutions of MEDI0382 (0.5 mg/mL) will be supplied in 1 mL pre-
filled syringes containing between 0.2 mL and 0.6 mL, depending on the dose.  Buffer placebo 
will be supplied in 1 mL pre-filled syringe containing 0.3 mL.  The different fill volumes and 
the relative position of the plunger rods will be visually distinct during administration.  The IP 
kit cartons are identical in appearance which will be opened exclusively by subjects, just 
before taking the study drug (preferably at home).  The sponsor staff, the subjects, and the 
Investigators involved in the treatment of subjects or in the clinical evaluation of subjects will 
not be aware of the treatment received (International Council on Harmonisation [ICH] E9).  IP 
will be handled by a designated individual (IP manager – pharmacist/study nurse) at the study 
site who will not be involved in the management or evaluation of study subjects.  The tasks 
will/ may include dispensing of IP, collection of used IP boxes along with unused doses, drug 
accountability, instructing the subject on self-administration.  This designated individual may 
also administer the IP during the subject’s on-site visit, and answer the subject’s questions 
related to the IP administration.
There may also be a designated Site Monitor to verify drug accountability performed by 
designated IP manager.
The results for fasting plasma glucose (FPG) and HbA1c are blinded to the Investigator for all 
visits except Visits 1 to 3.  FPG and HbA1c values are blinded to the Investigator site until the 
unblinding criteria for rescue therapy are met.  Once the criteria are met, FPG and HbA1c will 
be reported to the site for an individual subject (see Section 4.2.1.4 and 4.2.2.1).  Previous 
values will remain blinded and the site will only receive the values going forward from the 
point the criteria were met.  However, after Week 26, during the treatment extension period, a 
different glycaemic rescue criterion has been defined for the safety of the subjects (see Section 
4.2.2.1).  The central laboratory will notify the Investigator to repeat HbA1c without 
providing an explanation, and if the repeated HbA1c value is at or above the defined level for 
the visit an instruction will be sent to the site by the Central Laboratory to start glycaemic 
rescue therapy in the subject.
3.7
Methods for unblinding
Individual treatment codes, indicating the treatment randomisation for each randomised 
subject, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS.  Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to the subject to the AstraZeneca staff.


Clinical Study Protocol
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Study Code D5670C00004
Version 5.0
Date 04 December 2018
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AstraZeneca retains the right to break the code for serious adverse events (SAEs) that are 
unexpected and are suspected to be causally related to an IP and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
subject have been made and documented.
The exception to the above is for those personnel analysing the PK samples.  The 
randomisation code will be provided to ensure that only samples from subjects who were on 
active study treatment are analysed.  Samples from subjects not dosed with the relevant active 
study treatment will only be analysed on a ‘for cause’ basis, for example, if there is suspicion 
that a subject has been dosed incorrectly.  The treatment allocation information will be kept in 
a secure location until the end of the study.
For the purpose of the primary analysis and the 26-week analysis, any study team members 
who serve in the unblinded analysis group will stop day-to-day work on the study and other 
pre-selected personnel will take over these roles for the remainder of the trial.  The study team 
members will remain blinded to treatment assignment until the data base lock after the 
treatment extension is finished.
3.8
Restrictions
Once screened and qualified for entry, subjects will be instructed as follows:

Any new prescription medications or over-the-counter preparations must be 
reported to study site staff.  For restrictions on concomitant medications, see 
Section 3.1 and Section 3.2 (Inclusion and Exclusion Criteria) and Section 7
(Investigational Product and Other Treatments).

Continue metformin therapy at current dosage (if applicable) and at approximately 
the same time each day.

Fast overnight for at least 8 hours prior to study site visits (all except Visits 2, 12, 
13, 15, 16, 17 and 18), ie, no food or beverage except water.

Withhold alcohol, and refrain from intense exercise 24 hours prior to each study site 
visit.

Do not donate blood for the duration of the study.

Delay administering the morning dose of metformin therapy (if applicable) and IP 
(as applicable) on the morning of each study site visit and bring antidiabetic 
medication (as applicable) and IP to each study site visit.

Subjects should not be prescribed GLP-1 receptor agonists (Byetta®, Bydureon®, 
or Victoza®) or any other GLP-1 analogs during the 4-week safety follow-up 
period.


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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
If a subject comes to a visit without having followed at least one of the above 
instructions, then the subject should be re-scheduled for the entire visit (if possible 
within the allowed time-window and feasible in Investigator’s judgment).  The 
sponsor or designee should be contacted if the Investigator is informed of any 
restriction violations.  The sponsor will decide whether a subject with restriction 
violations will be allowed to continue study participation.
3.9
Discontinuation of investigational product
Subjects may be discontinued from the IP in the following situations:

Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment.

An AE that, in the opinion of the Investigator or the sponsor, warrants 
discontinuation from further dosing.

Subject noncompliance that, in the opinion of the Investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits).

Pregnancy in a female subject.

Calculated creatinine clearance <30 mL/min confirmed by repeat testing or a 
decrease in renal function that would preclude continued treatment with metformin 
according to local guidance.

Loss of glucose control.  If any subject experiences a loss of glucose control, in 
addition to IP, the Investigator should initiate rescue therapy and the subject may 
continue study participation.  The Investigator should follow local prescribing 
information for the rescue therapy and may discuss appropriate rescue therapy with 
the AstraZeneca Medical Monitor if needed.  Subjects must first complete the 
Rescue visit procedures before receiving open-label rescue therapy.  Rescued 
subjects judged by the Investigator to have inadequate glycaemic control despite a 
maximum tolerated dose of rescue therapy will be discontinued from the IP and 
referred for additional anti-hyperglycaemic therapy (see Sections 4.2.1.4 and 
4.2.2.1).

Subjects with a central laboratory ALT and/or AST >3 × ULN will be scheduled for 
a follow-up visit within 3 days following the receipt of the result (see Appendix D).  
Subjects should be discontinued from study medication if the initial and repeat 
laboratory tests meet any of the following criteria:

ALT and/or AST are >3 × ULN and TBL >2 × ULN

ALT and/or AST are >5 × ULN for ≥14 consecutive days, at any time after 
initial confirmatory results


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
41 (111)

ALT and /or AST are >8 × ULN.

Lost to follow-up.  
Every effort will be made to ensure that the subject continues to return to the clinic for study 
visits and to avoid “lost to follow-up” during the conduct of the study.  It is important that 
Investigators and site staff familiarise themselves with procedures for maintaining such 
subjects in the study to collect their data as scheduled.  The study staff should make diligent 
attempts to contact subjects who fail to return for study visits by using institutional databases, 
subject’s health professionals, and any other means that comply with country and local laws 
and regulations.  After the first missed visit, subjects who are considered temporarily lost to 
follow-up will have 2 documented telephone contact attempts and 1 certified letter in an effort 
to contact them.
Any withdrawal must be fully documented in the subject’s source records and recorded in the 
electronic Case Report Form (eCRF).  The documentation must include the reason for the 
withdrawal and details of any sequelae (followed until symptoms resolve or improve, as 
appropriate).
If a subject is withdrawn from the study during treatment phase, he/she must complete the 
procedures outlined in Section 3.9.1 and the sponsor should be contacted.
3.9.1
Procedures for discontinuation of a subject from investigational product
At any time, subjects are free to discontinue IP or withdraw from the study (ie, IP and 
assessments – Section 3.10), without prejudice to further treatment.  A subject who decides to 
discontinue IP will always be asked about the reason(s) and the presence of any AEs.  The 
reasons for premature discontinuation of IP should be recorded in the eCRF.  If possible, the 
subject will be seen and assessed by an Investigator(s).  Adverse events will be followed up 
(Section 6).  All IP should be returned by the subject.
If a subject discontinues from the IP, he or she should be asked, at the discretion of the 
treating physician, to return to the study site for the Early Termination Visit as soon as 
possible, but not later than 7 days from last IP dose.  All endpoint assessments must be 
performed at this visit (Table 2).  The subject should also be asked to return 4 weeks (±3 days) 
after the last IP dose, for follow-up assessments (see Section 4.3).  If the subject is unable or 
unwilling to return, a phone follow-up should be conducted.
Subjects who discontinue IP will be recommended to continue on the study and follow the 
original visit schedule without taking IP. A follow-up visit should be performed as advised by 
the study plan.  The next visits should be planned in accordance to the original visit schedule 
(apart from the IP resupply visits). If the subject is unable or unwilling to return to the study 
site for visits according to the original visit schedule, the subject should be asked to undergo 
modified visits and schedule (eg, less frequent visits, regular telephone contacts, a contact at 
study closure, or other means).


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
42 (111)
If a subject is withdrawn from the study, see Section 3.10.
3.10
Criteria for withdrawal
3.10.1
Screen failures
Screening failures are subjects who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These subjects should have the reason for study 
withdrawal recorded as ‘Screen failure’.  ‘Failure to meet randomisation criteria’ should be 
selected for an indication that the subject has been unable to fulfil/satisfy the criteria required 
for assignment into a randomised group.
Given some variability in HbA1c, subjects may be eligible for re-testing of HbA1c, if deemed 
applicable by the Investigator.  These subjects will not be automatically listed as screen 
failures.  For such subjects the results measured as part of Screening will be replaced by a re-
test result obtained within the screening period.  For these subjects, the screening will be 
extended to up to 18 days.
3.10.2
Withdrawal of the informed consent
Subjects are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The Investigator will follow up AEs outside of the clinical study.  
AstraZeneca or its delegate may request investigators to collect information on subjects’ vital 
status (dead or alive; date of death when applicable) at the end of the study from publicly 
available sources, in accordance with local regulations.  Knowledge of the vital status at study 
end in all subject is crucial for the integrity of the study.
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.  Withdrawn subjects will not be replaced.
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that:

are assessed as causally related to IP

are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the Case Report Form (CRF).  All reasons 
for discontinuation of treatment must be documented.  In terminating the study, the sponsor 
will ensure that adequate consideration is given to the protection of the subjects’ interests.


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
43 (111)
4.
STUDY PLAN AND TIMING OF PROCEDURES


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
44 (111)
Table 2
Study plan (screening, run-in, and 14-week treatment period)
Evaluation
For details 
refer to 
CSP 
section
Screeningi
Run-in
Baseline
Dosing period
ETt
FUu
Rescue
treatment
Visit Number
1
2
3
4
5
6
7
8
Study Day 
-28 to -15
-14 to 0
1
8
15 
43 
71
99
Study Week
0
1
2
6
10
14
Visit Window (days)
Up to 7
Up to 2
± 2
± 2
± 3
± 3
± 3
± 3
Outpatient visit
X
X
X
X
X
X
X
X
X
X
X
Telephone contact 1 day after dosing visit 
during treatment up-titrationa
4.2.1.2
X
X
Verify subject has fasted 8 hours
4.1, 4.2
X
X
X
X
X
X
X
X
X
Contact IVRS/IWRS
4.1.1
X
X
X
X
X
X
X
X
X
Informed consent (written, general)
4.1.1
X
 
4.1.1
X
Demographics
4.1.1
X
Medical and disease history (including 
smoking, drug, and alcohol history)
4.1.1
X
Complete physical examination (including 
screening for diabetic neuropathy)
5.2.2
X
X
Brief physical examination
5.2.2
X
X
X
X
X
X
X
X
5.3.3
X
X
X
5.3.3
X
X
5.3.4
X
X
Body weight
5.1.2
X
X
X
X
X
Height
5.3.2.1
X
Body mass indexc
5.3.2.1
X


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
45 (111)
Table 2
Study plan (screening, run-in, and 14-week treatment period)
Evaluation
For details 
refer to 
CSP 
section
Screeningi
Run-in
Baseline
Dosing period
ETt
FUu
Rescue
treatment
Visit Number
1
2
3
4
5
6
7
8
Study Day 
-28 to -15
-14 to 0
1
8
15 
43 
71
99
Study Week
0
1
2
6
10
14
Visit Window (days)
Up to 7
Up to 2
± 2
± 2
± 3
± 3
± 3
± 3
Waist circumference
5.3.2.2
X
X
X
X
Digital 12-lead ECG
5.2.3
X
X
X
X
X
Vital signs (BP, pulse)
5.2.4.1
X
X
X
X
X
X
X
X
X
X
X
Assessment of AEs and SAEsd
5.2, 6
X
X
X
X
X
X
X
X
X
X
Concomitant medication review (including 
any dose changes to medications for 
diabetes)e
7.7
X
X
X
X
X
X
X
X
X
X
X
Retinal assessmentf
5.3.2.3
X
Glucometer provision/trainingg
4.1.3
X
Provide subject diary/instructionsg
4.1.3
X
X
X
X
X
X
X
X
Review subject’s diary and blood glucose 
measurements
5.3.1
X
X
X
X
X
X
X
X
X
Calcitonin
5.2.1.4
X
X
X
HIV-1 and HIV-2 antibodies
5.3.6
X
Hepatitis screenh
5.3.6
X
HbA1ci
5.1.1
X
X
X
X
X
X
X
Serum chemistry
5.2.1.2
X
X
X
X
X
X
X
X
Haematology
5.2.1.1
X
X
X
X
X
X
Pancreatic amylase and lipase
5.2.1.3
X
X


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
46 (111)
Table 2
Study plan (screening, run-in, and 14-week treatment period)
Evaluation
For details 
refer to 
CSP 
section
Screeningi
Run-in
Baseline
Dosing period
ETt
FUu
Rescue
treatment
Visit Number
1
2
3
4
5
6
7
8
Study Day 
-28 to -15
-14 to 0
1
8
15 
43 
71
99
Study Week
0
1
2
6
10
14
Visit Window (days)
Up to 7
Up to 2
± 2
± 2
± 3
± 3
± 3
± 3
Fasting blood sample for glucose
5.2.1.5
X
X
X
X
X
X
X
X
X
 j
5.2.1.8
X
X
X
X
X
Fasting blood sample for C-peptide and 
insulin, GLP-1 and glucagon
5.2.1.8
X
X
Coagulation studiesk
5.2.1.7
X
Pre-dose pharmacokinetics for MEDI0382 5.4
X
X
X
X
X
X
X
X
Immunogenicity blood sample
5.2.1.8
X
X
X
X
X
X
X
 
5.6
X
5.7
X
X
Urine ‘drug’ screen
4.1.1
X
Urine hCG Test (pregnancy test)m
5.2.1.8
X
X
X
X
Urinalysis 
5.2.1.6
X
X
X
X
X
Check subject’s ability to self-administer 
SC injectionn
4.1.3
X
X
X
X
Provide education on diet and exercise 
4.1.3
X
X
X
X
X
X
X
X
 
4.2.1.3
X
Verify eligibility criteriap
3.1, 3.2
X
X
Randomisation
4.2.1.1
X


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
47 (111)
Table 2
Study plan (screening, run-in, and 14-week treatment period)
Evaluation
For details 
refer to 
CSP 
section
Screeningi
Run-in
Baseline
Dosing period
ETt
FUu
Rescue
treatment
Visit Number
1
2
3
4
5
6
7
8
Study Day 
-28 to -15
-14 to 0
1
8
15 
43 
71
99
Study Week
0
1
2
6
10
14
Visit Window (days)
Up to 7
Up to 2
± 2
± 2
± 3
± 3
± 3
± 3
MEDI0382/
placebo/
liraglutide dispensationq
4.1, 7.2
X
X
X
X
X
X
Placebo kit dispensation (for run-in)
4.1.3
X
Collect used/unused IPr
4.2.3
Xs
X
X
X
X
X
X
Provide instructions for user
4.1.3
X
X
X
X
X
X
X
Collect instructions for user
4.1.3
X
X
X
X
X
X
X
AE  adverse event; βhCG  beta subunit of human chorionic gonadotropin; BMI  body mass index; BP  blood pressure; CRF  case report form; CSP  clinical study protocol;
; ECG  electrocardiogram; 
; ET  early termination; 
FU  follow-up; GLP-1  glucagon-like peptide-1; HbA1c  haemoglobin A1c; 
; HIV  human immunodeficiency virus; IFU  instructions for 
use; IVRS/IWRS  interactive voice/web response system; IP  investigational product; 
; 
; PK  
pharmacokinetics; SAE  serious adverse event; SC  subcutaneous.
a
During the up-titration phase, the subjects will be contacted via telephone 1 day following on-site dosing visit.  The adverse events/concomitant medication changes will 
be collected, if applicable
b
c
Body mass index will be calculated directly in RAVE [BMI = weight/ (height)2] where weight is measured in kg and height in metres.
d
AEs will be recorded from the time of first IP dose and SAEs will be recorded from the time of informed consent.
e
Subjects should be specifically asked at each visit if there have been any changes to the type and/or doses of their diabetes medications, or if they have needed treatment 
for a hypoglycaemic episode and this information should be recorded in the CRF
f
Window for retinal assessment is 6 months prior to administration of first dose of IP  if performed according to local standard requirements, and as long as the assessment 
can be entered  and stored in the subject’s source documentation
g
Subjects will be provided with a glucometer and training at the beginning of run-in period.  Supply of the glucometer related materials will be provided on an ongoing 
basis as needed if reported by the subject.  Subjects will be asked to complete their glucose diaries at the discretion of the Investigator.  
h
Hepatitis B surface antigen and Hepatitis C virus antibody.
i
Given some variability in HbA1c, subjects may be eligible for re-testing of HbA1c, if deemed applicable by the Investigator. For such subjects the results measured as 
part of Screening will be replaced by a re-test result obtained within the screening period.  For these subjects, the screening will be extended to up to 18 days.


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
48 (111)
j
k
Coagulation studies should only be done in subjects taking oral anticoagulants/ or SC low molecular weight heparin.
l
 
m
Female subjects with childbearing potential only
n
At screening, the Investigator will judge if the subject is able to self-administer SC injection.  Later, subjects will be trained on subcutaneous self-injection technique by 
administering placebo doses during 2 weeks run-in period until the subject is deemed competent by the Investigator or designee.  Further visits may occur for training as 
required 
o
 
p
Subjects must meet all screening eligibility criteria with the exception of the clause relating to a stable dose of metformin in subjects who have had a dose modification of 
metformin due to renal impairment detected at screening.
q
All subjects, together with open-label liraglutide subjects, will be asked to attend all outpatient clinic visits, including weekly dosing visits, as listed in the protocol.
r
From Visit 2, subjects will be provided with instructions for use (IFU) for MEDI0382 and placebo by the IP manager at the site.  For the open-label arm, IFU for 
liraglutide will be provided at Visit 3 following randomisation.  The IFUs will be collected and resupplied at each visit thereafter, till end of treatment or early 
termination visit.  If needed, the IFU can be provided in between the visits.  The IP manager will dispense the IP, collect used IP boxes along with unused doses, perform 
drug accountability, instruct the subject on self-administration, as well as, if required, administer the IP during the subject’s on-site visits.  
s
At Visit 3, subject will be returning used/unused placebo kit doses dispensed at the beginning of run-in
t
ET is an early termination visit for subjects who discontinued the treatment with IP prematurely at any time, and for any reason. IVRS/IWRS should be contacted for 
discontinuation transaction
u
FU is a follow-up visit that should be scheduled 4 weeks (±3 days) following the last dose of IP administered, and is applicable for subjects who either discontinued the 
treatment with IP prematurely at any time and for any reason or completed a minimum of 54 weeks of treatment with IP


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
49 (111)
Table 3
Study plan (minimum 40-week treatment extension period and follow-up)
Evaluation
For 
details 
refer to 
CSP 
section
Minimum 40-Week Treatment Extension Period
ETj
FUk Rescue 
treatment
Visit Number
9
10
11
12
13
14 l
15 l
16 l
17 l 18 l
19/
EoT l
Study Week
18
22
26
30
42
54 l
66 l
78 l
90 l 102 l EoT l
Visit window (days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3
± 3
± 3
Outpatient visitab
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
Brief physical examination
5.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
5.3.3
X
X
X
X
5.3.4
X
X
X
Body weight
5.1.2
X
X
X
X
X
Waist circumference
5.3.2.2
X
X
X
X
X
Digital 12-lead ECGd
5.2.3
X
X
X
X
Vital signs (BP, pulse)
5.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of AEs/SAEs
5.2, 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication review (including any dose changes to 
medications for diabetes)e
7.7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Provide subject diary/instructions
4.1.3
X
X
X
X
X
X
X
X
X
X
X
X
Review subject’s diary and blood glucose measurements
5.2.1.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
5.2.1.2
X
X
X
X
X
X
Haematology
5.2.1.1
X
X
X
X
X
HbA1ce
5.1.1
X
X
X
X
X
X
X
X
X
X
X
Pancreatic amylase and lipase
5.2.1.3
X
Calcitonin
5.2.1.4
X
X
Fasting blood sample for glucose
5.2.1.8
X
X
X
X
X
X
X


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
50 (111)
Table 3
Study plan (minimum 40-week treatment extension period and follow-up)
Evaluation
For 
details 
refer to 
CSP 
section
Minimum 40-Week Treatment Extension Period
ETj
FUk Rescue 
treatment
Visit Number
9
10
11
12
13
14 l
15 l
16 l
17 l 18 l
19/
EoT l
Study Week
18
22
26
30
42
54 l
66 l
78 l
90 l 102 l EoT l
Visit window (days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3
± 3
± 3
Fasting serum lipidsf
5.2.1.8
X
X
X
X
X
Fasting blood sample for C-peptide and insulin, GLP-1, and 
glucagon
5.2.1.8
X
X
X
X
Pre-dose pharmacokinetics for MEDI0382
5.4
X
X
X
X
X
X
X
X
Immunogenicity blood sample
5.2.1.8
X
X
X
X
X
X
5.7
X
Urinalysis 
5.2.1.6
X
X
X
X
X
Urine hCG Test (pregnancy test)g
5.2.1.8
X
X
X
Provide education on diet and exercise
4.1.3
X
X
X
X
X
X
X
X
X
X
X
X
MEDI0382/placebo/liraglutide dispensation
4.1, 7.2
X
X
X
X
X
X
X
X
X
X
4-weekly interval IP supplyh
4.2.3
Collect used/unused IP
4.2.3
X
X
X
X
X
X
X
X
X
X
X
X
Provide instructions for usei
4.1.3
X
X
X
X
X
X
X
X
X
X
Collect instructions for usei
4.1.3
X
X
X
X
X
X
X
X
X
X
X
X
AE  adverse event; βhCG  beta subunit of human chorionic gonadotropin; BP  blood pressure; CRF  case report form; CSP  clinical study protocol; 
 
 ECG  electrocardiogram; EoT  End of treatment; 
 ET  early termination; 
FU  follow-up; HbA1c  haemoglobin A1c; GLP-1  glucagon-like peptide-1; 
; IFU  instructions for use; IP  investigational product;  
 
; PK  pharmacokinetics; SAE  serious adverse event
a
During the minimum 40-week treatment extension period, when diabetes medication is changed an unscheduled telephone visit should be performed one week after the 
occurrence
b
Subjects should be fasted for at least 8 hours prior to all study visits except Visits 12, 13, 15, 16, 17 and 18


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c
Applicable for English speaking subjects in the US and Canada only
d
A single ECG will be performed at Week 54 and at Visit 19 (EoT)
e
Subjects should be specifically asked at each visit if there have been any changes to the type and/or doses of their diabetes medications, or if they have needed treatment 
for a hypoglycaemic episode and this information should be recorded in the CRF
f
g
Female subjects with childbearing potential only
h
The subjects will be asked to return to study site between visits, every 4 weeks (±3 days) to collect the resupply of investigational product (IP).  
i
Subjects will be provided with instructions for use (IFU) for MEDI0382 and placebo, or liraglutide.  The IFU will be collected and re-dispensed at each visit.
j
ET is an early termination visit for subjects who discontinued the treatment with IP prematurely at any time, and for any reason. IVRS/IWRS should be contacted for 
discontinuation transaction
k
FU is a follow-up visit that should be scheduled 4 weeks (±3 days) following the last dose of IP administered, and is applicable for subjects who either discontinued the 
treatment with IP prematurely at any time and for any reason, or completed treatment with IP per protocol (see footnote 1, below).
l
Per CSP Amendment 5, the end of study treatment visit is to be performed at Visit 19 (EoT), as follows:  

Subjects receiving study treatment who have not reached Week 54, will continue per protocol up to Week 54 at which time study treatment will end, subjects will 
complete the Visit 19 (EoT) schedule of assessments, and a FU visit schedule of assessments 4 weeks (±3 days) following the last dose of IP administered. 

Subjects receiving study treatment who have completed Week 54, will end study treatment as soon as possible, preferably at the next scheduled visit (including IP-
supply visits), but in no case longer than 4 weeks beyond the next scheduled visit.  These subjects will complete the Visit 19 (EoT) schedule of assessments, and a FU 
visit schedule of assessments 4 weeks (±3 days) following the last dose of IP administered. 

Subjects who are off drug and continuing in the study per protocol (see Section 3.9.1) but have not reached Week 54, will complete the study up to Week 54, at which 
time they will complete the Visit 19 (EoT) schedule of assessments.

Subjects who are off drug and continuing in the study per protocol (see Section 3.9.1) but have completed Week 54, will complete the Visit 19 (EoT) scheduled of 
assessments,  as soon as possible, but in no case longer than the next scheduled visit.


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4.1
Screening/Enrolment period
Procedures will be performed according to the Study Plan (Table 2).  At screening, consenting 
subjects are assessed to ensure that they meet eligibility criteria.  Subjects who do not meet 
these criteria must not be enrolled in the study.  Subjects will be instructed to arrive in the 
morning of each scheduled visit.  
4.1.1
Visit 1 assessments - Screening 
The maximum duration of the screening period will be 2 weeks (from provision of informed 
consent to completion of screening procedures).
Each potential subject will provide written informed consent prior to any study-specific 
procedures and undergo assessments applicable for the visit (see Table 2). Subjects must sign 
the Informed Consent Form (ICF) prior to any Visit 1 procedures and prior to being instructed 
to fast or withhold any medication unless it is usual site practice to ask all patients to come to 
regular visits having fasted. Registration of subject’s enrolment via IVRS/IWRS should occur 
on the day of ICF signature. 
 
If a subject has not fasted, the subject will sign the informed consent, perform all non-
laboratory screening assessments, and return at least 1 day later in a fasted state for collection 
of screening laboratory assessments.
Throughout the study, subjects will be instructed to delay administering their morning dose of 
metformin on the morning of study site visits, as well as to abstain from strenuous exercise 
and alcohol for 24 hours before each visit.  As above, in case such requests are not usual 
practice, the procedures that could potentially be affected will be rescheduled for a later day 
within the maximum duration of 2 weeks planned for screening.
Demographics data collected will include age, gender, race, and ethnicity. Date of birth will 
be collected if allowed by local regulations.  The subject’s complete medical history will be 
recorded, and will include current medical conditions, past or present, and any diseases or 
disorders.  Visit 1 assessments are primarily concerned with confirmation of the underlying 
disease state and the requisite level of severity based on background medications.  A record of 
physician-diagnosed T2DM is required in source documentation prior to enrolment.  A 
subject’s verbal history suggestive of T2DM symptoms, but without supporting 
documentation, is not sufficient to satisfy this inclusion criterion.
All concomitant medications will be recorded.  See Section 7.7 for more information on 
concomitant medications. The ability of the subject to self-administer SC injection will be 
checked. 
A complete physical examination will be conducted, vital signs will be measured, and a digital 
12-lead electrocardiogram (ECG) will be performed.  Body weight and height will be 
measured, and BMI will be calculated directly in RAVE.


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Blood samples will be taken for laboratory evaluations, including HbA1c measurements, 
calcitonin, serum chemistry, haematology, fasting blood glucose, and fasting serum lipids.  
Urine will be collected for urinalysis, pregnancy testing, and drug screening.  A screen for 
hepatitis and tests for HIV-1 and HIV-2 antibodies will also be performed.  
Given some variability in HbA1c, subjects may be eligible for re-testing of HbA1c, if deemed 
applicable by the Investigator.  For such subjects the results measured as part of screening will 
be replaced by a re-test result obtained within the screening period.  For these subjects, the 
screening will be extended to up to 18 days. Additionally, in case of laboratory results that are 
deemed questionable or unreliable by the investigator or if the blood sample is hemolyzed, re-
testing is permitted.
Screening values will be used to determine if the subject is eligible for randomisation.  In case 
of HbA1c, as described above, the re-test value may be used instead.  All samples will be 
processed by a central laboratory and results will be reported back to the clinic.  Subjects will 
not be randomised if results of any laboratory test are abnormal and clinically significant as 
judged by the Investigator or study physician.  Individuals may requalify for study enrolment 
within 2 weeks of screening following an abnormal test result by having that test repeated 
once with acceptable results as judged by the Investigator and study physician (or designee).
When all of the screening results are available, individuals will be notified by telephone of 
their preliminary eligibility status.
4.1.2
Re-screening
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure or unforeseen personal events that mandate missed screening visits), 
re-screening can be allowed only once.  All study procedures of initial Visit 1 must be 
repeated at the re-screening visit (Table 2).  Re-screened subjects should re-sign informed 
consent on the re-screening Visit 1.  If a subject is re-screened, he/she must continue to meet 
all inclusion/exclusion criteria.  All procedures from screening should be repeated.
The re-screening and HbA1c re-test are independent from one another.  Subjects who fail the 
central HbA1c testing twice during screening may still be re-screened within the 
recommended window but not sooner than 12 weeks (or 3 months) following the date of 
second failed test.
Re-screened subjects keep an originally assigned enrolment number.
4.1.3
Visit 2 assessments - 2-week run-in period
Subjects must come to the clinic for Visit 2 within a maximum of 7 days upon completion of 
the screening period.  Subjects will be instructed to arrive in the morning of the visit and to 
abstain from strenuous exercise and alcohol for 24 hours before the visit.  Subjects should also 
delay administering their morning dose of metformin.


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Visit 2 assessments are primarily concerned with preparing the subject for the study by 
providing education in diet and exercise, training in SC injection administration, and 
instruction on monitoring capillary blood glucose levels.  Visit 2 will also be the initiation of 
placebo run-in.  The assessments required during the 2-week run-in period are detailed in the 
Study Plan (Table 2).
During this visit, a brief physical examination will be conducted, vital signs will be measured.  
Serious AEs will be assessed.  All concomitant medications will be reviewed.
All subjects will receive placebo IP kits to be administered daily during the 2-week placebo 
run-in.  Subjects will be instructed to continue taking metformin as directed during this period.  
During Visit 2, designated IP manager/ caregiver will go through the Instructions for Use 
(IFU) for MEDI0382, placebo, or liraglutide in detail.  Subjects will be trained in self-
administration of IP, disposal of used needles, and all the other IP handling steps while they 
administer the drug at home.  Moreover, subjects will be asked to return the used IP kit boxes 
along with sharp containers and unused syringes to investigational site at their next scheduled 
visit.
Moreover, subjects will receive education on diet and exercise to promote weight loss and will 
be asked to refrain from alternative weight loss programmes; they will be expected to follow 
this advice for the duration of the study and will receive periodic education updates and 
support.
During the run-in subjects will be provided with a blood glucometer and training for its use.  
Subjects will be asked to monitor their capillary blood glucose levels two times per day and 
complete a diary to record these levels while at home for the duration of run-in.  For more 
details, see Section 5.3.1.
All concomitant medications will be reviewed and updated.  Subjects will refrain from taking 
prohibited medications, but will continue to take their prescribed stable dose of metformin 
during the run-in and for the remainder of the study.
 
4.2
Treatment period
The study will comprise a 14-week treatment period, followed by a minimum 40-week 
treatment extension.
Subjects will be instructed to arrive in the morning of each visit and to abstain from strenuous 
exercise and alcohol for 24 hours before scheduled visits.  Prior to each study visit subjects are 
to have fasted overnight for at least 8 hours (no food or beverage except water).  Subjects 
should delay administering their morning dose of metformin and IP on the morning of study 
site visits, and bring the IP (used IP kit boxes, as well as the unused syringes) along with IFU 
with them to the study site for each visit in treatment period.  


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Subjects who complete the study will be asked to return to site 4 weeks (±3 days) after the last 
dose of IP administered for a follow-up visit (see Section 4.3).  Subjects discontinued from the 
treatment prematurely will be asked to return to the study site as soon as possible but not later 
than 7 days from the last IP dose (see Section 3.9) for their Early Termination Visit, and 4 
weeks (±3 days) after the last dose of IP administered for a follow-up visit.  
Subjects will be randomised at Visit 3 (Day 1) to receive either MEDI0382, liraglutide, or 
placebo.  The assessments required during the treatment period are detailed in the Study Plan 
(Table 2 and Table 3).
4.2.1
14-week treatment period
Procedures will be performed according to the Study Plan (Table 2).  A 14-week treatment 
period is required to properly evaluate the dose range.  The procedures and visit schedule is 
more frequent in this initial treatment period.  
4.2.1.1
Visit 3 assessments - Baseline
Subjects must come to the clinic for Visit 3 (baseline) within a maximum of 2 days upon 
completion of the run-in period.  Visit 3 assessments are primarily concerned with baseline 
assessments and randomisation.  
Visit 3 will constitute the end of the placebo run-in period.  The designated IP manager at the 
site will check that subjects are able to self-administer the SC injections and able to adhere to 
IP related study procedures (ie, if subject returned IFU, cartons after used doses, unused 
syringes etc).  
 
 A brief physical examination will be conducted, vital signs will be measured, and a 
digital 12-lead ECG will be performed.  Body weight and waist circumference will be 
measured.  Serious AEs will be assessed and all concomitant medications will be reviewed.
For most inclusion and exclusion criteria, screening values will be used to determine if subject 
is eligible for randomisation.  Eligibility criteria will be verified.  The subject’s diary and 
blood glucose measurements will be reviewed, and education and diet and exercise will be 
provided.  
At Visit 3 blood samples will be taken to measure HbA1c.  Samples will also be taken for the 
following laboratory safety assessments: haematology, serum clinical chemistry, pancreatic 
amylase and lipase, calcitonin, and coagulation panel.  In addition, fasting blood tests will be 
performed for plasma glucose, serum lipids, C peptide, insulin, GLP-1, and glucagon. At 
Visit 3 samples will be taken for non-genetic research, 
 
  Urine will be collected for urinalysis, and pregnancy 
testing.
Blood samples for PK and immunogenicity will be taken prior to administering the 
randomised treatment.


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During this visit, the subject will be randomised, and dosing will commence according to 
assigned treatment arm.  A designated IP manager will go through the IFU for MEDI0382, 
placebo, or liraglutide in detail.  The subject will be asked to self-administer SC IP under 
supervision, used IP will be collected, and the subject will be discharged home following 
2 hours of observation with sufficient IP supply.
Standardised assessments of the eyes, such as dilated fundoscopic examination/fundus 
photography, will also be collected at this visit.  For more details, see Section 5.3.2.3.
4.2.1.2
Visits 4 to 5 assessments – Up-titration
Visits 4 to 5 assessments are primarily concerned with up-titration and establishing a 
maintenance dose.  
On Day 8 (Visit 4) and Day 15 (Visit 5), subjects will return to the clinical unit (outpatient 
visit).  A brief physical examination will be conducted, and vital signs will be measured.  
Adverse events and SAEs will be assessed.  All concomitant medications will be reviewed.  
Education on diet and exercise will be provided.
At Visits 4 and 5 samples will be taken for FPG.  Pre-dose PK samples will also be taken at 
both visits. An immunogenicity sample will be taken at Visit 4. At Visit 5 samples will be 
taken for haematology and serum chemistry.
At each outpatient visit, an up-titration step will be made; this process will be repeated until 
all subjects are established on a maintenance dose which will be continued for the remainder 
of the treatment period.  Subjects will be given additional supply of IP, and used/unused IP 
will be collected.  A designated IP manager/ caregiver will go through the IFU for 
MEDI0382/placebo/liraglutide in detail; the IFU will also be collected at these visits (see 
Table 2).
Telephone contact with the subject will occur between outpatient clinic visits during the 
up-titration phase (see Table 2).  The responses regarding concomitant medications, AEs and 
SAEs will be transferred into the eCRF.  Telephone contact should be appropriately 
documented in the medical records.
The subject’s diary and blood glucose measurements will be reviewed.  Subjects will be 
expected to test capillary blood glucose levels at the discretion of the Investigator and per 
local treatment guidelines, before a study visit, and for 2 weeks following a change in diabetes 
medication.  Subjects should also be advised to check their blood glucose level if they have 
symptoms of hypoglycaemia (hunger, dizziness, shaking, sweating etc.) or feel unwell.  Any 
blood glucose level <3.0 mmol/L (54 mg/dL) is considered clinically significant 
hypoglycaemia and should be reported by Investigators as an AE (see Section 6.3.8).  For 
more details, see Section 5.3.1.  Rescue therapy will be considered for any subject with 
persistent hyperglycaemia (see Section 4.2.1.4 for more details).  


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4.2.1.3
Visits 6 to 8 assessments - maintenance period
Subjects will return to the clinical unit (outpatient visit) every 4 weeks (±3 days).  A brief 
physical examination will be conducted at Visits 6 and 7 and a full physical examination at 
Visit 8.  At each visit in the maintenance period (Visits 6 to 8), vital signs will be measured, 
AEs and SAEs will be assessed, and concomitant medications will be reviewed.  Education on 
diet and exercise will be provided.  
At Visits 6 to 8, HbA1c will be measured and samples will be taken for serum chemistry, and 
FPG.  A pre-dose PK sample will also be taken at each visit.  An immunogenicity sample will 
be taken at Visits 6, 7 and 8.  At Visit 8 (Week 14) the following additional laboratory tests 
will be performed: haematology, pancreatic amylase and lipase, and fasting serum lipids.  
Samples will be collected at Week 8 for future non-genetic research.  Additionally, complete 
urinalysis will be performed at Visit 8 (Week 14).
 
 At Visit 8, along with the complete physical evaluation, body weight 
and waist circumference will be measured and a digital 12-lead ECG will be performed.  
 
 
 
 
 
  
At all 3 visits, subjects will be given additional supply of IP, and used/unused IP will be 
collected.  Subjects will be resupplied with IP for at least 4 weeks (±3 days).  A designated IP 
manager will go through the IFU for MEDI0382, placebo, or liraglutide in detail; the IFU will 
also be collected and resupplied at all treatment visits (see Table 2).
The subject’s diary and blood glucose measurements will also be reviewed.  Subjects will be 
expected to test capillary blood glucose levels at the discretion of the Investigator and per 
local treatment guidelines before a study visit, and for two weeks following a change in 
diabetes medication.  Subjects should also be advised to check their blood glucose level if 
they have symptoms of hypoglycaemia (hunger, dizziness, shaking, sweating etc.) or feel 
unwell.  Any blood glucose level <3.0 mmol/L (54 mg/dL) is considered as clinically 
significant hypoglycaemia and should be reported by Investigators as an AE (See Section 
6.3.8).  For more details, see Section 5.3.1.  Rescue therapy will be considered for any subject 
with persistent hyperglycaemia (see Section 4.2.1.4 for more details).
4.2.1.4
Initiation of rescue medication (14-week treatment period)
Pre-specified glycaemic criteria (see Table 4), based upon central laboratory FPG and repeat 
confirmatory FPG, have been established during the 14-week treatment period, starting at 
Week 0 and up to Week 14 visits, to determine eligibility for open-label rescue medication.


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Subjects with a central laboratory FPG value meeting the lack of glycaemic control criterion 
at a pre-specified visit will be scheduled for a follow-up visit (within 3 to 5 days) to obtain a 
second central laboratory FPG value and review the subject’s glucometer readings.  If the 
repeat central laboratory FPG value still meets the criterion, the subject must be rescued.
Subjects who meet rescue criteria in the 14-week treatment period must first complete the 
rescue visit procedures before receiving open-label rescue medication to ensure that important 
trial endpoint measurements are collected.
Following completion of the rescue visit, rescued subjects will be given open-label 
antidiabetic rescue medication (insulin or other antidiabetic agents except GLP-1 receptor 
agonists, dipeptidyl peptidase-4 (DPP4) and/or sodium-glucose co-transporter 2 inhibitors or 
metformin) to be initiated at the lowest starting dose and titrated in accordance with the 
approved product label in the applicable country at the discretion of the Investigator, in 
addition to their metformin and IP.  Rescued subjects will then continue in the treatment 
period according to their original visit schedule.
Following initiation of open-label rescue antidiabetic medication, rescued subjects should be 
scheduled for titration visits to increase their antidiabetic medication dose, as tolerated and in 
accordance with the approved product label for that country and by their glycaemic response 
and as per the Investigator’s judgment.
Table 4
Criteria for initiation of rescue medication (14-week treatment period)
Time interval on treatment
Rescue therapy is recommended if any of the 
following apply
Week 0 to Week 6 including day of Visit 6
Fasting plasma glucose greater than 270 mg/dL 
(15 mmol/L)
Week 6 to Week 14 including day of Visit 8
Fasting plasma glucose greater than 240 mg/dL 
(13.3 mmol/L)
Rescue therapy with add-on insulin is the preferred option, but additional drug classes are 
permitted (see Table 6).  Rescue therapy with any GLP-1 receptor agonist or DPP4 inhibitor 
based intervention is prohibited (see Section 7.7.3).
4.2.1.5
Rescue visit
Subjects who require rescue will complete rescue procedures.  If subjects are still taking IP at 
the time of the rescue visit, they should delay administering the morning dose of metformin (if 
applicable) and IP on the day of the visit and bring oral antidiabetic medication to the study 
site visit.
Rescue procedures are detailed in Table 2 and Table 3.  


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4.2.2
Minimum 40-week extension period
All subjects will continue into the minimum 40-week treatment extension designed to evaluate 
safety, tolerability, and efficacy over the longer term.  At all visits apart from the IP resupply 
visits, a brief physical examination will be conducted and vital signs will be measured.  
Adverse events and SAEs will be assessed.  All concomitant medications will be reviewed.  
The subject’s diary and blood glucose measurements will be reviewed.  Education on diet and 
exercise will be provided.  Procedures will be performed according to the Study Plan (Table 
3).
All subjects will complete an end of treatment (EoT) visit, which is to be performed according 
to the Visit 19 (EoT) schedule of assessments, as follows:  
Subjects receiving study 
treatment who have not 
reached Week 54
These subjects will continue per protocol up to Week 54, at 
which time study treatment will end. These subjects will 
complete the Visit 19 (EoT) schedule of assessments, and a FU 
visit schedule of assessments 4 weeks (±3 days) following the 
last dose of IP administered.
Subjects receiving study 
treatment who have 
completed Week 54
These subjects will end study treatment as soon as possible, 
preferably at the next scheduled visit (including IP-supply 
visits), but in no case longer than 4 weeks beyond the next 
scheduled visit.  These subjects will complete the Visit 19 (EoT) 
schedule of assessments, and a FU visit schedule of assessments 
4 weeks (±3 days) following the last dose of IP administered
Subjects who are off 
drug and continuing in 
the study per protocol 
(see Section 3.9.1) but 
have not reached 
Week 54
These subjects will complete the study up to Week 54, at which 
time they will complete the Visit 19 (EoT) schedule of 
assessments.
Subjects who are off 
drug and continuing in 
the study per protocol 
(see Section 3.9.1) but 
have completed 
Week 54
These subjects will complete the Visit 19 (EoT) scheduled of 
assessments, as soon as possible, but in no case longer than the 
next scheduled visit.
The first four visits – Visit 9 (Week 18), Visit 10 (Week 22), Visit 11 (Week 26), and Visit 12 
(Week 30) will be scheduled in 4-week (±3 days) intervals to facilitate adequate safety 
monitoring of subjects during the initial approximate 6 months of treatment.  For the 


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remainder of the visits in the treatment extension, subjects will return to the clinical unit 
(outpatient visit) every 3 months.
A pre-dose PK sample will be collected at Visits 9, 10, 11, 14, 15 and 19 (EoT).
At Visits 11, 14, and 19 (EoT)
 
body weight and waist circumference will be measured.  
Blood samples will be taken for haematology, fasting serum lipids, and fasting C-peptide, 
insulin, GLP-1, and glucagon.  Urine will be collected for urinalysis with the same frequency.
At Visits 9, 10, 11, 14, and 19 (EoT), blood samples will be taken for fasting blood glucose.
At Visits 11, 14, 16, and 19 (EoT) a blood sample will be taken for serum chemistry.  An 
immunogenicity blood sample will be collected at Visits 11, 14, 15, and 19 (EoT).  A digital 
12-lead ECG will be performed at Visits 14 and 19 (EoT).
HbA1c will be measured at Visits 11 to 19 (EoT).
 
 
At Visit 19 (EoT), blood samples will be collected for pancreatic amylase and lipase, for 
calcitonin, and for future non-genetic research.  Additionally, at Visit 19 (EoT), urine will be 
collected for pregnancy testing.  
As before, subjects will be expected to test capillary blood glucose levels at the discretion of 
the Investigator and per local treatment guidelines, before a study visit, and for two weeks 
following a change in diabetes medication.  Subjects should also be advised to check their 
blood glucose level if they have symptoms of hypoglycaemia (hunger, dizziness, shaking, 
sweating etc.) or feel unwell.  Any blood glucose level <3.0 mmol/L (54 mg/dL) is considered 
as clinically significant hypoglycaemia and should be reported by Investigator as an AE (see 
Section 6.3.8).  For more details, see Section 5.3.1.  Rescue therapy will be provided to 
subjects with persistent hyperglycaemia (see Section 4.2.2.1 for more details) and there will 
be periodic diet and exercise education updates.
At each visit, subjects will be given additional supply of IP, and used/unused IP will be 
collected.  Subjects will be resupplied with IP every 4 weeks (±3 days).  A designated IP 
manager will go through the IFU for MEDI0382/placebo, or liraglutide in detail; the IFU will 
also be collected at these visits (see Table 3).
4.2.2.1
Initiation of rescue medication (minimum 40-week treatment extension)
Pre-specified glycaemic criteria (see Table 5), based upon central laboratory FPG or HbA1c 
have been established during the period to determine eligibility for open-label rescue 
medication for subjects not previously rescued in the 14-week treatment period.


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Table 5
Criteria for initiation of rescue medication (minimum 40-week 
treatment extension)
Time interval on treatment
Rescue therapy is recommended if any of the 
following apply
Week 14 to Week 26 including day of Visit 11
Fasting plasma glucose greater than 200 mg/dL 
(11.1 mmol/L) (repeated and confirmed)
Week 26 to Week 54 including day of Visit 14, 
but excluding day of Visit 19 (EoT)
Central laboratory HbA1c >8% (repeated and 
confirmed)
Week 54a to Week 66 including day of Visit 15, 
but excluding day of Visit 19 (EoT)
Central laboratory HbA1c >7.5% (repeated and 
confirmed)
Greater than Week 66 a excluding day of Visit 19 
(EoT)
Central laboratory HbA1c >7.0% (repeated and 
confirmed)
a
These time intervals apply to subjects who had completed Visit 14 at the time the CSP Amendment 5 was 
implemented. 
Subjects who meet rescue criteria in the 40-week treatment extension period, must first 
complete the “Rescue” Visit procedures (see Table 3) before receiving open-label rescue 
medication to ensure that important trial endpoint measurements are collected.  Rescued 
subjects will then continue in the 40-week treatment extension period according to their 
original visit schedule.
Rescue therapy with add-on insulin is the preferred option, but additional drug classes are 
permitted (see Table 6).  Rescue therapy with any GLP-1 receptor agonist or DPP4 inhibitor 
based intervention is prohibited (see Section 7.7.3).
4.2.3
Resupply of investigational product visits
Subjects will be resupplied with IP every 4 weeks (±3 days).  Used/unused IP will be 
collected. A designated IP manager will go through the IFU for MEDI0382/placebo, or 
liraglutide in detail; the IFU will also be collected and resupplied at these visits.
4.2.4
Unscheduled visits
Unscheduled visits may be initiated as needed, and any additional assessments might be 
performed at this visit at the discretion of the Investigator.  In case safety laboratory 
assessments are required, the Investigator should refer to the Laboratory Manual for more 
details.
4.2.5
Early termination
If a subject discontinues early from the IP, he or she should be asked to return to the study site 
as soon as possible, but not later than 7 days from last IP dose (see Table 2 and Table 3).  If 
the subject is unable or unwilling to return, a phone follow up should be conducted.


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
62 (111)
4.3
Last dose of investigational product follow-up visit
A follow-up outpatient visit should be scheduled 4 weeks (±3 days) following the last dose of 
IP administered, and is applicable for subjects who either discontinued the treatment with IP 
prematurely at any time, and for any reason, or completed treatment with IP at Visit 19 (EoT).  
Procedures will be performed according to the Study Plan (see Table 2 and Table 3). 
At the follow-up visit, a brief physical examination will be performed and body weight, waist 
circumference, and vital signs will be measured.  A 12-lead ECG will be performed.  Adverse 
events and SAEs will be assessed.  All concomitant medications will be reviewed.  The 
subject’s diary and blood glucose measurements will be reviewed.  Blood samples will be 
taken for clinical laboratory evaluations, HbA1c, fasting blood glucose, and fasting serum 
lipids.  Urine samples will be taken for urinalysis and pregnancy testing.  A blood sample for 
immunogenicity and a PK sample will also be taken.  
After the end of the follow-up period, subjects will return to the care of their own physicians 
according to local requirements and local standards.
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The Investigator will ensure that data are recorded on the eCRFs as specified 
in the Clinical 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 (CSA).  
The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site.
5.1
Efficacy assessments
Study outcome measures are summarised in Section 8.4.
5.1.1
HbA1c
Blood samples for measurement of HbA1c will be collected according to the schedule 
presented in the Study Plan (Table 2 and Table 3).  The instructions for collection, processing, 
packaging, and shipping of the samples will be detailed in the Laboratory Manual.
5.1.2
Body weight 
Body weight will be measured according to the schedule presented in the Study Plan (Table 2
and Table 3).  Body weight should be measured in the morning while the subject is fasted and 
prior to breakfast.  At screening (Visit 1), baseline Visit 3 (Day 1), Visit 8 (Week 14), Visit 11 
(Week 26), Visit 14 (Week 54), and Visit 19 (EoT), the subject’s weight should be measured 
with the subject wearing a surgical gown and no shoes, and the weight of the surgical gown 
should be subtracted from the result.  The subject’s body weight will be recorded in kilograms 


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
63 (111)
(kg) to one decimal place.  All readings should be recorded as accurately as possible and the 
same scale should be used for all assessments for a given subject.  The same scale should be 
used throughout the study and calibrated on a regular basis as recommended by the 
manufacturer.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
The date, time of collection, and sample ID will be recorded on the appropriate eCRF.  
Clinical laboratory tests will be performed at a central laboratory.  The samples will be 
processed by a central laboratory and results will be reported back to the clinic.  The 
instructions for collection, processing, packaging, and shipping of the samples will be detailed 
in the Laboratory Manual.
Laboratory safety variables that will be measured are summarised in Section 5.2.1.  Other 
clinical laboratory evaluations are summarised in Section 5.2.1.8.
5.2.1.1
Haematology
Blood samples will be drawn for measurement of haematology according to the schedule 
presented in the Study Plan (Table 2 and Table 3).
Haematology assessments will include the following: red cell count, haemoglobin, 
haematocrit, white cell count, platelets count, differential count, mean cell volume, mean 
corpuscular haemoglobin, and mean corpuscular haemoglobin concentration.
5.2.1.2
Serum clinical chemistry
Blood samples will be drawn for measurement of serum chemistry according to the schedule 
presented in the Study Plan (Table 2 and Table 3).
Chemistry assessments will include the following: blood urea nitrogen, creatinine, total 
protein, albumin, uric acid, TBL, alkaline phosphatase (ALP), ALT, AST, gamma glutamyl 
transpeptidase, amylase, lipase, creatine phosphokinase (CPK), creatine kinase, muscle and 
brain (CK-MB) (if CPK is elevated), troponin T (if CK-MB is elevated), sodium, potassium, 
chloride, bicarbonate, magnesium, phosphorus, and calcium.  Note that, if a subject shows an 
AST or ALT ≥3 × ULN AND TBL ≥2 × ULN, refer to Appendix D ‘Actions Required in 
Cases of Increases in Liver Biochemistry and Evaluation of Hy’s Law’, for further 
instructions.
5.2.1.3
Serum amylase and lipase
Blood samples will be drawn for measurement of amylase and lipase, along with the clinical 
chemistry according to the schedule presented in the Study Plan (Table 2 and Table 3).
If amylase and/or lipase values increase ≥3 × ULN:

Confirm by repeat testing.


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
64 (111)

Perform diagnostic work-up for evaluation of pancreatitis according to clinical 
practice.
The Investigator should make an assessment of the available clinical laboratory safety results 
with regard to clinically relevant abnormalities.  The laboratory results should be signed and 
dated and retained at the centre as source data for laboratory variables.  The Investigator 
should follow all clinically significant laboratory abnormalities occurring during the study that 
were not present at baseline.  These abnormalities should be evaluated with additional tests, if 
necessary, until the underlying cause is diagnosed or resolution occurs.  The diagnosis and 
resolution date must be reported to the sponsor.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.
5.2.1.4
Serum calcitonin
Blood samples will be drawn for measurement of serum calcitonin concentrations according 
to the schedule presented in the Study Plan (Table 2 and Table 3).
If an elevation of calcitonin is noted and deemed of clinical concern, typically a level above 
10 ng/L or pg/mL:

The Investigator should assess for factors that could be impacting calcitonin 
concentrations (ie, concomitant medications) and consider stopping concomitant 
medications prior to rechecking calcitonin concentrations.

If calcitonin concentrations remain elevated upon recheck, the subject should be 
referred to their healthcare provider for appropriate follow-up.

Any subsequent testing and interpretation of results should be provided to the study 
site personnel.
The Investigator should discuss subject continuation in the study with the study physician.
5.2.1.5
Fasting plasma glucose
Blood samples for measurement of FPG will be collected according to the schedule presented 
in the Study Plan (see Table 2 and Table 3), and analysed by a central laboratory.  The 
instructions for collection, processing, packaging, and shipping of the samples will be detailed 
in the Laboratory Manual, which will be distributed to each study site during site initiation.
If the FPG (value from central laboratory) meets rescue limits (see Sections 4.2.1.4 and 
4.2.2.1), the subject should return within 3 to 5 days for an unscheduled confirmatory visit to 
confirm the high FPG and assess eligibility for rescue during the treatment period.
5.2.1.6
Urinalysis
Urine samples will be collected for urinalysis according to the schedule presented in the Study 
Plan (Table 2 and Table 3).


Clinical Study Protocol
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Study Code D5670C00004
Version 5.0
Date 04 December 2018
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Urinalysis assessments will include the following: pH, specific gravity, glucose (urine glucose 
will be blinded throughout the study), blood (urine haemoglobin/erythrocytes/blood), ketones, 
protein, and microscopic analysis.
5.2.1.7
Coagulation panel
Blood samples will be drawn for measurement of the coagulation panel according to the 
schedule presented in the Study Plan (Table 2).

Prothrombin time (baseline only)

Activated partial thromboplastin time (baseline only)
5.2.1.8
Other clinical laboratory evaluations
Fasting blood samples
Fasting blood samples will be taken for the measurement of the following according to the 
schedule presented in the Study Plan (Table 2 and Table 3):

 
 

Fasting plasma C-peptide and insulin

Fasting plasma glucagon and GLP-1
The instructions for collection, processing, packaging, and shipping of the samples will be 
detailed in the Laboratory Manual.
Pregnancy testing
A pregnancy test should be conducted on any female subject of childbearing potential as 
detailed in the Study Plan (Table 2 and Table 3).  Pregnancy tests do not need to be conducted 
in women who are surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or 
complete hysterectomy), or are postmenopausal.  The presence of βHCG in urine is to be 
assessed at the study centre by dipstick.  The first dose of IP or any other in-clinic dose of IP 
must not be administered until a negative urine pregnancy test result is obtained.  A positive 
urine pregnancy test should be confirmed by a serum pregnancy test.  Serum pregnancy tests 
will be tested by a central laboratory.
Immunogenicity
Instructions for MEDI0382 immunogenicity (ADA) sample collection, processing, storage, 
and shipment can be found in the Laboratory Manual. Serum samples for analysis of ADA 
will be collected for subjects on MEDI0382/Placebo arms according to the schedule presented 
in the Study Plan (Table 2 and Table 3). Samples for determination of ADA will be analysed 
by a selected laboratory on behalf of AstraZeneca, using a validated bioanalytical method. A 
summary of the analysis will be presented in the clinical study report (CSR). Details of the 


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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analytical method used will be described in a bioanalytical report. Tiered analyses will be 
performed to include screening, confirmatory, and titre assay components, and the positive-
negative cut points will be statistically determined from drug-naïve validation samples. Serum 
samples collected for ADA should be stored for 2 years after marketing approval, and they 
may be utilised for further characterisation of the antibody response.
5.2.2
Physical examination
A complete physical examination will be performed according to the schedule presented in the 
Study Plan (Table 2).  The complete physical examination includes an assessment of the 
following: general appearance including skin inspection, lymph nodes, thyroid, 
musculoskeletal/extremities, CV, lungs, abdomen, and reflexes.  
A brief physical examination should be conducted according to the schedule presented in the 
Study Plan (Table 2 and Table 3).  A brief physical examination includes the following: skin, 
extremities, CV, lungs, and abdomen.  Clinically significant abnormalities in physical 
examination findings at study termination must be followed up by the Investigator and 
evaluated with additional tests if necessary, until the underlying cause is diagnosed or 
resolution occurs.  As appropriate, the diagnosis and resolution date of the physical 
examination abnormalities must be reported as AEs.
See Section 6 for information on reporting AEs.
5.2.3
Resting 12-lead ECG
A digital 12-lead ECG will be performed in accordance with the schedule provided in the 
Study Plan (Table 2 and Table 3).  A 12-lead ECG will be taken in the supine position after 
the subject has been resting for at least 10 minutes.  If the ECG must be performed with the 
subject in another position (sitting, standing, etc.), the Investigator should record the alternate 
position.  The Investigator should date and sign the ECG tracing and record the clinical 
significance of any abnormal result on the tracing.  The ECGs will be interpreted by a 
qualified physician (the Investigator or qualified designee) at the clinical study site.  The 
ECGs will be stored at the study centre.  ECG data and evaluation will be recorded in the 
eCRF.  See Section 6 for information on reporting AEs.
5.2.4
Vital signs
Pre-dose vital signs (pulse and BP) are to be obtained in accordance with schedule provided in 
the Study Plan (Table 2 and Table 3).  Vital signs are to be taken prior to IP administration, 
and, if possible, before blood drawing.  Vital signs should be measured after the subject rests 
for approximately 5 minutes and with the subject in a sitting position.
5.2.4.1
Pulse and blood pressure
One pulse measurement will be taken after the subject has been sitting and resting for at least 
5 minutes, and before blood samples are taken. If a semi-automatic device is used, 
extrapolation to 1 minute is recommended. If using manual BP measurements, a full sixty 
second period for recording the pulse is required.  The pulse measurement will be followed by 


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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two BP measurements separated by 2 minutes each.  The two BP readings should be recorded.  
At Visit 1 the seated BP will be recorded two times in both the left and the right arms.  The 
two measurements should be made in one arm before transferring the cuff to the other arm.  
The arm with the highest mean seated BP readings will be the one used for all subsequent 
readings throughout the study.  Blood pressure readings should be taken while the subject is in 
a comfortable seated position with the arm supported at the level of the heart.  All readings 
should be recorded.  Ideally, BP should be measured with the same machine, at the same time 
of day with a two hour window, and by the same personnel at each visit.  
At each visit, two BP measurements separated by 2 minutes each will be done.  The two BP 
readings should be recorded and entered in eCRF.
5.2.4.2
Orthostatic blood pressure
In the event that the subject experiences symptoms of dizziness or light-headedness or visual 
blurring, orthostatic BP and pulse should be collected if deemed necessary by the Investigator.  
Supine and standing measurements should be made after the seated BP and pulse 
measurements have been made, using the same arm that was used for the seated BP 
measurements.  All readings should be recorded.  
Supine BP and pulse
The supine BP and pulse must be measured prior to the standing BP and pulse.  After the 
subject rests in the supine position for at least 5 minutes, supine BP and pulse will be 
determined from two replicate measurements obtained 2 minutes apart.  The two readings 
must be recorded.
Standing BP and pulse
After the supine BP and pulse measurements are obtained, the subject will stand for 2 to 
3 minutes.  After this time, the BP will be measured with the arm supported at the level of the 
heart.  Standing BP and pulse will be determined from two replicate measurements obtained at 
least 2 minutes apart. The two readings must be recorded.  If a new occurrence of previously 
absent orthostatic hypotension is demonstrated, it should be recorded in the appropriate 
section of the CRF.  The Investigator may consider reducing concomitant anti-hypertensive 
medication to alleviate signs and symptoms of orthostatic hypotension, without 
discontinuation of IP.
5.2.5
Other safety assessments
5.2.5.1
Drug-induced liver injury
Liver enzymes (ALT, AST, and ALP) and TBL should be monitored for abnormalities 
indicative of drug-induced liver injury.  Investigators should contact the study physician if a 
subject develops a liver function test abnormality.
Laboratory values meeting the criteria for Hy’s Law are to be reported to AstraZeneca as 
SAEs in the same time frame as defined for other SAEs.


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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A Hy’s Law case is defined as any subject with an increase in AST or ALT ≥3 × ULN 
together with TBL ≥2 × ULN, where no other reason can be found to explain these increases.
Potential Hy’s Law cases that meet any of the identification criteria specified in Appendix D
will require an unscheduled laboratory draw for assessment by the central laboratory (see 
central laboratory manual for further instructions on appropriate laboratory kit).  See 
Appendix D for further details.
5.3
Other assessments
5.3.1
Glucose measurements
Subjects will be asked to monitor blood glucose levels at the discretion of the Investigator and 
per local treatment guidelines, before a study visit, and for 2 weeks following a change in 
diabetes medication (see Table 2 and Table 3) to help in the clinical management.  The 
exception to this is during run-in, where subjects will be asked to monitor blood glucose twice 
per day for 1 week before this visit.  Subjects should also be advised to check their blood 
glucose level if they have symptoms of hypoglycaemia (hunger, dizziness, shaking, sweating 
etc.) or feel unwell.  Any blood glucose level <3.0 mmol/L (54 mg/dL) is considered as 
clinically significant hypoglycaemia and should be reported by Investigators as an AE (see 
Section 6.3.8).  Pharmacological treatments administered for hypoglycaemia, eg, 
dextrose/glucose tablets, glucagon etc., should be recorded.  Rescue therapy will be 
considered for any subject with persistent hyperglycaemia.  Self-monitored plasma glucose or 
blood glucose readings and hypoglycaemic events will be collected and reviewed by the 
Investigator.  Subjects may be expected to be educated and knowledgeable about their actions 
in case of hypoglycaemia, but study personnel will offer education and contact information 
during visits.
5.3.2
Clinical outcome assessments
5.3.2.1
Calculation of BMI
Weight and height will be measured, in accordance with schedules provided in the Study Plan 
(Table 2 and Table 3).  The subject's weight will be recorded in kilograms (see Section 5.1.2
for more details); height will be recorded in centimetres.  Body mass index will be calculated 
directly in RAVE [BMI =weight / (height)2], where weight is measured in kg, and height in 
metres).
5.3.2.2
Waist circumference
For waist circumference measurement, the study site personnel must ensure that:

The subject stands and the examiner places a measuring tape in a horizontal plane 
around the abdomen at the level of the umbilicus

The measuring tape is snug, but does not compress the skin, is parallel to the floor, 
and is not twisted


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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
The measurement is taken at the end of a normal respiratory expiration.

The measurement is recorded in centimeters to the first decimal point.
Waist circumference will be measured according to the schedules presented in the Study Plan 
(Table 2 and Table 3).
5.3.2.3
Retinal assessment
Standardised assessments of the eyes, such as dilated fundoscopic examination/fundus 
photography will be collected at baseline and stored in the subject’s source documentation.  If 
the subject has underlying retinopathy, the baseline assessment will be entered also in the 
eCRF.  According to local practice the retina assessment may be in the form of detailed 
dilated fundoscopic examination by a healthcare professional experienced in the procedure, or 
a retinal photograph.  Where AEs associated with worsening of diabetic eye disease are 
reported, baseline assessments of diabetic eye disease will be reviewed.  The time window for 
baseline retinal assessment is 6 months prior to administration of first dose of IP if done in 
accordance to local standard requirements.  
5.3.3
 
 
 
 
 
 


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Study Code D5670C00004
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5.3.3.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3.3.2
 
 
 
 
5.3.3.3
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
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5.3.4
 
 
 
 
5.3.5
Calculation of eGFR 
The central laboratory will calculate eGFR using CKD-EPI creatinine formula (Levey et al 
2009).
5.3.6
Serology 
At Visit 1 samples will be collected to test for serum hepatitis B surface antigen, serum 
hepatitis C antibody, and serum HIV-1 and serum HIV-2 antibodies.  Testing will be 
performed at the central laboratory.
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate Laboratory Manual provided to the study centres.
5.4
Pharmacokinetics
5.4.1
Collection of samples
Blood samples for determination of MEDI0382 in plasma will be taken at the times presented 
in the Study Plan (Table 2 and Table 3).
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
5.4.2
Determination of drug concentration
Samples for determination of drug concentration in plasma will be analysed by LGC on behalf 
of AstraZeneca, using an appropriate bioanalytical method.  Full details of the analytical 
method used will be described in a separate bioanalytical report.


Clinical Study Protocol
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Study Code D5670C00004
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5.4.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalisation or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses.
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling.  
Additional analyses may be conducted on the anonymised, pooled PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to the appropriate AstraZeneca 
biobank; see details in the Laboratory Manual).
5.5
Pharmacodynamics - Not Applicable
5.6
 
 
  
5.6.1
5.6.2
 
 
 
5.7
Biomarker analysis
Three additional blood samples will be collected according to the schedule presented in the 
Study Plan (Table 2 and Table 3) for potential future measurement of other analytes, if 
indicated upon review of the data.  Biological samples for future research will be retained at 


Clinical Study Protocol
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Study Code D5670C00004
Version 5.0
Date 04 December 2018
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the AstraZeneca Biobank or an AstraZeneca approved storage facility for a maximum of 15 
years after the blood sample collection date or according to local legislation.  Samples may be 
destroyed prior to this timeframe if the subject has withdrawn consent.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.  
 
5.7.1
Storage, re-use, and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the last subject’s last visit, 
after which they will be destroyed.  The results of this biomarker research will be reported 
either in the CSR itself or as an addendum, or separately in a scientific report or publication.  
The results of this biomarker research may be pooled with biomarker data from other studies 
with the IP to generate hypotheses to be tested in future research.
5.7.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria); 
see Appendix B, IATA 6.2 Guidance Document.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca and appropriate 
labelling, shipment, and containment provisions are approved.
5.7.3
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the subjects while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites, and auditing of external laboratory providers.
Samples retained for further use are registered in the appropriate AstraZeneca biobank during 
the entire life cycle.


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Study Code D5670C00004
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5.7.4
Withdrawal of informed consent for donated biological samples
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Principal Investigator:

Ensures subject’s withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca.

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented.

Ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented, and the signed document returned to the study site.

Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavourable and unintended 
sign (eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.
The term AE is used to include both serious and nonserious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in period, even if no study treatment has been administered, but will for the purpose of 
this study only be recorded from the time of first IP dose (see Section 6.3.1).


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Study Code D5670C00004
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6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, follow-up), that 
fulfils 1 or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of an SAE, see Appendix A.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse events will be collected from time of first IP dose, throughout the treatment period 
and including the follow-up period, final visit (4 weeks post last dose ± 3 days).
Serious AEs will be recorded from the time of signature of informed consent.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the subject’s last AE assessment in the study are 
followed up by the Investigator for as long as medically indicated, but without 
further recording in the CRF.  AstraZeneca 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.
6.3.3
Variables
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity

Whether the AE is serious or not


Clinical Study Protocol
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
Investigator causality rating against the IP (yes or no)

Action taken with regard to IP

AE caused subject’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for each SAE:

Date AE met criteria for SAE

Date Investigator became aware of SAE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication

Description of AE
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between the IP and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the investigational product?’


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For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes.’
A guide to the interpretation of the causality question is found in Appendix A to the clinical 
study protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit’, or 
revealed by observation will be collected and recorded in the CRF.  When AEs are reported, 
the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms.  However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
6.3.6
Adverse events based on examinations and tests
The results from the mandated laboratory tests and vital signs will be summarised in the CSR.  
Deteriorations as compared to baseline in protocol-mandated laboratory values, vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the reason 
for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible, the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.3.7
Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3xULN together with TBL ≥2xULN may need to be 
reported as SAEs.  Refer to Appendix D for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law.
6.3.8
Hypoglycaemia
Spontaneous and clinically significant hypoglycaemia has not been experienced in prior 
studies with MEDI0382 up to a dose of 300 μg alongside metformin treatment.  
Subjects will be asked to test their blood glucose if they develop symptoms suggestive of 
hypoglycaemia and to record specific symptoms and glucose values in the subject’s diary.  


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Investigators should follow local protocols for treatment and follow-up of the hypoglycaemic 
episode.  Clinically important biochemical hypoglycaemia defined as glucose levels less than 
3.0 mmol/L (54 g/dL) by the recent joint position statement of the American Diabetes 
Association and the European Association for the Study of Diabetes (International 
Hypoglycaemia Study Group 2017) should be reported as an AE, and both the AE and the 
hypoglycaemia eCRF pages must be completed.  
Following at least two clinically significant biochemical hypoglycaemia episodes (defined as a 
glucose <3.0 mmol/L or <54 mg/dL) arising over a period of less than 2 weeks, down-titration 
of metformin or liraglutide (if relevant) may be considered by the Investigator.  In the event 
that hypoglycaemia is seen in subjects prescribed rescue medication, the rescue medication 
should be down-titrated first before dose reduction of either liraglutide (where relevant) or 
metformin is considered.  Capillary blood glucose level readings recorded a week before a 
visit, or 2 weeks after a change in diabetes medications may be used as an adjunct to help 
guide decisions on dose modification of rescue medication, liraglutide, and metformin.  
If the subject is no longer receiving metformin treatment and is receiving MEDI0382 or 
placebo alone, IP discontinuation may be the next step and this should be discussed with the 
study physician.
6.3.9
Pancreatitis
Information on the clinical course of the event, treatment, and relevant diagnostic, laboratory, 
or other investigations will be collected on the eCRF.  All SAEs of pancreatitis should be 
reported according to Section 6.5.  
6.3.10
Pancreatic carcinoma
Information on the clinical course of the event, treatment, and relevant diagnostic, laboratory, 
or other investigations will be collected on the eCRF.  All SAEs of pancreatic carcinoma 
should be reported according to Section 6.5.  
6.3.11
Thyroid neoplasm
Brief information on the clinical course of the event, treatment, and relevant diagnostic, 
laboratory or other investigations will be collected on the eCRF.  All SAEs of thyroid 
neoplasm should be reported according to Section 6.5.
6.3.12
Clinical events for adjudication
A number of clinical events (including CV events and deaths) will be monitored in the study 
population and an independent adjudication committee will review events.  These clinical 
events will be analysed in conjunction with events observed in Phase III studies and reported 
elsewhere.  For details see Section 6.4.  


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6.3.13
Injection site adverse events
Injection sites should be routinely examined at each study site visit.  If any injection-site 
reaction meets the criteria for an AE (see Section 6.1), the event is to be reported on the AE 
eCRF, with the reaction described as specifically as possible.
6.3.14
Disease under study – Not Applicable
6.4
Clinical Event Adjudication
A CEA committee, blinded to the treatment of the subject, will independently adjudicate 
certain clinical AEs, and they will operate in accordance with the CEA Charter and Event 
Handling Manual for Sites and Monitors.  The CEA committee will adjudicate events possibly 
related to the following:
1.
All deaths:

CV death

Non-CV death
2.
Cardiac ischaemic events:

MI

Unstable angina (UA)
3.
Cerebrovascular events:

Stroke

TIA
4.
Hospitalisation for heart failure and urgent heart failure visit
5.
Pancreatic disease including pancreatic carcinoma
6.
Thyroid neoplasm
For all clinical events identified for adjudication, the Investigator will complete the 
appropriate modules of the eCRF, and provide source documentation.  In order to provide the 
independent CEA with appropriate and adequate information for adjudication of the listed 
events, please consult the CEA Charter and Event Handling Manual for Sites and Monitors.  
These clinical events will be analysed in conjunction with similar clinical events observed in 
Phase III studies and reported elsewhere.  


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6.5
Reporting of serious adverse events
All SAEs must be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca 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 
AstraZeneca 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 WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports an 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.  
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug and the EU Summary of Product Characteristics for the active comparator product 
(including any AstraZeneca comparator.).
6.6
Overdose
An overdose is defined as a subject receiving a dose of IP in excess of that specified in this 
protocol.  No specific treatment is recommended for an overdose.  The Investigator will use 
clinical judgment to treat any overdose.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF 
module.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 6.5.  
For other overdoses, reporting must occur within 30 days.


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6.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

Pregnancies discovered before the study subject has received any IP

Pregnancies in the partner of male subjects
6.7.1
Maternal exposure
If a subject becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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 in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.5 for timeframe guidelines) and within 30 days for all 
other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.8
Medication error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca IP that either causes harm to the subject or has the 
potential to cause harm to the subject.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error:

occurred


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
was identified and intercepted before the subject received the drug

did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually 
given to the subject

Drug not administered as indicated, eg, wrong route or wrong site of administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as 
a solid tablet

Drug not stored as instructed eg, kept at room temperature when it should be stored 
in the fridge 

Wrong subject received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to subject (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one 
of the above listed events that would otherwise have been a medication error

Subject accidentally missed drug dose(s) (eg, forgot to take medication)

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication 
in open-label studies, even if an AstraZeneca product
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
If an medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (Section 6.5) and within 30 days for all other medication errors.


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6.9
Management of investigational product-related toxicities (Dose 
reductions)
6.9.1
Tolerability 
If symptoms of nausea and vomiting occur, subjects should be counselled about meal size and 
eating habits, notably consuming small, frequent meals four to five times a day that are low in 
fat and contain only soluble fiber, avoiding carbonated beverages, alcohol and smoking.  If 
symptoms do not improve, it is possible to hold metformin for 3 days. Down-titration of IP is 
not permitted.
6.9.2
Renal impairment 
For subjects who have an eGFR of 31 to 45 mL/min (inclusive) at screening and are taking an 
existing dose of metformin that is higher than the recommended dose for that degree of renal 
impairment, the dose of metformin should be reduced at Visit 2 in accordance with local 
guidelines on metformin prescription in renal impairment, or to 500 mg once daily if no 
guidance is in place.  Similarly, any subject experiencing a decline in eGFR during the study 
to 31 to 45 mL/min (inclusive) should have their dose of metformin reduced.  
For subjects who are found to have an eGFR ≤30 mL/min, the subject should undergo a repeat 
level 1 week later, and if the eGFR remains ≤30 mL/min on a second consecutive test, the IP 
(MEDI0382, placebo, and liraglutide) should be discontinued, but the subject should remain in 
the study for all other study procedures until their scheduled end of study.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
MEDI0382
Solution for injection in 
1.0 mL pre-filled syringe, 
100 μg per dose, 1 dose 
AstraZeneca a
MEDI0382
Solution for injection in 
1.0 mL pre-filled syringe 
200 μg per dose, 1 dose 
AstraZeneca a
MEDI0382
Solution for injection in 
1.0 mL pre-filled syringe, 
300 μg per dose, 1 dose 
AstraZeneca a
Placebo
Solution for injection in 
1.0 mL pre-filled syringe, 
1 dose
AstraZeneca a
Liraglutide (Victoza) 
Solution for injection in 
multi-dose pre-filled pen 
containing 3 mL
Sourced from Novo Nordisk a.  


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a
Final Qualified Person certification and responsible manufacturer is AstraZeneca.
The MEDI0382 and placebo will be packed into kits enough for 1-week treatment, supplied as 
blinded kits each containing 8 pre-filled syringes.  A unique identifying number will appear on 
both the syringes and kit label.  
Liraglutide (6.0 mg/mL, open label) as active drug will be administered by SC injection once 
daily for the 14-week treatment period and a minimum 40-week extension period using a 
3 mL pen-injector.  Liraglutide will be repacked/relabelled by AstraZeneca as applicable 
according to regulatory requirements.
7.2
Dose and treatment regimens
The study consists of a screening visit (Visit 1), a run-in period of 2 weeks (Visit 2), and a 
baseline visit (Visit 3), followed by a 14-week randomised, double-blind placebo-controlled 
treatment period with open-label active comparator, and a minimum 40-week double-blind 
placebo-controlled treatment extension with open-label active comparator.  
AstraZeneca or a designated representative will provide all IPs (MEDI0382, placebo, 
liraglutide).  At each visit, subjects will receive sufficient quantity of drug to last the duration 
of time between visits.  In the event the subject loses her/his IP, the study centre should call 
into the IVRS/IWRS system to allow the system to determine the appropriate alternative kit 
identification number(s) to be dispensed from the study centre’s remaining inventory.
Run-in period (Visit 2)
Subjects will receive placebo to be injected daily for the 2-week placebo run-in period.  A 
medically qualified staff member will demonstrate injection techniques, after which the 
patient (or designated caregiver) will administer the placebo injection.  Subjects will be 
instructed to continue taking metformin as directed during this period.
14-week treatment period (Visits 3 to 8)
At Visit 3 subjects will be randomly assigned to 1 of the 5 treatment arms and randomised IP 
will be dispensed.  The first day of dosing is considered Day 1.  For subjects randomised to 
MEDI0382 or placebo.  MEDI0382 will be initiated at 100 μg, and dose increments may 
occur in 100 μg steps every week until the predefined maintenance dose is reached.  Subjects 
and Investigators will be advised that there may be dose increments.  During the 14-week 
treatment period, open label liraglutide will be initiated at 0.6 mg and up titrated by an 
additional 0.6 mg weekly until a stable daily dose of 1.8 mg is reached.  All subjects, together 
with the open-label liraglutide subjects inclusive, will be asked to attend all outpatient clinic 
visits, including weekly dosing visits, as listed in the protocol.  For MEDI0382, placebo and 
liraglutide, the initial doses of IP will be taken at the study site.  Subjects will subsequently 
self-administer MEDI0382 or placebo or liraglutide at home (or have it administered by a 
caregiver) once daily through end of treatment.


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Each subject will be provided with an IFU for self-administration at home.  A once-daily dose 
is to be self-administered by SC injection at any time of day, preferably around the same time 
every day, independently of meals.  There is no restriction to metformin co-administration.  
Storage requirement for the IP kit boxes are included in the IFU.  
On weeks of scheduled study visits, subjects should bring their IP with them to the study site 
(subjects should be given instructions and supplies as appropriate for IP transportation to 
ensure proper temperature control, etc.) and will self-administer MEDI0382 or placebo or 
liraglutide as directed by designated study-site personnel (IP manager).  If a dose of 
MEDI0382 or placebo or liraglutide is missed, advise subjects to take it as soon as it is 
remembered unless it is almost time for the next dose, in which case subjects should skip the 
missed dose and take the medicine at the next regularly scheduled time.  Advise subjects not 
to take 2 doses of MEDI0382 or placebo or liraglutide at the same time.  Doses of MEDI0382 
or placebo are to be administered by SC injection in the abdomen, and doses of liraglutide are 
to be administered by SC injection in the abdomen, thigh, or upper arm.  The site of injection 
should be rotated within or across regions on a regular basis so that the same site is not used 
repeatedly.
If deemed necessary by the Investigator, IP can be stopped temporarily for up to 3 days once 
during the 14-week treatment period and then re-started. In case there is a need to stop IP for a 
different time period, a discussion with the study physician should take place. Situations will 
be handled on a case by case basis and all decisions will be documented in the patient’s study 
file.
Minimum 40-week treatment extension period (Visits 9 to Visit 19, EoT)
Investigational product will be dispensed every 4 weeks (±3 days) during this period.  Each 
subject will be provided with an IFU for self-administration at home.  A once-daily dose is to 
be self-administered by SC injection at any time of day, preferably around the same time 
every day, independently of meals.  There is no restriction to metformin co-administration.  
Storage requirement for the IP kit boxes are included in the IFU.  
On weeks of scheduled study visits, subjects should bring their IP with them to the study site 
(subjects should be given instructions and supplies as appropriate for IP transportation to 
ensure proper temperature control, etc.) and will self-administer MEDI0382 or placebo or 
liraglutide as directed by designate study-site personnel (IP manager).  If a dose of MEDI0382 
or placebo or liraglutide is missed, advise subjects to take it as soon as it is remembered unless 
it is almost time for the next dose, in which case subjects should skip the missed dose and take 
the medicine at the next regularly scheduled time.
If deemed necessary by the Investigator, IP can be stopped temporarily for up to 7 days and no 
more than 2 times during the minimum 40-week treatment period and then re-started. In case 
there is a need to stop IP for a different time period, a discussion with the study physician 


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should take place. Situations will be handled on a case by case basis and all decisions will be 
documented in the patient’s study file.
Any defects with the IP must be reported immediately to the Site Monitor and delegated to IP 
management by the IP manager/pharmacist to initiate the product complaint process according 
to applicable guidelines.
7.3
Labelling
Labelling of the IP (including packaging and assembly) will be carried out by AstraZeneca or 
designee in accordance with Annex 13 and current Good Manufacturing Practice and 
regulatory requirements of each country participating in the study.  The labels will be 
translated into local languages where applicable and required by local regulations.
7.4
Storage
All IP should be kept in a secure place under appropriate storage conditions.  The IP label on 
the IP kit specifies the appropriate storage.
7.5
Compliance
The distribution of IP for self-administration should be recorded in the appropriate sections of 
the eCRF.  
7.6
Accountability
The IP provided for this study will be used only as directed in the Clinical Study Protocol.
The designated IP Manager (pharmacist/ study nurse) is required to maintain accurate IP 
accountability records and will account for all IP dispensed to and returned from the subject.
Study site staff, if applicable, or the Site Monitor delegated to IP management will account for 
all IP received at the site, unused IP, and for appropriate destruction in accordance to local 
procedures.  Certificates of delivery and destruction should be signed.
In the case of a malfunctioning pre-filled syringe, the designated IP Manager (pharmacist/ 
study nurse) should contact the Site Monitor delegated to IP management to initiate a product 
complaint process according to applicable guidelines.
7.7
Concomitant medication and other treatments
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the study (final study visit).  Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
eCRF.


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7.7.1
Permitted concomitant medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications described in Section 7.7.2.  
Specifically, subjects should continue to take their metformin therapy at their regular dose 
prescribed, and any other medication prescribed for the treatment of comorbidities associated 
with T2DM. Use of another glucose-lowering medication for up to 2 weeks in the 2 months 
prior to screening is acceptable (a GLP-1 receptor agonist containing preparation cannot be 
used within the last 30 days or 5 half-lives of the drug, whichever is longer, at the time of 
screening). A stable regimen of antihypertensive agents for a minimum of 2 months prior to 
screening is permitted.  Similarly, a stable treatment regimen of thyroid replacement therapy 
for a minimum of 2 months prior to screening is permitted.  Subjects should receive full 
supportive care during the study in accordance with their institutional guidelines.  If nausea or 
vomiting occurs, subjects should be encouraged to reduce oral intake of food until symptoms 
pass.  In the event that symptoms do not improve, subjects should be offered anti-emetic 
therapy in accordance with institutional and local practice guidelines as long as medications 
that are prokinetic agents such as domperidone or metoclopramide are avoided.  Hormone 
replacement therapy and agents for benign prostatic hyperplasia are also permitted.
7.7.2
Prohibited concomitant medications
Other than the medications described above, use of the following medications is restricted, 
generally speaking, from the time specified in the entry criteria until after the final follow-up 
visit:

Concurrent or prior use of any herbal preparations or dietary supplements marketed 
for control of body weight or appetite within 1 week prior to the start of screening

Concurrent or previous use of drugs approved for weight loss (eg, orlistat, 
bupropion -naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as 
those drugs used off-label, within the last 30 days or 5 half-lives of the drug, 
whichever is longest, prior to the start of screening

Antidepressant agents must either not be started or must be on a stable dose for a 
minimum of 2 months prior to screening.

Systemic corticosteroids by oral, intravenous, intra-articular, or intramuscular route 
are prohibited within 3 months prior to screening and during the study unless 
prescribed for a very brief period of less than 7 days.
This is not a comprehensive listing.  If the exclusion status of any concomitant medication is 
in question, the study physician should be contacted for discussion.  The sponsor or designee 
should be contacted if the Investigator is informed of any restriction violations.  The sponsor 
will decide whether a subject with restriction violations will be allowed to continue study 
participation.  


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7.7.3
Rescue therapy for hyperglycaemia
Rescue therapy with add-on insulin is the preferred option, but additional drug classes are 
permitted.  Rescue therapy with any GLP-1 receptor agonist or DPP4 inhibitor based 
intervention is prohibited.  For details of permitted and prohibited rescue therapies, see Table 
6.
Table 6
Permitted and prohibited rescue therapies
Permitted rescue therapies
Prohibited rescue therapies
Any type of insulin
GLP-1 receptor agonist
Sulphonylurea
DPP4 inhibitor
Glinide
GLP-1 receptor agonist/ insulin combination eg 
iDegLira
Acarbose
SGLT2 inhibitor
Increased dose of metformin
Pramlintide
Thiazolidinediones
DPP4  dipeptidyl peptidase-4; GLP-1  glucagon-like peptide-1; SGLT2  sodium-glucose co-transporter 2
7.7.4
Other concomitant treatment
Medication other than that described above, which is considered necessary for the subject’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
7.7.4.1
Anti-hypertensive drug dose reduction
During a study visit existing anti-hypertensive drug medication may be decreased if in the 
Investigator’s judgment the subject has symptomatic hypotension or has documented 
orthostatic hypotension (see Section 5.2.4.2).  Such a dose reduction does not reflect rescue or 
a rescue visit.  Investigators can alter anti-hypertensive medication if in the subject’s best 
interest for example in case of renal impairment or angina.  Changes in anti-hypertensive 
drugs must be recorded in the appropriate section of the eCRF.
7.8
Post study access to study treatment – Not Applicable
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
The following analyses are planned for this study:

A primary analysis when all subjects reach 14 weeks treatment 


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
An analysis when all subjects reach 26 weeks treatment

A final analysis at the end of the study.  
All personnel involved with the conduct of the study will remain blinded until database lock.  
For the purpose of the primary and the 26-week analysis, any study team members who serve 
in the unblinded analysis group will stop day-to-day work on the study and other pre-selected 
personnel will take over these roles for the remainder of the trial. 
Analyses will be performed by AstraZeneca or its representatives.  More details will be 
provided in the statistical analysis plan (SAP).
8.2
 
 
 
 
 
8.3
Definitions of analysis sets
8.3.1
Efficacy analysis set
The Intent-to-treat (ITT) population includes all subjects who receive at least one dose of any 
IP and will be analysed according to their randomised treatment group.  The analysis will 
include the post IP-discontinuation data and post rescue data for those subjects who 
discontinue from study treatments or are rescued, but are still followed up for their scheduled 
visits.
8.3.2
Safety analysis set
The As-treated population includes all subjects who receive at least one dose of any study IP 
and will be analysed according to the treatment they actually receive.  Safety analyses will be 
based on this population.
8.3.3
PK analysis set
The PK population includes all subjects who received at least one dose of MEDI0382 and had 
at least one post-baseline MEDI0382 PK sample taken that is above the lower limit of 
quantitation.


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8.3.4
Other analysis sets
8.3.4.1
Per Protocol analysis set
The Per Protocol (PP) analysis set includes only treatment completers and excludes those with 
important protocol violation(s).  Important protocol violations are those that have the potential 
to affect the result of the primary analysis.  Detailed exclusion criteria for the PP population 
will be specified in the SAP.  Subjects excluded from the PP analysis will be identified before 
the final database lock.  
8.4
Outcome measures for analyses
8.4.1
Primary efficacy endpoint
The primary efficacy endpoints are the change in HbA1c and percent change in body weight 
from baseline to Week 14.
8.4.2
Secondary efficacy endpoints
The secondary efficacy endpoints are:

Change in HbA1c from baseline to 26 weeks, and 54 weeks

Percentage of subjects achieving an HbA1c target of <7.0% after 14 weeks, 
26 weeks, and 54 weeks

Percent and absolute change in body weight from baseline to 14 weeks, 26 weeks, 
and 54 weeks

Percentage of subjects achieving weight loss of ≥5% and ≥10% after 14 weeks, 
26 weeks, and 54 weeks
8.5
Methods for statistical analyses
In general, data will be provided in listings and tabular summaries.  Categorical data will be 
summarised by the number and percentage of subjects in each category.  Continuous variables 
will be summarised by descriptive statistics, including mean, standard deviation, median, 
minimum, and maximum.  Baseline values will be defined as the last assessment prior to the 
first administration of IP.  Additional details will be described in the SAP.
8.5.1
Analysis of primary variable (s)
The co-primary efficacy endpoints of HbA1c change and weight change from baseline to 
14 weeks will be compared between MEDI0382 and placebo arms.  For these endpoints, an 
analysis of covariance (ANCOVA) model with last-observation-carried-forward (LOCF) 
approach to handle missing data will be used and adjusted for treatment and measurement at 
baseline.  For weight loss, the strata of screening HbA1c (≤8% or >8%) will be added into the 
model as a covariate.  Analyses will be based on the ITT population, which includes all 
randomised subjects who received at least one dose of IP.  The analysis will include the post 


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IP-discontinuation data and post rescue data for those subjects who discontinue from study 
treatments or are rescued, but are still followed up for their scheduled visits.
8.5.2
Analysis of secondary variable(s)
8.5.2.1
Efficacy
Secondary efficacy endpoints of body weight and HbA1c change at 26 weeks, and 54 weeks 
will be analysed by ANCOVA model with LOCF, including fixed effect and covariates of 
treatment, baseline measurement, strata of screening HbA1c (≤8% or >8%; except for HbA1c 
related analyses).  For the secondary proportion-related endpoints, a logistic regression model 
will be used with similar fixed effect and covariates.  These analyses will be performed for the 
ITT population.  
8.5.2.2
Safety
Adverse events and SAEs will be coded by the most updated version of the Medical 
Dictionary for Regulatory Activities (MedDRA), and the type, incidence, severity and 
relationship to study IP will be summarised by MedDRA System Organ Class and Preferred 
Term and by treatment.  Adverse events leading to discontinuation, AEs leading to death, and 
deaths will also be summarised.  Specific AEs will be counted once for each subject for 
calculating percentages.  In addition, if the same AE occurs multiple times within a particular 
subject, the highest severity and level of relationship observed will be reported.  Subject-level 
data listings of all AEs will be presented.  
Other safety data, such as vital signs, clinical laboratory data, ECG, and physical examination 
findings will be descriptively summarised at each time point by treatment.  
8.5.2.3
Pharmacokinetics and immunogenicity
Individual MEDI0382 plasma concentrations will be summarised by treatment and visit.  
MEDI0382 plasma concentration at trough (Cmin) may be summarised by treatment and visit 
using descriptive statistics for the MEDI0382 treatment arms.
A population PK analysis may be performed to further evaluate the PK properties of 
MEDI0382, but will not be reported in the CSR.
The immunogenicity of MEDI0382 will be evaluated.  The number and percentage of subjects 
with confirmed positive serum antibodies to MEDI0382 will be reported by treatment.  If 
possible, the incidence of ADA positivity will be correlated with the observed PK.
8.5.3
Subgroup analysis
For body weight and HbA1c related primary and secondary endpoints, subgroup summary or 
analysis by whether a subject received rescue therapy will be performed.  Full details of any 
subgroup analysis will be pre-specified in the SAP.


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8.5.4
Interim analysis – Not Applicable
8.5.5
Sensitivity analysis
For the primary endpoints, three sensitivity analyses will be performed.  First, an ANCOVA 
analysis that only contains data before subjects discontinue study treatments and before 
subjects receive rescue therapy will be performed.  Second, an ANCOVA analysis based on 
PP population will be done.  Third, a multiple imputation based ANCOVA model will be 
done.  Missing endpoints will be imputed based on only those subjects who discontinued 
study IP but still remain in the study and have endpoint measures.  If there are not sufficient 
numbers of such subjects, then the missing endpoints will be imputed based on all available 
endpoint measures from the placebo group.  Full details of any sensitivity analysis will be pre-
specified in the SAP.
8.5.6
 
 
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site staff
Before the first subject is entered into the study, an AstraZeneca 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 (including IP 
administration), and the WBDC, IVRS/IWRS, PROs, and other systems to be utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of the 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).
9.2
Monitoring of the study
During the study, an AstraZeneca 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 Clinical Study 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 IP accountability 
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
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 AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre need information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for location of source data.
9.2.2
Study agreements
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this Clinical Study Protocol and the CSA, the terms of the 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 CSA 
shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.  
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with MEDI0382.
9.4
Data management by AstraZeneca
Data management will be performed by AstraZeneca Data Management Centre staff 
according to the Data Management Plan (DMP).
The data collected through third-party sources will be obtained and reconciled against study 
data.  Adverse events and medical/surgical history will be classified according to the 
terminology of the latest version the MedDRA.  Medications will be classified according to 


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the WHODrug™ Dictionaries.  Classification coding will be performed by the Medical 
Coding Team at the AstraZeneca Data Management Centre.
Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the DMP.  Quality control procedures will be applied 
to each stage of data handling to ensure that all data are reliable and have been processed 
correctly.  The DMP will also clarify the roles and responsibilities of the various functions and 
personnel involved in the data management process.  When all data have been coded, 
validated, signed and locked, clean file will be declared.  Any treatment revealing data may 
thereafter be added and the final database will be locked.
Serious adverse event reconciliation
Serious AE reconciliation reports are produced and reconciled with the Patient Safety
database and/or the investigational site.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements, 
and the AstraZeneca policy on Bioethics and Human Biological Samples.
10.2
Subject data protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final Clinical Study Protocol, including the final 
version of the ICF and any other written information and/or materials to be provided to the 
subjects.  The Investigator will ensure the distribution of these documents to the applicable 
Ethics Committee and to the study site staff.
The opinion of the Ethics Committee should be given in writing.  The Investigator should 
submit the written approval to AstraZeneca before enrolment of any subject into the study.
The Ethics Committee should approve all advertising used to recruit subjects for the study.


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AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
Ethics Committee annually.
Before enrolment of any subject into the study, the final Clinical Study Protocol is approved 
by the national regulatory authority or a notification to the national regulatory authority is 
done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide regulatory authorities, Ethics Committees, and Principal 
Investigators with safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the Ethics Committees/Institutional 
Review Board (IRB) with reports of any serious and unexpected adverse drug reactions from 
any other study conducted with the IP.  AstraZeneca will provide this information to the 
Principal Investigator so that he/she can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:

Ensure each subject is given full and adequate oral and written information about
the nature, purpose, possible risk, and benefit of the study.

Ensure each subject is notified that he/she is free to discontinue from the study at 
any time.

Ensure that each subject is given the opportunity to ask questions and allowed time 
to consider the information provided.

Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study.

Ensure the original, signed (ICF[s]) is/are stored in the Investigator’s Study File.

Ensure a copy of the signed ICF is given to the subject.

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are 
described in the ICF that is approved by an Ethics Committee.


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10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator(s) and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in the study protocol amendment and where required in a new version of the 
study protocol (Revised CSP).
The protocol amendment and/or a new version of the Clinical Study Protocol (Revised CSP) 
is to be approved by the relevant Ethics Committee and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for new versions of Clinical Study Protocols.
AstraZeneca will distribute any subsequent amendments and/ or new versions of the Clinical 
Study Protocol (Revised CSP) to each Principal Investigator(s).  For distribution to Ethics 
Committee, see Section 10.3.
If a change to a Clinical Study Protocol requires a change to a centre’s ICF, AstraZeneca and 
the centre’s Ethics Committee 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 EC. 
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, 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, analysed, and accurately reported according to the Clinical Study 
Protocol, GCP, guidelines of the ICH, and any applicable regulatory requirements.  The 
Investigator will contact AstraZeneca immediately if contacted by a regulatory agency about 
an inspection at the centre.
11.
LIST OF REFERENCES
American Diabetes Association 2017
American Diabetes Association.  Standards of Medical Care in Diabetes – 2017: Summary of 
Revisions.  Diabetes Care.  2017;40 Suppl 1:S4-S5.
Astrup et al 2012
Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean MEJ, et al.  Safety, tolerability 
and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.  
Int J Obes.  2012;36:843-54.


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CDC 2004
Centers for Disease Control and Prevention (CDC): Prevalence of overweight and obesity 
among adults with diagnosed diabetes-United States, 1988-1994 and 1999-2002.  MMWR 
Morb Mortal Wkly Rep.  2004;53:1066-8.
CDER Byetta 2005
Center for Drug Evaluation and Research.  Byetta Pharmacology Review.  2005.
CDER Victoza 2009
Center for Drug Evaluation and Research.  Victoza Pharmacology Review.  In: USFDA, 
editor.  2009.
Cegla et al 2014
Cegla J, Troke RC, Jones B, Tharakan G, Kenkre J, McCullough KA, et al.  Coinfusion of 
low-dose GLP-1 and glucagon in man results in a reduction in food intake.  Diabetes 2014; 
63(11):3711-20.  
CHMP 2012
European Medicines Agency (EMA) Committee for Medicinal Products for Human Use 
(CHMP).  Guideline on clinical investigation of medicinal products in the treatment or 
prevention of diabetes mellitus.  CPMP/EWP/1080/00 Rev.  1.  Available 
at:http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/W
C500129256.pdf.  Published 14 May 2012.
Davies et al 2015
Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Vang Skjøth T, et al.  Efficacy of 
Liraglutide for Weight Loss Among Patients With Type 2 Diabetes.  The SCALE Diabetes 
Randomized Clinical Trial.  JAMA.  2015;314(7):687-99.
Dworkin et al 2008
Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al.  Interpreting 
the Clinical Importance of Treatment Outcomes in Chronic Pain Clinical Trials: IMMPACT 
Recommendations.  J Pain.  2008;9(2):105-21.  
FDA 2008
Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER).  
Guidance for Industry: Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for 
Treatment and Prevention.  Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/ucm071624.pdf.  Published 13 February 2008.


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Garber et al 2009
Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et 
al.  Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a 
randomised, 52-week, phase III, double-blind, parallel-treatment trial.  Lancet.  
2009;373(9662):473-81.
Habegger et al 2013
Habegger KM, Stemmer K, Cheng C, Müller TD, Heppner KM, Ottaway N, et al.  Fibroblast 
growth factor 21 mediates specific glucagon actions.  Diabetes.  2013;62(5):1453-63.  
Henderson et al 2016
Henderson SJ, Konkar A, Hornigold DC, Trevaskis JL, Jackson R, Fritsch Fredin M, et al.  
Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist 
in rodents and non-human primates.  Diabetes Obes Metab.  2016;18(12):1176-90.
International Hypoglycaemia Study Group 2017
Glucose Concentrations of Less Than 3.0 mmol/L (54 mg/dL) Should Be Reported in Clinical 
Trials: A Joint Position Statement of the American Diabetes Association and the European 
Association for the Study of Diabetes.  Diabetes Care 2017;40:155–7.  
Japan PMDA 2009
Japanese Pharmaceuticals and Medical Devices Agency.  Review Report (1) for Victoza 
subcutaneous injection 18 mg.  Available at 
http://www.pmda.go.jp/english/service/pdf/drugs/victoza_jan2010_e.pdf2009
Levey et al 2009
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, 
Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration).  A new equation to estimate glomerular filtration rate.  Ann 
Intern Med.  2009; 150(9):604-12.
Lynch et al 2014
Lynch AM, Pathak N, Pathak V, O’Harte FP, Flatt PR, Irwin N, et al.  A novel DPP IV-
resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-
protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor 
activation.  Diabetologia.  2014;57(9):1927-36.  
Nauck et al 2009
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, During M, 
Matthews DR.  Efficacy and Safety Comparison of Liraglutide,Glimepiride, and Placebo, All 
in Combination With Metformin, in Type 2 Diabetes.  Diabetes Care.  2009;32(1):84–90.
NHLBI 1998
National Heart, Lung, and Blood Institute (NHLBI) Clinical Guidelines on the Identification, 
Evaluation, and Treatment of Overweight and Obesity in Adults.  NIH publication No.  98-


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4083.  Available at: http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm.  Published 
September 1998.
Petersen et al 2005
Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI.  Reversal of 
nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate 
weight reduction in patients with Type 2 Diabetes.  Diabetes.  2005;54(3):603-8.
Wynne et al 2006
Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, Bloom SR.  Oxyntomodulin 
increases energy expenditure in addition to decreasing energy intake in overweight and obese 
humans: a randomised controlled trial.  Int J Obes.  2006;30(12):1729-36.


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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the adverse 
event (AE) as it occurred or it is suspected that use or continued use of the product would 
result in the subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a 
more severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability, or incapacity but may jeopardise the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug.


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
Time Course.  Exposure to suspect drug.  Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class?  Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped?  AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix B
International Airline Transportation Association 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes, the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There 
is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, hepatitis A, B, C, D, and E viruses, 
human immunodeficiency virus types 1 and 2.  They are assigned the following UN number 
and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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Appendix C
 
 
 
 
  
 
 
 
 
 
 
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Appendix D
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
1.  Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.  
Specific guidance on managing liver abnormalities can be found in Section 5.2.5.1 of the 
Clinical Study Protocol (CSP).
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 PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated alanine aminotransferase (ALT) from a central laboratory 
and/or elevated total bilirubin (TBL) from a local laboratory.  
The Investigator will also review adverse event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational 
medicinal product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting serious adverse events (SAEs) and AEs according to the outcome of the review and 
assessment in line with standard safety reporting processes.
2.  Definitions
Potential Hy’s Law
Aspartate aminotransferase (AST) or ALT ≥ 3x upper limit of normal (ULN) together with
TBL ≥ 2xULN at any point during the study following the start of study medication
irrespective of an increase in alkaline phosphatase (ALP).  
Hy’s Law
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  


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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.
3.  Identification of Potential Hy’s Law Cases
In order to identify cases of PHL, it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
Central laboratories being used
When a subject meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the PHL
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative.

Request a repeat of the test (new blood draw) by the central laboratory without delay.

Complete the appropriate unscheduled laboratory Case Report Form (CRF) module(s) 
with the original local laboratory test result.
When the identification criteria are met from central or local laboratory results, the 
Investigator will without delay:

Determine whether the subject meets PHL criteria (see Section 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results)
4.  Follow-up
4.1 Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria, the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.


Clinical Study Protocol Appendix D
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
108 (111)

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP.
4.2 Potential Hy’s Law Criteria met
If the subject does meet PHL criteria, the Investigator will:

Notify the AstraZeneca representative, who will then inform the central Study Team.

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE 
of potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting.

For subjects that met PHL criteria prior to starting IMP, the investigator is not required 
to submit a PHL SAE unless there is a significant change in the subject’s condition.

The Study Physician contacts the Investigator to provide guidance and discuss and 
agree an approach for the study subjects’ follow-up (including any further laboratory 
testing) 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. Completes follow-up SAE form as 
required.

Investigate the aetiology of the event and perform diagnostic 
investigations as discussed with the Study Physician.  This includes 
deciding which the tests available in the HL lab kit should be used.

Complete the 3 Liver CRF Modules as information becomes available.
5.  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.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts 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 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
form the date PHL criteria were met.  The AstraZeneca Global Clinical Lead or equivalent 
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.


Clinical Study Protocol Appendix D
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
109 (111)
Where 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 CRF.

If the alternative explanation is an AE/SAE: update the previously submitted PHL
SAE and AE CRFs accordingly, with the new information (reassessing event term; 
causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca 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 15 calendar days, 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:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE 
reporting.

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 previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
6.  Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended when using a central laboratory. For individual studies, the list may be reduced 
to a subset of tests after consultation with the Hepatic Safety Knowledge Group.


Clinical Study Protocol Appendix D
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
110 (111)
Some of the tests may also be considered for use with local laboratories that have respective 
testing capabilities. Any test results need to be recorded in the CRF.
Hy’s Law lab kit for central laboratories
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgM and IgG anti-HCV
HCV RNA
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-
LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’


Clinical Study Protocol Appendix E
Drug Substance MEDI0382
Study Code D5670C00004
Version 5.0
Date 04 December 2018
111 (111)
Appendix E
Appendix F
Appendix G


Clinical Study Protocol Appendix E
Drug Substance
Medi0382
Study Code:
D5670C00004
CSP Appendix E


Clinical Study Protocol Appendix E
Drug Substance Medi0382
Study Code D5670C00004
2(2)
TABLE OF CONTENTS


  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
  
 
  
 
  
 
 
 
 
  
 
  
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
   
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
  
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 


  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Clinical Study Protocol Appendix F
Drug Substance
MEDI382
Study Code:
D5670C00004
CSP Appendix F


Clinical Study Protocol Appendix F
Drug Substance MEDI0382
Study Code D5670C00004
2(2)
TABLE OF CONTENTS


 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
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Clinical Study Protocol Appendix G
Drug Substance
Medi0382
Study Code
D5670C00004
CSP Appendix G


Clinical Study Protocol Appendix G
Drug Substance Medi0382
Study Code D5670C00004
2
TABLE OF CONTENTS
PAGE


Clinical Study Protocol Appendix G
Drug Substance Medi0382
Study Code D5670C00004
3
1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol Appendix G
Drug Substance Medi0382
Study Code D5670C00004
4
-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5670c00004-csp-v5
Document Title:
D5670C00004 Clinical Study Protocol version 5
Document ID:
Doc ID-003614306
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
05-Dec-2018 16:19 UTC
Management Approval
05-Dec-2018 14:13 UTC
Author Approval
05-Dec-2018 15:09 UTC
Content Approval
05-Dec-2018 14:12 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_003.pdf: 
 
 
 
SAP approval template version 2.0 
 
      
     
 
Statistical Analysis Plan Approval 
 
 
Date: 
 
 
20MAR2019 
To: 
 
 
Study File 
From:  
 
 
Re: 
 
 
Statistical Analysis Plan Approval for Study D5670C00004 
 
 
The Statistical Analysis Plan, version 3.0, for Study D5670C00004 has been reviewed and 
approved. 
 
Name: 
 
Signature: ___
_____________ 
 
Role: 
 
Statistician 
 
Date:         ________________________________ 
 
Name: 
 
Signature: ____
__________________ 
 
Role: 
 
Statistical Programmer 
 
Date:         ________________________________ 
 
Name: 
 
Signature: ________________________________ 
 
Role: 
 
Clinical Development Lead 
 
Date:         ________________________________ 
 
Name: 
 
Signature: _____
________________ 
 
Role: 
 
Clinical Biostatistics Therapeutic 
Area Head 
 
 
Date:         ________________________________ 
Name: 
 
Signature: ___
__________________ 
 
Role: 
 
Head of Clinical Biostatistics & 
Data Management 
 
 
Date:         ___
__________________ 
 
 
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MedImmune 
Statistical Analysis Plan for Protocol D5670C00004 
MEDI0382 
 
20MAR2019; version 3.0 
CONFIDENTIAL AND PROPRIETARY 
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SAP template version 3.0 
Statistical Analysis Plan 
A Phase IIb, Randomized, Parallel, Double-Blind Placebo-Controlled and Open-Label 
Active Comparator Study to Evaluate the Efficacy and Safety of MEDI0382 in the 
Treatment of Overweight and Obese Subjects with Type 2 Diabetes Mellitus 
 
Protocol Number: D5670C00004 
 
 
 


MedImmune 
Statistical Analysis Plan for Protocol D5670C00004 
MEDI0382 
 
20MAR2019; version 3.0 
CONFIDENTIAL AND PROPRIETARY 
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SAP template version 3.0 
TABLE OF CONTENTS 
1 
INTRODUCTION ...........................................................................................................5 
2 
STUDY OVERVIEW .....................................................................................................5 
2.1 
Study Objectives ...................................................................................................5 
2.1.1Primary Study Objective(s) ..........................................................................5 
2.1.2Secondary Study Objectives .........................................................................5 
 .......................................................................6 
2.2 
Study Design .........................................................................................................7 
2.3 
Treatment Assignment and Blinding ....................................................................8 
2.4 
...........................................................................................................9 
3 
STATISTICAL METHODS ...........................................................................................9 
3.1 
General Considerations .........................................................................................9 
3.2 
Analysis Populations...........................................................................................10 
3.2.1Important Protocol Violations ....................................................................11 
3.3 
Study Subjects.....................................................................................................12 
3.3.1Subject Disposition and Completion Status................................................12 
3.3.2Demographics and Baseline Characteristics ...............................................12 
3.3.3Study Drug Exposure ..................................................................................12 
3.3.4Concomitant Medications ...........................................................................12 
3.4 
Efficacy Analyses ...............................................................................................13 
3.4.1Primary Efficacy Endpoint(s) and Analyses ...............................................13 
3.4.1.1 
Primary Efficacy Endpoint(s) ...................................................13 
3.4.1.2 
Primary Efficacy Analysis ........................................................13 
3.4.1.3 
Additional Analyses of the Primary Efficacy Endpoint(s) .......13 
3.4.2Secondary Efficacy Endpoint(s) and Analyses ...........................................13 
3.4.2.1 
Secondary Efficacy Endpoint(s) ...............................................13 
3.4.2.2 
Secondary Efficacy Analyses ...................................................14 
3.4.3Subgroup Analyses .....................................................................................14 
3.5 
Other Additional Analyses..................................................................................15 
3.6 
Safety Analyses...................................................................................................15 
3.6.1Adverse Events and Serious Adverse Events .............................................15 
3.6.2Deaths 
16 
3.6.3Clinical Laboratory Evaluation ...................................................................16 
3.6.4Other Safety Evaluations ............................................................................17 
3.6.4.1 
Vital Signs .................................................................................17 
3.6.4.2 
Electrocardiogram .....................................................................17 
3.7 
Immunogenicity ..................................................................................................17 
3.8 
Pharmacokinetics ................................................................................................18 


MedImmune 
Statistical Analysis Plan for Protocol D5670C00004 
MEDI0382 
 
20MAR2019; version 3.0 
CONFIDENTIAL AND PROPRIETARY 
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4 
VERSION HISTORY ...................................................................................................18 
 
LIST OF TABLES AND FIGURES 
Figure 2.2-1 
Study flow diagram ................................................................................8 
Table 3.2-1 
Analysis Populations ............................................................................10 
TaTable 3.2.1-1 
List of Important Protocol Violations ..................................................11 
 
 


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Statistical Analysis Plan for Protocol D5670C00004 
MEDI0382 
 
20MAR2019; version 3.0 
CONFIDENTIAL AND PROPRIETARY 
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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate transaminase 
ATC 
Anatomical therapeutic chemical 
BMI 
Body mass index 
CSR 
Clinical study report 
 
 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
 
  
 
 
FPG 
Fasting plasma glucose 
HbA1c 
Hemoglobin A1c 
 
 
 
 
IM 
Immunogenicity 
ITT 
Intent-to-Treat 
IP 
Investigational product 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
 
 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
PK 
Pharmacokinetics 
PP 
Per protocol 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
T2DM 
Type 2 diabetes mellitus 
TBL 
Total bilirubin level 
ULN 
Upper limit of normal 
URC 
Unblind Review Committee 
 
 


MedImmune 
Statistical Analysis Plan for Protocol D5670C00004 
MEDI0382 
 
20MAR2019; version 3.0 
CONFIDENTIAL AND PROPRIETARY 
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SAP template version 3.0 
1 
INTRODUCTION 
This document describes the statistical analysis for protocol D5670C00004, a phase IIb study 
to evaluate the efficacy and safety of MEDI0382 in the treatment of overweight and obese 
Subjects with type 2 diabetes mellitus (T2DM). In addition, a set of table templates and 
specifications will be included in a statistical programming plan to complement this 
document. 
2 
STUDY OVERVIEW 
2.1 
Study Objectives 
2.1.1 
Primary Study Objective(s) 
Primary objective: 
Outcome measure: 
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on haemoglobin A1c 
(HbA1c) and body weight versus placebo  
Change in HbA1c from baseline to 14 weeks   
Percent change in body weight from baseline to 
14 weeks 
 
2.1.2 
Secondary Study Objectives 
Secondary objective: 
Outcome measure: 
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on additional measures 
of glycaemic control and body weight versus 
placebo  
Change in HbA1c from baseline to 26 weeks, and 
54 weeks 
Percentage of subjects achieving an HbA1c target of 
<7.0% at 14 weeks, 26 weeks, and 54 weeks 
Percent change in body weight from baseline to 
26 weeks, and 54 weeks 
Absolute change in body weight from baseline to 
14 weeks, 26 weeks, and 54 weeks 
Percentage of subjects achieving weight loss of ≥5% 
and ≥10% after 14 weeks, 26 weeks, and 54 weeks 
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on the requirement for 
additional blood glucose lowering therapies 
versus placebo  
Proportion of subjects rescued or discontinued 
for lack of glycaemic control at 14 weeks, 26 weeks, 
and 54 weeks 
To assess the effect of 100 μg, 200 μg and 
300 μg of MEDI0382 on weight versus 
liraglutide 1.8 mg once daily  
Percent and absolute change in body weight from 
baseline to 14 weeks, 26 weeks, and 54 weeks 
To characterise the PK profile and 
immunogenicity of 100 μg, 200 μg and 300 μg 
of MEDI0382  
PK endpoints (trough plasma concentration, Cmin) 
Development of anti-drug antibodies and titre (if 
positive) during dosing and follow-up 


MedImmune 
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MEDI0382 
 
20MAR2019; version 3.0 
CONFIDENTIAL AND PROPRIETARY 
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MEDI0382 
 
20MAR2019; version 3.0 
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2.2 
Study Design 
This is a randomized, double-blind, placebo-controlled study with an open-label active 
comparator (liraglutide) arm, designed to evaluate the efficacy and safety of MEDI0382 in 
overweight and obese subjects with T2DM.  This study will enroll male and female subjects 
aged ≥18 years, with a BMI ≥25 and ≤45 kg/m2.  Subjects will have a diagnosis of T2DM, 
and inadequate blood glucose control as defined by an HbA1c of 7.0% to 10.5%, and are on 
metformin monotherapy.  Approximately 750 subjects will be randomized and it is 
anticipated that approximately 542 subjects will complete the study, taking into account a 
projected annual study drop-out rate of 15%.  The study has a run in period of 2 weeks, a 14-
week treatment period, followed by a minimum 40-week treatment extension.   
Prior to the run-in period, subjects will be consented and screened for suitability.  During the 
run-in period, subjects will refrain from taking prohibited medications, but will continue to 
take their prescribed stable dose of metformin for the remainder of the study.  After 
completion of run-in, subjects who are still eligible will be randomized within 1 week.  Diet 
and exercise counselling will be provided from the beginning and throughout the duration of 
the study.  Only subjects who are treated with metformin monotherapy will be enrolled; this 
will ensure that subjects with an early stage of T2DM are treated in this study. 
To achieve the enrolment goal for the initially planned interim analysis, subjects will be 
randomly assigned with a ratio of 2:2:2:1:1 to 1 of 5 treatment arms to receive MEDI0382 at 
dose level of 300 μg, 200 μg, or 100 μg, placebo or liraglutide respectively.  After 
approximately the first 400 subjects have been enrolled, the randomization ratio will be 
changed to 5:5:0:2:2 to fully enroll the remaining 350 subjects.  Randomization will be 
stratified with respect to screening HbA1c (≤8% or >8%).   
For subjects randomized to MEDI0382 or placebo, MEDI0382 will be initiated at 100 μg, 
and dose increments may occur in 100 μg steps every week until the predefined maintenance 
dose is reached.  Subjects and Investigators will be advised that there may be dose 
increments.  During the 14-week treatment period, open-label liraglutide will be initiated at 
0.6 mg and up titrated by an additional 0.6 mg weekly until a stable daily dose of 1.8 mg is 
reached. After the 14-week treatment period, subjects will continue with the allocated 
treatment for a further minimum of 40 weeks of extension treatment, after which study 
treatment will end.  An Early Termination visit will be performed for subjects who 
discontinue treatment prematurely at any time and for any reason as soon as possible, but not 
later than 7 days from last investigational product (IP) dose.  A follow-up visit will be 
performed for final safety assessments 4 weeks after the last dose of IP. 


MedImmune 
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MEDI0382 
 
20MAR2019; version 3.0 
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See Figure 2.2-1 for a summary of the study design.  Details of assessments at each visit are 
summarized in the study protocol. 
Figure 2.2-1 
Study flow diagram 
 
 
 
2.3 
Treatment Assignment and Blinding 
Assignment to treatment groups will be determined by a computer-generated random 
sequence using an IVRS/IWRS.     
The study will be conducted in a double-blind fashion for MEDI0382 and placebo.  The 
treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization.  The 
Investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to the subject to the AstraZeneca staff. 


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MEDI0382 
 
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AstraZeneca retains the right to break the code for serious adverse events (SAEs) that are 
unexpected and are suspected to be causally related to an IP and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each 
individual subject have been made and documented. 
The exception to the above is for those personnel analyzing the PK samples.  The 
randomization code will be provided to ensure that only samples from subjects who were on 
active study treatment are analysed.  Samples from subjects not dosed with the relevant 
active study treatment will only be analysed on a ‘for cause’ basis, for example, if there is 
suspicion that a subject has been dosed incorrectly.  The treatment allocation information will 
be kept in a secure location until the end of the study. 
For the purpose of the primary analysis and the 26-week analysis, any study team members 
who serve in the unblinded analysis group will stop day-to-day work on the study and other 
pre-selected personnel will take over these roles for the remainder of the trial.  The study 
team members will remain blinded to treatment assignment until the data base lock after the 
treatment extension is finished. 
2.4 
 
 
 
 
 
 
 
 
 
3 
STATISTICAL METHODS 
3.1 
General Considerations 
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. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous 
variables will be summarized by descriptive statistics, including mean, standard deviation, 
median, minimum, and maximum.  


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MEDI0382 
 
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Baseline values will be defined as the last measurements prior to the first administration of IP 
at the randomization visit.  
Unless otherwise specified, efficacy analyses will be based on ITT population (Section 3.2) 
and include post IP-discontinuation and post rescue data. Last observation carried forward 
(LOCF) method will be applied for efficacy endpoints to handle missing data, that is, a 
missing endpoint will be replaced with the last available post-baseline measurement prior to 
the missing endpoint.  
Data analyses will be conducted using the SAS® System Version 9.3 or higher (SAS 
Institute Inc., Cary, NC). 
The following analyses are planned for this study: 
 
A primary analysis when all subjects reach 14 weeks treatment. 
 
An analysis when all subjects reach 26 weeks treatment 
 
A final analysis at the end of the study.   
3.2 
Analysis Populations 
The analysis populations are defined in Table 3.2-1. 
Table 3.2-1 
Analysis Populations 
Population 
Description 
Intent-to-treat 
(ITT) population 
Subjects who receive any study IP will be included in the ITT population and subjects 
will be analyzed according to their randomized treatment group. The analysis will include 
the post IP-discontinuation data and post rescue data for those subjects who discontinue 
from study treatments or are rescued, but are still followed up for their scheduled visits. 
As-treated 
population 
Subjects who receive any study IP will be included in the as-treated population and 
subjects will be analyzed according to the treatment they actually receive. 
Per-protocol 
population 
The Per Protocol (PP) analysis set includes only subjects who didn’t discontinue study IP 
during the relevant treatment period and excludes those with important protocol 
violation(s) during the relevant treatment period that lead to complete data exclusion. 
Important protocol violations are those that have the potential to affect the result of the 
primary efficacy results. Partial data will be excluded for PP subjects who meet those 
important protocol violation(s) during the relevant treatment period that lead to partial 
data exclusion. PP population will be analyzed according to the treatment they actually 
receive. 
PK population 
The PK population includes all subjects who received at least one dose of MEDI0382 and 
had at least one post-baseline MEDI0382 PK sample taken that is above the lower limit of 
quantitation. 
 


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3.2.1 
Important Protocol Violations  
Protocol deviations that are determined to affect the primary efficacy results are deemed 
important protocol violations. The list of important protocol violations and data exclusion 
rules are described in Table 3.2.1-1. Since some important protocol deviations include 
unblinding information and data are subject to clean before data base lock, the important 
protocol deviations will be reviewed and confirmed as much as possible before data base 
lock, and will be finalized by the unblinded study physician based on pre-specified criteria 
below after data base locks for the primary, the 26-week, and the final analyses.  
aTable 3.2.1-1 
List of Important Protocol Violations 
Number 
Important Protocol violation criteria 
Complete/Partial data 
exclusion 
1 
Randomized patients without Type 2 Diabetes at 
screening 
Complete data exclusion
2 
Has HbA1c of [<7%, or >10.5%] at screening
Complete data exclusion
3 
Receipt of wrong study medication during the 
study 
Complete data exclusion
4 
IP compliance <80% or >120% during 
the treatment period
Complete data exclusion
5 
Hemolytic anemia, or chronic anemia (hemoglobin 
concentration <11.5 g/dL [115 g/L] for males, <10.5 
g/dL [105 g/L] for females) prior to V3
Complete data exclusion
6 
Systemic corticosteroids within 3 months prior 
to Screening (Visit 1) by oral, intravenous, intra-
articular, or intramuscular route
Complete data exclusion
7 
Concurrent or previous use of drugs approved for 
weight loss (orlistat, bupropion -naltrexone, 
phentermine-topiramate, phentermine, lorcaserin) 
within the last 30 days, prior to screening (V1)
Complete data exclusion 
8 
Same subject randomized to current study more 
than once 
Complete data exclusion; 
Note: the identification of 
subjects who meet this criteria 
will be based on study and site 
monitoring 
9 
Randomized patients who received no study 
medication for ≥1 week (7 consecutive days) 
during the 14 week treatment period, or > 2 
consecutive weeks in the treatment extension 
period 
Partial data exclusion: exclude 
data on or after the first violation 
date (violation date is defined as 
the date when any rules 
becomes violated; e.g. the 7th 
day without receiving study 
medication during the 14 week 
treatment period) 
10 
Receipt of glucose lowering medication, (other 
than IP, metformin, or protocol allowed rescue 
therapy) for ≥ 14 consecutive days during the 
double blind treatment period
Partial data exclusion: exclude 
data on or after the first violation 
date 
 


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3.3 
Study Subjects 
3.3.1 
Subject Disposition and Completion Status 
A summary of subjects treated at each treatment group will be provided. In addition, 
disposition of subjects throughout the study with respect to completion of treatment and 
study and the reasons for discontinuation will be provided. 
3.3.2 
Demographics and Baseline Characteristics 
Demographic information related to gender, age, race, ethnicity, weight, height, body mass 
index (BMI= weight (kg) / [height (m)]2), and BMI categories (< 25, ≥ 25 to < 30, or ≥30) 
will be presented by treatment group and for all subjects combined. A summary of baseline 
disease characteristics will include but may not be limited to: baseline HbA1c, the strata of 
screening HbA1c (≤8% or >8%), duration of diabetes, duration of diabetes category (<3 
years, ≥3 to ≤10 years, >10 years), FPG, blood pressure, pulse rate, smoking history, alcohol 
history, eGFR, and eGFR categories (< 30, ≥ 30 to <60, ≥ 60 to <90, and ≥ 90).  
3.3.3 
Study Drug Exposure 
The number of doses of study drug (investigational product) received will be summarized. In 
addition, the duration of drug exposure and the percent of compliance (the ratio of the 
number of actual dose received to the number of planned doses) will also be summarized by 
treatment group. The percent of compliance will then be categorized to <80%, 80% to 
<120%, and ≥120%. The total number of doses received will be calculated based on the drug 
exposure data. Extent of exposure will be calculated for each patient using the last study 
medication date minus the first study medication date plus 1 and excluding the off-treatment 
days. Extent of exposure will also be categorized into fixed intervals. In addition, the extent 
of exposure will also be summarized by country. 
3.3.4 
Concomitant Medications 
Concomitant medications will be coded using WHO Drug Dictionary (March 2017 or higher 
version). Concomitant medications will be summarized using frequency count and 
percentage by the highest anatomical therapeutic chemical (ATC) class and preferred term. 
The following three situations will be summarized separately: the concomitant medications 
with stop date prior to the first randomized dose; the concomitant medications with start date 
prior to the first randomized dose and continued afterwards; the concomitant medications 
with start date on or after the first randomized dose. All concomitant medications will also be 
presented in a data listing. 


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Rescue medications will be summarized and listed separately. 
3.4 
Efficacy Analyses 
3.4.1 
Primary Efficacy Endpoint(s) and Analyses 
3.4.1.1 
Primary Efficacy Endpoint(s) 
1. Change in HbA1c from baseline to 14 weeks 
2. Percent change in body weight from baseline to 14 weeks 
3.4.1.2 
Primary Efficacy Analysis 
HbA1c change and weight percent change from baseline to 14 weeks will be compared 
between MEDI0382 and placebo arms. For these endpoints, an analysis of covariance 
(ANCOVA) model will be used and adjusted for treatment and measurement at baseline. For 
weight loss, the strata of screening HbA1c (≤8% or >8%) will be added into the model as a 
covariate. Analyses will be based on the ITT population. The comparisons will be performed 
at the 0.05 significance level (2-sided).  HbA1c change and weight percent change from 
baseline for all scheduled visits will also be summarized descriptively by treatment. 
3.4.1.3 
Additional Analyses of the Primary Efficacy Endpoint(s) 
For the primary endpoints, three sensitivity analyses will be performed. First, an ANCOVA 
analysis that only contains data before subjects discontinue study treatments and before 
subjects receive rescue therapy will be performed. Second, an ANCOVA analysis based on 
PP population will be done. Third, a multiple imputation based ANCOVA model will be 
done. Missing endpoints for subjects from a specific treatment group will be imputed based 
on only those subjects who are from the same treatment group and discontinued study IP but 
still remain in the study and have endpoint measures. After the imputed datasets are obtained, 
they will be analyzed by ANCOVA model and then the analysis results from ANCOVA 
models will be combined by considering both within and between imputation variabilities. If 
the “MI” procedure does not converge, then the missing endpoints will be imputed based on 
all subjects from the placebo group with non-missing endpoint measures. 
3.4.2 
Secondary Efficacy Endpoint(s) and Analyses 
3.4.2.1 
Secondary Efficacy Endpoint(s) 
 Change in HbA1c from baseline to 26 weeks, and 54 weeks. 


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 Percentage of subjects achieving an HbA1c target of <7.0% at 14 weeks, 26 weeks, 
and 54 weeks. 
 Percent change in body weight from baseline to 14 weeks (MEDI0382 vs Lira), 
26 weeks, and 54 weeks (MEDI0382 vs Placebo; MEDI0382 vs Lira). 
 Absolute change in body weight from baseline to 14 weeks, 26 weeks, and 54 weeks 
(MEDI0382 vs Placebo; MEDI0382 vs Lira). 
 Percentage of subjects achieving weight loss of ≥5% and ≥10% after 14 weeks, 26 
weeks, and 54 weeks (MEDI0382 vs Placebo; MEDI0382 vs Lira). 
 Proportion of subjects rescued or discontinued for lack of glycemic control at 14 
weeks, 26 weeks, and 54 weeks. 
3.4.2.2 
Secondary Efficacy Analyses 
Secondary efficacy endpoints will be summarized by treatment and by visit. Body weight 
(percent) change and HbA1c change at 26 weeks and 54 weeks will be analysed by 
ANCOVA model with LOCF, including fixed effect of treatment and covariates of treatment, 
baseline measurement, strata of screening HbA1c (≤8% or >8%). Strata of screening HbA1c 
will not be included in HbA1c related analyses, as baseline HbA1c will be included as a 
covariate.  For the secondary proportion-related endpoints, a logistic regression model will be 
used with similar fixed effect and covariates. These analyses will be performed based on the 
ITT population. In addition, repeated measures modeling or generalized estimation equation 
modeling may be performed.  
3.4.3 
Subgroup Analyses 
Subgroup analyses will be conducted for the following subgroup factors and for HbA1c and 
body weight related primary and secondary endpoints. The data will be presented by 
subgroups and by treatments. The statistical analysis will be based on similar models as those 
for primary and secondary endpoints with the addition of the interaction between subgroup 
and treatment, and the p-value for the subgroup effect (interaction effect) will be reported. 
The statistical testing on treatment effect within each of the subgroup categories will also be 
conducted, and p-value and confidence interval will be reported. Subgroup Identification 
based on Differential Effect Search (SIDES) analysis may be performed if deemed 
appropriate. Subgroup factors to be analyzed are:  
1. Whether a subject received rescue therapy; 
2. Baseline BMI: ≥ 25 to < 30 or ≥ 30; 


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3. Baseline HbA1c: < 8%, ≥ 8% to < 9%, or ≥ 9%; 
4. Diabetes duration: < 3 years, ≥ 3 to ≤ 10 years or > 10 years; 
5. eGFR: < 30, ≥ 30 to <60, ≥ 60 to <90, or ≥ 90; 
6. Age group: < 65 years, ≥ 65 to <75 years, or ≥ 75 years; 
7. Region: US or the rest of the world. 
3.5 
Other Additional Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6 
Safety Analyses 
3.6.1 
Adverse Events and Serious Adverse Events 
All safety analyses will be based on the As-treated population. Only AEs/SAEs that are 
collected on or after the randomization visit will be summarized. Adverse events and SAEs 
will be coded by the most updated version of the MedDRA and be summarized by System 
Organ Class and Preferred Term and by treatment. Additionally, AEs with ≥5% incidence 
Redacted
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rate in any treatment group will be summarized. Study IP related AEs and SAEs, and AEs 
leading to treatment discontinuations or death will also be summarized. Specific AEs will be 
counted once for each subject for calculating percentages. In addition, if the same AE occurs 
multiple times within a particular subject, the highest severity and level of relationship 
observed will be reported. Subject level data listings of all AEs will be presented.  
Additionally, the incidence and event rate of nausea and vomiting will be summarized for the 
time intervals of interest: e.g. for the first 3 weeks, 4-14 weeks and the first 14 weeks. The 
incidence and percentage of subjects that meet Hy’s law criteria (AST or ALT >3x ULN and 
TBL >2x ULN) will also be summarized for the time intervals of interest.  
No formal statistical testing will be performed for safety analyses; only descriptive 
summaries will be provided.  
3.6.2 
Deaths 
All deaths recorded on the AE page of the CRF will be listed and summarized. Any deaths 
that occur during the study will be described in depth as narrative in the CSR.  
3.6.3 
Clinical Laboratory Evaluation 
 
, the hematology and serum chemistry parameters (including serum Amylase, 
Lipase, and Calcitonin) as well as their changes from baseline will be listed and summarized 
with descriptive statistics by treatment group at each of the time points specified in the study 
schedule. The urinalysis results will also be listed. The hematology and serum chemistry 
results will also be classified into low, normal, and high. The urinalysis results will be 
classified into normal and abnormal. The shift from baseline hematology, serum chemistry, 
and urinalysis results will be summarized by treatment group. 
Additionally, for liver safety, a summary of the incidence and proportion of patients with 
elevated liver tests that meet the following criteria by visit will be provided: 
 
ALT and/or AST are >5 × ULN  
 
ALT and /or AST are >8 × ULN. 
Redacted


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3.6.4 
Other Safety Evaluations 
3.6.4.1 
Vital Signs 
In addition to blood pressure that are already included in the exploratory objectives, values 
and changes from baseline for pulse rate will be summarized by treatment group at each 
scheduled visit. 
3.6.4.2 
Electrocardiogram 
The normality/abnormality of the ECG tracing (as determined by the investigator or qualified 
designee) will be summarized using frequency tables on number of patients with a 
normal/abnormal ECG tracing at each scheduled visit. A listing of patients will be produced 
which will display all ECG findings in patients with abnormal ECGs. 
3.7 
Immunogenicity 
All subjects in the safety analysis set with reported ADA results (ADA positive or ADA 
negative, titer, cross-reactivity to GLP1: positive or negative, cross-reactivity to glucagon: 
positive or negative) will be shown in the data listing. 
ADA status (positive vs. negative) will be summarized by treatment group according to the 
following categories: 
• 
ADA prevalence: subjects who are ADA positive at any visit (including baseline)  
• 
Subjects who are ADA positive at baseline only  
• 
Subjects who are ADA positive at baseline and positive post baseline  
• 
Subjects who are ADA positive post-baseline only (treatment-induced ADA) 
• 
Subjects who are persistently positive; persistently positive is defined as at least 2 post-
baseline ADA positive measurements (with >=16 weeks apart) or an ADA positive result at 
the last available assessment 
• 
Proportion of subjects who are transiently positive; transiently positive is defined as at 
least one post-baseline ADA positive measurement and not fulfilling the conditions for 
persistently positive. 


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• 
Proportion of subjects who are treatment-boosted ADA; treatment-boosted ADA is 
defined as baseline ADA titer that was boosted to a 4-fold or higher level following drug 
administration   
• 
ADA incidence (treatment-emergent ADA), defined as the sum of treatment-induced 
ADA (post-baseline positive only) and treatment-boosted ADA 
Similar summary will be performed for ADA cross-reactivity to GLP1 and/or glucagon (as 
data allows and if applicable). 
The association of ADA status with PK, pharmacodynamics endpoints, efficacy, and safety 
may be evaluated if data allows and if applicable. 
3.8 
Pharmacokinetics 
Actual time of sampling, rather than nominal (planned) sampling time, will be used to derive 
PK parameters. Nominal sampling time will be used for the summary of PK concentrations 
and will be utilized in the descriptive summaries in mean and median plots. Missing PK 
parameters will not be imputed.  
Individual MEDI0382 plasma concentrations will be summarized by treatment and visit.  
MEDI0382 plasma concentration at trough (Cmin) may be summarized by treatment and 
visit using descriptive statistics for the MEDI0382 treatment arms. 
A population PK analysis may be performed to further evaluate the PK properties of 
MEDI0382, but will not be reported in the CSR. 
 
 
4 
VERSION HISTORY 
Version 
Date 
Summary of Changes 
Reason for Change 
1 
24Aug2017 
Initial document 
Initial document 
2 
21May2018 
Removed the section of Interim Analysis; 
Removed or adjusted “interim analysis” or 
“26-week analysis for 296 subjects” 
related languages in Section 2.2, 2.3, and 
3.1; 
Added “26-week analysis when all 
subjects reach 26 weeks” related 
languages; 
Revised Per-protocol population definition 
in Section 3.2; 
According to study protocol amendment, 
Interim and 26-week analysis based partial 
data were removed, and 26-week analysis 
based on all subjects was added; 
Revised Per-protocol population definition 
in Section 3.2 to take into account the 
complete and partial data exclusions; 
The important protocol violations contain 
unblinding information and data are 
subject to clean before data base lock, so 
cannot be finalized before data base lock; 
BMI subgroup typos corrected;


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Revised language about how to finalize 
the important protocol violation review in 
Section 3.2.1; 
Revised in Section 3.2.2 the BMI 
subgroups; 
Revised in Section 3.3.3 how to calculate 
the dose received; 
 
  
Add general description in Section 3.6.1 
for time intervals to be more accurate. 
Corrected typo in Section 3.7 for 
“Reactivity”.
Drug accountability data didn’t contain 
information if a syringe is broken or has 
other pre-existing issues, so cannot be 
used as the source for calculating the 
actual received doses; 
 
 
3 
20Mar2019 
Revised in Sections 2.1.2 and 2.1.3 
removing Week 106 in endpoints. 
Revised treatment extension from 92 
weeks to minimum of 40 weeks 
throughout the document. 
According to study protocol amendment 
5, the length of the treatment extension 
period was reduced from 92 to 40 weeks. 
Week 54 (Visit 14) will be the minimum 
required time point for treatment 
comparisons. Study duration will now be a 
minimum of 62 weeks, including a 2-week 
screening period, a 2-week run-in period, 
a 14-week treatment period, a minimum 
40-week treatment extension, and a 4-
week follow-up.  The rationale for this 
change is to allow subjects adequate time 
to transition to other therapies and allow 
continued collection of safety and efficacy 
data to inform further decisions regarding 
MEDI0382 doses. 
 


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