Clinical trial NCT03244800
Conditions: Type 2 Diabetes Mellitus
Keywords: 0382, T2DM
Sponsor: MedImmune LLC
Start date: 2017-09-04; Completion date: 2018-01-23
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2 study with two cohorts of differing doses designed to evaluate the efficacy, safety and pharmacokinetics (PK) of MEDI0382 in patients with Type 2 Diabetes Mellitus (T2DM). Approximately 63 subjects will be enrolled across two cohorts.

Detailed description:
This is a randomised, double-blind, placebo-controlled study designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics of different doses of MEDI0382 administered as multiple SC doses to subjects with T2DM. Approximately 63 subjects will be enrolled across two cohorts.

For cohort 1, sufficient subjects will be invited to participate in the study such that a maximum of 39 subjects will complete dosing. Subjects in cohort 1 will be randomised using a ratio of 2:1 to one of 2 treatment arms to receive either MEDI0382 or placebo. A maximum of 26 will complete dosing in the active arm and 13 will complete dosing in the placebo arm.

For cohort 2, sufficient subjects will be invited to participate in the study such that a maximum of 24 subjects will complete dosing. Subjects in cohort 2 will be randomised using a ratio of 3:1 to receive either MEDI0382 or placebo. A maximum of 18 will complete dosing in the active arm and 6 will complete dosing in the placebo arm.

Arms: arm 1: Participants will receive placebo matching with MEDI0382 subcutaneously once daily for 49 days. arm 2: Participants will receive subcutaneous injection of MEDI0382 once daily for 49 days as Dose 1 for 7 days, followed by Dose 2 for 7 days, Dose 3 for 7 days, and Dose 4 for 28 days arm 3: Participants will receive placebo matching with MEDI0382 subcutaneously once daily for 49 days. arm 4: Participants will receive subcutaneous injection of MEDI0382 once daily for 49 days as Dose 1 for 14 days, followed by Dose 2 for 14 days, Dose 3 for 14 days, and Dose 4 for 7 days.
Interventions: intervention 1: MEDI0382 intervention 2: Placebo
Intervention descriptions: intervention 1: MEDI0382 will be administered subcutaneously once daily for 49 days. intervention 2: Placebo will be administered subcutaneously once daily for 49 days.

Protocol documents:
Prot_000.pdf: 
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A Phase 2, Randomised, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of Different Doses of 
MEDI0382 in Overweight and Obese Subjects with Type 2 
Diabetes Mellitus
Sponsor Protocol Number: D5670C00011
Application Number:
EudraCT number 2017-002025-38
Investigational Product:
MEDI0382
Sponsor:
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca, Milstein Building, Granta Park, Cambridge, 
CB21 6GH, UK
Medical Monitor:
 MedImmune
Contract Research Organization: Covance Clinical and Periapproval Services GmBH, 
Carl-Wery-Straβe 42, 81739 Munich, Germany
Protocol History, Date:
Original Protocol, 30May2017
Protocol Amendment 1, 25Jul2017
Protocol Amendment 2, 17Oct2017
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorisation from MedImmune.


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PROTOCOL SYNOPSIS
TITLE
A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of Different Doses of MEDI0382 in Overweight and Obese Subjects with 
Type 2 Diabetes Mellitus
HYPOTHESES
Primary Hypothesis: 
Administration of MEDI0382 once daily titrated up to a dose level of 300 μg will result in superior blood 
glucose control and weight loss versus placebo after 49 days of treatment in overweight and obese subjects 
with type 2 diabetes mellitus (T2DM)
Secondary Hypotheses: 
•
Administration of MEDI0382 once daily titrated up to a dose level of 300 μg across 49 days will be safe 
and well tolerated in overweight and obese subjects with T2DM 
•
Administration of MEDI0382 once daily titrated up to a dose level of 300 μg from 50 μg will have a 
predictable pharmacokinetic (PK) profile
•
Administration of MEDI0382 once daily at a dose level of 50 μg will result in superior blood glucose 
control versus placebo after 7 days of treatment in overweight and obese subjects with T2DM
OBJECTIVES AND ENDPOINTS 
Objectives
Endpoints
Primary
To assess the effects of MEDI0382 titrated up to a 
dose level of 300 μg on glucose control and body 
weight versus placebo after 49 days of treatment 
(Cohort 1 only)
•
Percentage change in glucose area under the curve 
(AUC) as measured by a standardised mixed-meal 
tolerance test (MMTT) from baseline (Day -1) to 
the end of 49 days of treatment 
•
Percentage change in body weight from baseline 
(Day 1) to the end of 49 days of treatment 
Secondary 
To assess the effects of MEDI0382 titrated up to a 
dose level of 300 μg on additional measures of 
glucose control and body weight versus placebo 
after 49 days of treatment (Cohort 1 only)
•
Change in glycated haemoglobin (HbA1c) from 
baseline (Day -1 ) to the end of 49 days of 
treatment
•
Change in fasting plasma glucose (Day -1) from 
baseline to the end of 49 days of treatment
•
Change in body weight (kg) from baseline 
(Day 1) to the end of 49 days of treatment
•
Proportion of subjects achieving > 5% body 
weight loss from baseline (Day 1) after 49 days of 
treatment
To characterise the safety profile and tolerability of 
MEDI0382 titrated up to a dose level of 300 μg
during dosing and follow-up (Cohorts 1 and 2)
•
Measures of safety and tolerability (24-hour heart 
rate and blood pressure, other vital signs, 
electrocardiogram [ECG], laboratory test results, 
adverse events [AEs])








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Under the conservative assumption that the two endpoints are independent, the overall power that hypotheses 
for both endpoints are met is over 80%. From the 2 cohorts, the combined 44 subjects in the MEDI0382 arms 
and 19 subjects in the placebo arms can also provide 80% power to detect a 12% glucose AUC change-from-
baseline difference between MEDI0382 50 μg and placebo at Day 7.
Statistical analyses:  
The efficacy analysis will be based on the Intent-to-treat population. The coprimary efficacy endpoints of 
percentage glucose AUC change and percentage weight change from baseline to 49 days will be compared 
between the MEDI0382 and placebo arms using an analysis of covariance (ANCOVA) model, adjusting for 
treatment and measurement at baseline. A similar ANCOVA model will also be used for other continuous 
endpoints. For the other proportion-related endpoints, a logistic regression model will be used with fixed 
effects of treatment and baseline measurement. 
Safety analyses: 
The safety analyses will be based on the As-treated population. Safety data, such as vital signs, clinical 
laboratory data, ECG, and physical examination findings will be descriptively summarised at each time point 
by treatment period. 
Pharmacokinetic analysis and immunogenicity: 
Pharmacokinetic parameters such as MEDI0382 Cmax and area under the concentration-time curve from 0 to 
infinity (AUC(0-inf)) will be evaluated from plasma concentration-time data for MEDI0382 at 50 and 300 μg. 
Descriptive statistics including mean, standard deviations, median, minimum, and maximum will be 
generated for all PK parameters for MEDI0382 at each dose level separately. Samples confirmed positive for 
ADA will be tested and analysed for antibody titre and reported. ADA incidence rate and titre will be 
tabulated for each treatment.
Interim analysis:  An interim analysis of PK data only will be performed following last subject last dose.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ................................................................................................2
LIST OF ABBREVIATIONS........................................................................................12
1
INTRODUCTION ..............................................................................................14
1.1
Disease Background..................................................................................14
1.2
MEDI0382 Background............................................................................14
1.3
Summary of Nonclinical Experience .........................................................14
1.4
Summary of Clinical Experience...............................................................15
1.5
Rationale for Conducting the Study...........................................................15
1.6
Benefit-risk and Ethical Assessment..........................................................16
1.7
Research Hypotheses ................................................................................16
1.7.1 Primary Hypothesis.........................................................................16
1.7.2 Secondary Hypotheses ....................................................................16
2
OBJECTIVES AND ENDPOINTS .....................................................................17
2.1
Primary Objective and Associated Endpoints ............................................17
2.2
Secondary Objectives and Associated Endpoints.......................................17
2.3
Exploratory Objectives..............................................................................18
3
STUDY DESIGN................................................................................................19
3.1
Description of the Study............................................................................19
3.1.1 Overview ........................................................................................19
3.1.2 Treatment Regimen.........................................................................23
3.1.3 Dose Escalation ..............................................................................23
3.1.4 Management of Study Medication Related Toxicities......................23
3.1.4.1
Tolerability ......................................................................23
3.1.4.2
Hypoglycaemia ................................................................23
3.1.4.3
Hyperglycaemia ...............................................................24
3.2
Study Design and Dose Rationale .............................................................24
3.2.1 Dose Rationale................................................................................24
3.2.2 Rationale for Study Population .......................................................26
3.2.2.1
Recruitment of Subjects with T2DM and a Body Mass 
Index 27 to 40 kg/m2..........................................26
3.2.2.2
Selection of Subjects with Stable HbA1c in the Range of 
6.5% to 8.5% (Inclusive) on Metformin .............26
3.2.3 Rationale for Endpoints ..................................................................27
3.2.3.1
Primary Endpoints............................................................27
3.2.3.2
Secondary Endpoints........................................................27
3.2.3.3
Exploratory Endpoints......................................................28
4
MATERIALS AND METHODS.........................................................................30


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4.1
Subjects….................................................................................................30
4.1.1 Number of Subjects ........................................................................30
4.1.2 Inclusion Criteria ............................................................................30
4.1.3 Exclusion Criteria ...........................................................................30
4.1.4 Subject Enrollment and Randomisation...........................................32
4.1.5 Withdrawal from the Study.............................................................33
4.1.6 Discontinuation of Investigational Product......................................33
4.1.7 Replacement of Subjects.................................................................34
4.1.8 Withdrawal of Informed Consent for Data and Biological Samples.34
4.2
Schedule of Study Procedures...................................................................35
4.2.1 Enrollment/Screening Period ..........................................................35
4.2.2 Randomised Treatment Period ........................................................37
4.2.3 Follow-up Period ............................................................................49
4.2.3.1
Early Discontinuation Visit or Unscheduled Study Visit...50
4.3
Description of Study Procedures ...............................................................50
4.3.1 Efficacy….. ....................................................................................50
4.3.1.1
Mixed-meal Tolerance Tests ............................................50
4.3.1.2
Weight….. .......................................................................52
4.3.2 Safety Assessments.........................................................................52
4.3.2.1
Medical History and Physical Examination ......................52
4.3.2.2
Assessment of the Injection Site.......................................53
4.3.2.3
Electrocardiograms ..........................................................53
4.3.2.4
Vital Signs .......................................................................53
4.3.3 Clinical Laboratory Tests................................................................54
4.3.3.1
Glucometer Measured Capillary Blood Glucose Readings 56
4.3.4 Pharmacokinetic Evaluation and Methods.......................................56
4.3.5 Immunogenicity Evaluation and Methods .......................................56
4.3.6 Pharmacodynamic Evaluation and Methods....................................57
4.3.6.2
Training for Application and Wearing of CGM Sensor.....58
4.3.6.3
Training for Application and Wearing of ABPM Device ..59
4.3.7 Biomarker Analysis ........................................................................59
4.3.7.2
Storage, Re-use, and Destruction of Pharmacodynamic 
Samples .............................................................59
4.3.8 Estimate of Volume of Blood to Be Collected.................................59
4.4
Study Suspension or Termination..............................................................60
4.5
Investigational Products............................................................................60


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4.5.1 Identity of Investigational Products.................................................60
4.5.1.1
Investigational Product Dose Preparation .........................61
4.5.1.2
Investigational Product Inspection....................................62
4.5.1.3
Dose Preparation Steps.....................................................62
4.5.1.4
Treatment Administration ................................................63
4.5.1.5
Monitoring of Dose Administration..................................64
4.5.1.6
Reporting Product Complaints .........................................64
4.5.2 Additional Study Medications.........................................................65
4.5.3 Labeling…..…................................................................................65
4.5.4 Storage…........................................................................................65
4.5.5 Treatment Compliance....................................................................65
4.5.6 Accountability….............................................................................65
4.6
Treatment Assignment and Blinding .........................................................65
4.6.1 Methods for Assigning Treatment Groups.......................................65
4.6.1.1
Cohort 1….......................................................................65
4.6.1.2
Cohort 2….......................................................................66
4.6.2 Methods for Ensuring Blinding .......................................................66
4.6.3 Methods for Unblinding..................................................................66
4.6.3.1
Unblinding in the Event of a Medical Emergency.............66
4.6.3.2
Unblinding for Interim Analysis Purposes........................66
4.7
Restrictions During the Study and Concomitant Treatment(s) ...................67
4.7.1 Permitted Concomitant Medications ...............................................67
4.7.2 Prohibited Concomitant Medications ..............................................67
4.8
Statistical Evaluation.................................................................................68
4.8.1 General Considerations...................................................................68
4.8.1.1
Analysis Populations........................................................68
4.8.3 Efficacy….. ....................................................................................69
4.8.3.1
Primary Efficacy Analysis................................................69
4.8.3.2
Secondary Efficacy Analyses ...........................................69
4.8.3.3
Exploratory Analyses.......................................................69
4.8.4 Safety…..........................................................................................69
4.8.4.1
Analysis of Clinical Laboratory Parameters......................70
4.8.5 Analysis of Immunogenicity/Pharmacokinetics...............................70
4.8.6 Interim Analysis .............................................................................70
5
ASSESSMENT OF SAFETY..............................................................................71
5.1
Definition of Adverse Events ....................................................................71
5.2
Definition of Serious Adverse Events........................................................71


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5.3
Definition of Adverse Events of Special Interest .......................................72
5.3.1 Hepatic Function Abnormalities......................................................72
5.4
Recording of Adverse Events....................................................................72
5.4.1 Time Period for Collection of Adverse Events ................................73
5.4.2 Follow-up of Unresolved Adverse Events.......................................73
5.5
Reporting of Serious Adverse Events ........................................................73
5.6
Other Events Requiring Immediate Reporting ...........................................74
5.6.1 Overdose….....................................................................................74
5.6.2 Hepatic Function Abnormality........................................................74
5.6.3 Pregnancy.......................................................................................75
5.6.3.1
Maternal Exposure ...........................................................75
6
STUDY AND DATA MANAGEMENT .............................................................75
6.1
Training of Study Site Personnel...............................................................75
6.2
Monitoring of the Study............................................................................76
6.2.1 Source Data ....................................................................................76
6.2.2 Study Agreements...........................................................................76
6.2.3 Archiving of Study Documents.......................................................77
6.3
Study Timetable and End of Study............................................................77
6.4
Data Management .....................................................................................77
6.5
Medical Monitor Coverage........................................................................77
7
ETHICAL AND REGULATORY REQUIREMENTS........................................78
7.1
Subject Data Protection.............................................................................78
7.2
Ethics and Regulatory Review...................................................................78
7.3
Informed Consent......................................................................................79
7.4
Changes to the Protocol and Informed Consent Form................................79
7.5
Audits and Inspections ..............................................................................80
8
REFERENCES ...................................................................................................81
9
CHANGES TO THE PROTOCOL......................................................................83
9.1
Protocol Amendment 2, 17Oct2017 ..........................................................83
9.2
Protocol Amendment 1, 25Jul2017............................................................84
10
APPENDICES ....................................................................................................86
10.1
Appendix 1 - Signatures............................................................................86
10.2
Appendix 2 – Contraception Guidance......................................................88
10.3
Appendix 3 - Additional Safety Guidance .................................................89
10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis.......................................................................................92
10.5
Appendix 5 - Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s law............................................................93


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10.7
Appendix 7 Biological Samples .............................................................. 101
LIST OF IN-TEXT TABLES
Table 2.1-1
Primary Objective and Associated Endpoints....................................17
Table 2.2-1
Secondary Objectives and Associated Endpoints...............................17
Table 2.3-1
Exploratory Objectives and Associated Endpoints ............................18
Table 3.2.1-1
Proposed Study Doses and Predicted Safety Margins Based on Rat and 
Cynomolgus Monkey Data ...............................................................26
Table 4.2.1-1
Schedule of Screening Procedures ....................................................35
Table 4.2.2-1
Schedule of Treatment Period Study Procedures: Cohort 1 ...............38
Table 4.2.2-2
Schedule of Treatment Period Study Procedures: Cohort 2 ...............44
Table 4.2.3-1
Schedule of Follow-up Procedures....................................................49
Table 4.5.1-1
Identification of Investigational Products..........................................61
Table 4.5.1.3-1
MEDI0382 and Placebo Dose Preparation ........................................62
Table 9.1-1
Summary of Revisions to the Protocol ..............................................83
Table 9.2-1
Summary of Revisions to the Protocol ..............................................84
Table 10.2-1
Highly Effective Methods of Contraception......................................88
LIST OF IN-TEXT FIGURES
Figure 3.1.1-1
Study Flow Diagram.........................................................................22


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialised Term
Definition
ABPM
ambulatory blood pressure monitoring 
AE
adverse event
AESI
adverse event of special interest
ADA
anti-drug antibodies
ALP
alkaline phosphatase
ALT
alanine transaminase
ANCOVA
analysis of covariance
AST
aspartate transaminase
AUC
area under the concentration-time curve
BMI
body mass index
BP
blood pressure
CI
confidence interval
Cmax
maximum observed concentration
CGM
continuous glucose monitoring
ECG
electrocardiogram
EDC
electronic data capture
eCRF
electronic case report form
FFA
free fatty acid
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
GMP
Good Manufacturing Practice
GFR
glomerular filtration rate
HbA1c
glycated haemoglobin
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
IB
investigator brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
ITT
intent-to-treat
IWRS
interactive voice response system
IXRS
interactive voice/web response system
MedDRA
Medical Dictionary for Regulatory Activities
MMTT
mixed-meal tolerance test
MDRD
Modification of Diet in Renal Disease


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Abbreviation or 
Specialised Term
Definition
NOAEL
no-observed-adverse-effect level
PD
pharmacodynamics
PK
pharmacokinetics
SAE
serious adverse event
SC
subcutaneous
SID
subject identification
T1/2
half-life
T2DM
type 2 diabetes mellitus
ULN
upper limit of normal
w/v
weight per volume


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1
INTRODUCTION
1.1
Disease Background
The rising prevalence of type 2 diabetes mellitus (T2DM) and obesity is a cause of 
substantial health and economic burden worldwide. In many cases of T2DM, significant 
weight loss (typically 5% of body weight or more) can promote improvements in glycaemic 
control, cardiovascular risk, and mortality rates, and may even slow or reverse disease 
progression (Petersen et al, 2005). Many existing therapies for T2DM focus upon lowering 
blood glucose; however, there is a major unmet need for treatments that both improve 
glycaemic control and achieve disease modifying weight. 
1.2
MEDI0382 Background
MEDI0382 is a synthetic peptide with both glucagon-like peptide-1 (GLP-1) and glucagon 
receptor co-agonist activity which is under development for the treatment of T2DM and 
obesity. GLP-1 receptor agonists are established treatments for T2DM that improve 
glycaemic control,
and depress appetite leading to modest, but often 
non-sustained weight loss (typically 3% versus baseline at one year). Glucagon has similar 
effects to GLP-1 on 
 
appetite, and has also been shown to promote 
increased energy expenditure (Lynch et al, 2014; Habegger et al, 2013). Oxyntomodulin, a 
naturally occurring peptide with GLP-1 and glucagon receptor co-agonist activity, has been 
shown to promote weight loss through effects on appetite and energy expenditure (Wynne et 
al, 2006) and co-infusion of GLP-1 and glucagon has synergistic effects on reducing food 
intake and promoting weight loss in human subjects (Bagger et al, 2015).
1.3
Summary of Nonclinical Experience
Refer to the current MEDI0382 Investigator’s Brochure (IB) for a complete summary of 
nonclinical information. Consistent with other GLP-1 receptor agonists, MEDI0382 exposure 
resulted in the anticipated pharmacologic effects on body weight (reduced gain or loss), food 
consumption (sporadic reductions), 
 
 
 
 


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1.4
Summary of Clinical Experience
In prior clinical experience (Cohort 4 of Study D5670C00002), treatment with MEDI0382 up 
to 200 μg from a start dose of 100 μg for 41 days with 2 titration steps of 4 days duration was 
associated with a mean reduction from baseline in body weight of 4.1% (90% confidence 
interval [CI] -4.9, -3.4) in MEDI0382-treated subjects versus 1.8% (90% CI -2.5, -1.0) in 
placebo, p < 0.001, and a mean reduction from baseline in glucose AUCMMT.4h of 32.8% 
(90% CI -37.0, -28.6) vs 10.2% (90% CI -14.1, -6.2) in placebo, p ≤0.0001. MEDI0382 was 
shown to have an acceptable safety profile. There were no unexpected safety signals and no 
increases in systolic or diastolic BP across the study. In Cohort 4, dosing over 41 days was 
associated with increased gastrointestinal (GI) adverse events (AEs) with 40 AEs of vomiting
observed in 8 (32%) of subjects; however, the number of events diminished in frequency 
with dose up-titration (n = 19 at 100 μg, n = 10 at 150 μg, and n = 11 at 200 μg). 
Extrapolating from these results it is anticipated that MEDI0382 will achieve GLP-1 receptor 
agonist-like glucose control, but with the potential for disease-modifying weight loss of 
greater than 10% of body weight over one year.
Refer to the current MEDI0382 IB for a complete summary of clinical information.
1.5
Rationale for Conducting the Study
This is a Phase 2a study designed to: 1) assess the efficacy, safety, tolerability, and the 
pharmacokinetic (PK) profile of MEDI0382 titrated up to a dose level of 300 μg from 50 μg 
across 49 days; 2) characterise the PK profile and blood glucose-lowering efficacy of 50 μg 
of MEDI0382 as this dose level has not been previously studied, and 3) to explore different 
dosing and titration schedules in order to determine if it is possible to minimise GI AEs
associated with MEDI0382 treatment. The results of this study will provide additional 
information about the safety, tolerability, PK profile, and exposure-response following 
extended dosing at the 300 μg dose level.


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1.6
Benefit-risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation
(ICH)/Good Clinical Practice (GCP), and applicable regulatory requirements.
MEDI0382 is a GLP-1 and glucagon receptor co-agonist which promotes glucose lowering 
and weight loss and is targeted at subjects with T2DM. MEDI0382 has the potential to 
deliver improvements in glycaemic control and lipid homeostasis, and is predicted to be a 
useful therapy for T2DM.
The study design aims to minimise potential risks to subjects participating in this study based 
on the proposed inclusion/exclusion criteria, safety monitoring, and up-titration dosing 
schedule. All subjects will be monitored throughout the study to ensure adequate glycaemic 
control. Subjects will be given appropriate training in subcutaneous (SC) injection 
administration as well as use of any devices. 
Refer to the current IB for information on the potential benefits of MEDI0382 and an 
assessment of the potential and known risks.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
Administration of MEDI0382 once daily titrated up to a dose level of 300 μg will result in 
superior blood glucose control and weight loss versus placebo after 49 days of treatment in 
overweight and obese subjects with T2DM. 
1.7.2
Secondary Hypotheses
•
Administration of MEDI0382 once daily titrated up to a dose level of 300 μg across 
49 days will have an acceptable safety profile and be well tolerated in overweight and 
obese subjects with T2DM 
•
Administration of MEDI0382 once daily titrated up to a dose level of 300 μg from 50 μg 
will have a predictable PK profile
•
Administration of MEDI0382 once daily at a dose level of 50 μg will result in superior 
blood glucose control versus placebo after 7 days of treatment in overweight and obese 
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2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoints
Table 2.1-1
Primary Objective and Associated Endpoints
Type
Objective
Endpoint
Efficacy
To assess the effects of MEDI0382 titrated 
up to a dose level of 300 μg on glucose 
control and body weight versus placebo 
after 49 days of treatment (Cohort 1 only)
•
Percentage change in glucose AUC as 
measured by a standardised MMTT 
from baseline (Day -1) to the end of 
49 days of treatment 
•
Percentage change in body weight 
from baseline (Day 1) to the end of 
49 days of treatment
AUC = area under the concentration-time curve; MMTT = mixed-meal tolerance test
2.2
Secondary Objectives and Associated Endpoints
Table 2.2-1
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
Efficacy
To assess the effects of MEDI0382 
titrated up to a dose level of 300 μg on 
additional measures of glucose control 
and body weight versus placebo after 
49 days of treatment (Cohort 1 only)
•
Change in HbA1c from baseline 
(Day - 1) to the end of 49 days of 
treatment
•
Change in fasting plasma glucose 
(Day -1) from baseline to the end of 
49 days of treatment
•
Change in body weight (kg) from 
baseline (Day 1) to the end of 49 days 
of treatment
•
Proportion of subjects achieving > 5% 
body weight loss from baseline (Day 1) 
after 49 days of treatment
Safety
To characterise the safety profile and 
tolerability of MEDI0382 titrated up to a 
dose level of 300 μg during dosing and 
follow-up (Cohorts 1 and 2)
Measures of safety and tolerability (24-hour 
heart rate and blood pressure, other vital 
signs, ECG, laboratory test results, and 
AEs)
PK, 
Immunogenicity
To characterise the PK profile and 
immunogenicity of 50 and 300μg of 
MEDI0382 (Cohorts 1 and 2)
•
PK endpoints for 50 μg MEDI0382 
after 1, 7, and 14 days of treatment and 
300 μg MEDI0382 after 1 and 28 days 
of treatment; AUC over a dosing 
duration, Cmax, Tmax, T1/2, trough 
plasma concentration (Ctrough), and 
accumulation ratio (Cmin [R0])
•
Development of anti-drug antibodies  
and titre (if confirmed positive)
Efficacy
To characterise the effect of 50 μg of 
MEDI0382 on glucose lowering versus 
placebo after 7 days (Cohorts 1 and 2)
Percentage change in glucose AUC as 
measured by a standardised MMTT from 
baseline (Day -1) to the end of 7 days of 
treatment






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Cohort 1
Subjects will undergo safety blood tests at any time from Day -7 to Day -3 if the screening 
visit is more than 7 days before Day 1. On Day -2, subjects will be admitted to the clinical 
unit for 2 nights and will undergo further initial safety assessments and training in SC 
injection administration; normal saline will be used for SC injection administration training.
At this time an ambulatory blood pressure monitoring (ABPM) device will be fitted on Day -
2 and worn for 24 hours; simultaneously a continuous glucose monitoring (CGM) device will 
be fitted on the contralateral arm and the subject will be given training for CGM use
(Figure 3.1.1-1). Subjects will be expected to wear the CGM continuously until the end of 
dosing. On Day -1, eligibility criteria will be verified and subjects will undergo 2 mixed-meal 
tolerance test (MMTT) assessments (Meal type A; with serial blood sampling in the morning, 
and meal type C without serial blood sampling on the evening of that day). Subjects can be 
randomised after confirming eligibility at any time from Day -1 to Day 1 (predose) to receive 
either MEDI0382 or placebo. On Day 1, dosing will commence following predose safety 
measures including vital signs, blood tests for safety, glycated haemoglobin (HbA1c) and 
exploratory biomarkers, an ECG, and measurement of weight. Since the dose of 50 μg will 
require a dilution by site staff prior to administration, subjects will have the option to remain 
as an inpatient or alternatively attend the clinical unit every day for dosing during the first 
week; during this time subjects will undergo supervision to self-administer the 
investigational product. On Day 7, safety assessments will be performed and the MMTT
meal type B, with serial blood sampling, will be repeated; where relevant, subjects will be 
discharged home (refer to Section 4.3.1.1 for description of MMTT meal types).
Subjects will then return to the clinical unit at weekly intervals until a maintenance dose of 
300 μg is achieved. On Day 22, subjects will be readmitted to the clinical unit for an 
overnight stay to undergo PK sampling and ABPM for 24 hours. Subjects will be discharged
on Day 23 and will thereafter attend for weekly visits for safety assessments and ABPM 
application. At the end of dosing, subjects will be readmitted to the clinical unit for a final 
overnight stay, and an MMTT (Type A) will be repeated alongside safety assessments, 
ABPM, measurement of weight, and blood tests. A second MMTT (Type C) without serial 
blood sampling will be performed on the evening of Day 49 and an HbA1c and exploratory 
biomarkers will be repeated. A 7- to 14-day post-last dose follow-up visit and final follow-up 
visit approximately 28 days after the last dose will be performed for safety assessments, and 
a final ABPM recording will be made at this time.


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Cohort 2
Study procedures for Cohort 2 will be similar to Cohort 1 at baseline, although subjects will 
not undergo ABPM assessments nor wear a CGM monitor in this cohort. 
 
 
 
 Safety bloods will be performed at anytime from Day -7 to 
Day -3 if the screening visit was more than 7 days before Day 1 (Figure 3.1.1-1). Subjects 
may be confined to rest for the duration of the breath test period. On admission to the clinical 
unit on Day -2, subjects will undergo further baseline safety assessments and undergo their 
first MMTT (Type A) with serial blood sampling on Day -1. Dosing will commence on Day 
1. Since the dose of 50 μg will require a dilution by site staff prior to administration, subjects 
will be given the option to either remain as an inpatient, or attend the clinical unit every day 
during the first 2 weeks of dosing, but will be required to stay overnight for a total of 5 nights 
across this period (on Days -2, -1, 1, 7, and 14); thereafter, subjects will attend the unit for 
dose up-titration. During this time subjects will self-administer investigational product under 
supervision. 
and MMTTs (Type B) with serial blood 
sampling will be repeated at different points across the study as described in the schedule. At 
the end of dosing on Day 49, subjects will be admitted for a final overnight stay; a repeat 
MMTT (Type A) will be performed, alongside measurement of weight and safety 
assessments. 
 
A 7- to 14-day post-last dose follow-up visit and final follow-up visit 
approximately 28 days after the last dose will be performed for safety assessments
 




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The endpoints to be measured in this study are described in Section 2.
3.1.2
Treatment Regimen
MEDI0382 or placebo will be administered once daily via SC injection.
Cohort 1
•
MEDI0382 50 μg for 7 days, followed by 100 μg for 7 days, followed by 200 μg for 
7 days, and 300 μg SC once daily for 28 days (n = 26)
•
Matched placebo SC once daily for 49 days (n = 13)
Cohort 2 
•
MEDI0382 50 μg for 14 days, followed by 100 μg for 14 days, followed by 200 μg for 
14 days, and 300 μg SC once daily for 7 days (n = 18)
•
Matched placebo SC once daily for 49 days (n = 6)
3.1.3
Dose Escalation
Doses will escalate from the initial dose of 50 μg to 300 μg in 1-week intervals for Cohort 1 
and in 2-week intervals for Cohort 2 (Section 3.1.2).
3.1.4
Management of Study Medication Related Toxicities
3.1.4.1
Tolerability
If a subject experiences nausea and vomiting in relation to investigational product, in the first 
instance, conservative measures should be advised including reducing meal size and 
maintaining adequate hydration. Where necessary, if there is persistent vomiting a subject 
may be given an antiemetic to control his/her symptoms; a 5HT3 receptor antagonist (eg, 
ondansetron) or cyclizine is preferable in this situation, rather than antiemetics 
 
 and in particular dopamine receptor antagonists (eg, metoclopramide 
or domperidone).
3.1.4.2
Hypoglycaemia
A hypoglycaemic event is considered severe if associated with severe cognitive impairment 
requiring external assistance for recovery, as defined by the American Diabetes Association.
Spontaneous and clinically significant hypoglycaemia defined as blood glucose 
< 3.0 mmol/L or 54 mg/dL with or without symptoms (Skyder et al, 2017) has not been 
experienced in prior studies with MEDI0382 up to a dose of 300 μg alongside metformin 


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treatment and is therefore unlikely to occur in this study. All subjects (both Cohorts 1 and 2) 
will be provided with a diary and a glucometer and will be advised to check their capillary 
blood glucose level if they have symptoms of hypoglycaemia (hunger, dizziness, shaking, 
sweating, or irritability) or feel unwell and will be expected to record the level in their diary. 
Local protocols for treatment and follow-up of any hypoglycaemic episode should be 
followed. Any blood glucose level of < 3.0 mmol/L (54 mg/dL) is considered as clinically 
important hypoglycaemia and should be reported by investigators as an AE. Pharmacological 
treatments administered for hypoglycaemia, eg, dextrose/glucose tablets, glucagon etc should 
be recorded in the electronic case report form (eCRF) as concomitant medications.
3.1.4.3
Hyperglycaemia
In the event of suspected persistent hyperglycaemia in a subject based on either symptoms of 
hyperglycaemia (eg, thirst, polyuria, blurred vision), capillary blood glucose readings (eg,
3 readings > 260 mg/dL [14.4 mmol/L] within one week) or CGM readings (eg, > 30% of 
readings above 260 mg/dL [14.4 mmol/L]), the investigator should perform additional fasting 
blood glucose levels as necessary to further investigate. If 2 or more laboratory plasma 
fasting glucose levels of > 260 mg/dL [14.4 mmol/L] more than 3 days apart are detected, the 
investigator should consider rescue therapy following discussion with the medical monitor. 
3.2
Study Design and Dose Rationale
3.2.1
Dose Rationale
PK information collected in previous single and multiple dose clinical studies (Studies 
D5670C00001 and D5670C00002) suggest that MEDI0382 has a linear profile in the dose 
range 5 to 300 μg with a half-life of approximately 8 to 13 hours, which allows minimal 
accumulation after repeat daily administration and achievement of steady state between 4 and 
7 days. Moreover, the absorption profile in the low-dose range tested suggests that doses 
lower than 100 μg may have a different bioavailability to doses greater than 100 μg.
Based on PK/pharmacodynamics (PD) modelling conducted using available clinical data and 
from a literature review of GLP-1 and glucagon modulators, the maximal clinically 
efficacious dose for glucose control of MEDI0382 was predicted to be in the range of 200 to 
300 μg/day; in addition early clinical data from a prior single-ascending-dose study 
(Study D5670C00001) identified potentially efficacious doses in a range lower than 100 μg. 
However, there is no information available on efficacy with repeat dosing at dose levels 
below 100 μg. The initial dose for Cohorts 1 and 2 of this study is therefore proposed to be 
50 μg and the maximum dose to be administered in this study will not exceed 300 μg/day. As 


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described above, the principle of dose up-titration to improve tolerability with higher doses is 
well established with short-acting GLP-1 analogues (Victoza, 2014).
The study is designed to provide efficacy information on glucose control and weight loss at 
300 μg administered daily for 28 days to allow comparison with previous clinical data 
collected at 200 μg at a similar administration duration. It will also explore a prolonged dose 
titration schedule for repeated doses of MEDI0382 to characterise the safety/tolerability 
profile and PK/PD profile of MEDI0382 at a relevant pharmacological range to facilitate 
rational design of future studies. Moreover, it is designed to establish the efficacy of repeated 
dosing of 50 μg MEDI0382 on glucose control.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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3.2.3
Rationale for Endpoints
3.2.3.1
Primary Endpoints
Coprimary endpoints of glucose AUC and weight loss are required to evaluate the efficacy of 
the 300 μg dose level over a longer duration of dosing than has been studied before at this 
dose level.
3.2.3.2
Secondary Endpoints 
Additional Measures of Glucose Lowering and Weight Loss
In order to better characterise the glucose-lowering efficacy of MEDI0382 up to 300 μg 
across 49 days of dosing, additional markers of glucose control including HbA1c and fasting 
glucose level will be measured, alongside exploratory measures of glucose control generated 
by CGM. Absolute change in weight will also be measured and the proportion of subjects 
achieving clinically significant weight loss (> 5% of body weight) will be recorded.
In evaluating the 50 μg dose of MEDI0382, this study will determine if repeat administration 
of 50 μg is more effective than placebo with respect to glucose lowering at 7 days through 
measurement of glucose AUC during a standardised MMTT. Results from the prior 
multiple-ascending-dose study (Study D5670C00002) of MEDI0382 on glucose AUC 
reduction have shown a reduction of 41.8% after 7 days at 100 μg, 36.7% after 11 days at 
150 μg following up-titration from 100 μg, and 39.6% after 15 days at 200 μg following 
up-titration from 100 μg and 150 μg. Results from this previous study will be used as a 
benchmark to further evaluate the results.
Safety and Tolerability 
In prior studies (Study D5670C00002), 300 μg of MEDI0382 has been administered to 
23 obese and overweight subjects with T2DM for 7 days after 2 up-titration steps, and was 
shown to have an acceptable tolerability and safety profile over this period of dosing. During 
treatment, there was no significant increase in systolic or diastolic BP, but a significant 
increase in heart rate of 6.6 beats per minute (90% CI 4.1, 9.1) was recorded after 7 days of 
dosing (Cohorts 5 and 6 pooled data; n = 19). In the cohorts that received MEDI0382 up-
titrated to 300 μg, nausea and vomiting were observed in a maximum of 41.7% (Cohort 6)
and 27.3% (Cohort 5) of subjects, respectively. Safety and tolerability with greater exposure 
at the 300 μg dose level will be measured with safety laboratory tests, ABPM recording of 
heart rate and BP and other vital signs, and recording of AEs. 


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Pharmacokinetic Profile and Immunogenicity
Plasma concentrations of MEDI0382 at 50 and 300 μg will be used to evaluate the PK profile 
(Cmax, time to maximum concentration [Tmax], AUCtau, and Cmin[R0] [accumulation ratio]). In 
addition, Ctrough at other dose levels will be evaluated to establish steady state achievement.
Anti-drug antibodies (ADA) incidence rate and titre will be tabulated for each treatment to 
monitor immunogenicity. Tiered analyses will be performed to include screening, 
confirmatory and titre assay components; samples confirmed positive for ADA will be tested 
and analysed for antibody titre and reported and may be utilised for further characterisation 
of the ADA response.
3.2.3.3
Exploratory Endpoints 
GLP-1 analogues are established to cause increased GI side-effects which are most 
pronounced in the early phases of treatment (Meier, 2012). The mechanisms underlying these 
symptoms are multifactorial and related to PK and effects on
 and vomiting 
centers of the brain (area postrema) (Orskov et al, 1996). An added dimension of complexity 
here is that tolerance to the effects of GLP-1 receptor agonism on 
 may 
develop with short-term treatment (Nauck et al, 2011). In attempts to improve GI tolerability 
in this drug class, both dose up-titration (Victoza, 2014) and lengthening of titration intervals
from between 1 to 4 weeks have been utilised (Exenatide, 2016). In a prior Phase 1/2 study 
(Study D5670C00002), subjects dosed with MEDI0382 titrated in 4-day intervals from 
100 μg up to 200 μg across 41 days reported mild to moderate nausea (13/25, 52%) and 
vomiting (8/25, 32%); however, the number of nausea and vomiting events diminished in 
frequency with dose up-titration (n = 19 at 100 μg, n = 10 at 150 μg, and n = 11 at 200 μg) 
and in most cases, events were noted to occur within 3 days of a dose up-titration step. In 
Cohorts 5 and 6 of Study D5670C00002, a comparison of different dose up-titration steps 
was made: 100 μg →150 μg →200 μg →300 μg (Cohort 5; n = 11) versus 
100 μg →200 μg →300 μg (Cohort 6; n = 12) with 5-day up-titration steps in between. The 
percentage of subjects reporting nausea was lower with an intermediate 150 μg dose up-
titration step between 100 and 200 μg (27% vs 42%); however, the percentage of subjects 
with vomiting was in fact higher in this group (27% vs 8%). These results and the prior 
clinical experience with GLP-1 analogues imply that further modulation of the titration 
schedule may help to minimise GI side-effects experienced with MEDI0382. To investigate 
different titration schedules, Cohort 1 of this study will test a lower starting dose of 
MEDI0382 (50 μg) than has been previously tested in overweight and obese subjects with 
T2DM, and with longer up-titration steps (7 days). Cohort 2 will run in parallel with Cohort 1 


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and will test up-titration of MEDI0382 every 2 weeks in order to assess if this further 
minimises GI AEs.
 
 
 
 
 
CGM is a minimally invasive device applied to the skin in the upper arm that provides a 
measure of interstitial glucose levels every 15 minutes. In this study, results of CGM will be 
used to calculate the average glucose level over 24-hour and 7-day periods, to observe 
glucose excursions during different meals and at different times of the day, and to determine 
the percentage of time subjects have abnormally high or low blood glucose levels. To further 
supplement this investigation, standardised meals (in some cases as part of an MMTT) will 
be given in the morning and evening to view the difference in post-prandial glucose
excursion at different times in the day. 
 
 
It is postulated that the glucagon receptor agonist component of MEDI0382 may lead to an 
increase in fatty acid oxidation in the liver (Keller and Shulman, 1979). Ketone bodies are 
the byproduct of fatty acid oxidation and may be increased if there is an up-regulation of 
fatty acid oxidation. Concurrent measurement of free fatty acids (FFAs) and amino acids will 
determine if there is increased consumption of these ketogenic substrates during treatment 
with MEDI0382.
 uric acid (Gagliardi et al, 2009) are 
markers of cardiovascular risk; measurements before and after MEDI0382 treatment will be 
interpreted in the context of change in weight and lipids to gain an early insight on the impact 
of MEDI0382 on cardiovascular risk.


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4
MATERIALS AND METHODS
4.1
Subjects…..
4.1.1
Number of Subjects
Enrollment of up to 63 subjects across multiple study sites is planned, 39 subjects in Cohort 1 
(26 subjects to receive MEDI0382 and 13 to receive matched placebo) and 24 subjects in 
Cohort 2 (18 subjects to receive MEDI0382 and 6 subjects to receive matched placebo).
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Male and female subjects aged ≥ 18 years at screening
2. Provision of signed and dated written informed consent 
 
nongenetic research) prior to any study specific procedures 
3. BMI between 27 and 40 kg/m2 (inclusive) at screening
4. HbA1c range of 6.5% to 8.5% (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 the 
3 months prior to screening
6. Subjects prescribed oral dual therapy with a dipeptidyl peptidase-4 inhibitor, 
sulphonylurea, glitinide, or a sodium-glucose co-transporter 2 inhibitor in addition to 
metformin at screening may be eligible to enter the study following a 4-week washout
period
7. Female subjects of childbearing potential must have a negative pregnancy test at 
screening and randomisation, and must not be lactating
8. Females of childbearing potential who are sexually active with a nonsterilised male 
partner must use at least one highly effective method of contraception (see Section 10.2
for definition of females of childbearing potential and for a description of highly effective 
methods of contraception) from screening and must agree to continue using such 
precautions through to the end of the study. It is strongly recommended for the male 
partner of a female subject to also use male condom plus spermicide throughout this 
period. Cessation of contraception after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.
*Note: Subjects may be retested for the HbA1c entry criterion only once.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:




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after 10 minutes of seated rest and confirmed by repeated measurement at screening. 
Subjects who fail BP screening criteria may be considered for 24-hour ABPM at the 
discretion of the investigator. Subjects who maintain a mean 24-hour systolic BP ≤160
or diastolic BP < 95 mm Hg with a preserved nocturnal dip of > 15% will be considered 
eligible.
11. Unstable angina pectoris, myocardial infarction, transient ischemic attack 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 III or IV)
13. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia
14. Haemoglobinopathy, haemolytic anemia, 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 (HBsAg), hepatitis C antibody,
and human immunodeficiency virus (HIV) antibody
17. History of substance dependence, alcohol abuse, or excessive alcohol intake (defined as 
an average weekly intake of > 21 alcoholic drinks for men or > 10 alcoholic drinks for 
women) within 3 years prior to screening, and/or a positive screen for drugs of abuse or 
alcohol at screening or on admission to the study unit. Subjects who use tricyclic 
antidepressants or benzodiazepines for an established clinical indication may be 
permitted to enter the study based upon the judgement of the investigator.
18. Involvement of any AstraZeneca, MedImmune, contract research organization, or study 
site employee or their close relatives
19. History of acute or chronic pancreatitis or other diseases of the pancreas
4.1.4
Subject Enrollment and Randomisation
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice/web response system [IXRS]), and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable.
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomised), including the reason(s) for screening failure.


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Subjects who fail to meet the eligibility criteria should not, under any circumstances, be
enrolled or receive investigational product. 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. 
Subjects may be rescreened once if, in the opinion of the investigator, there is a reason to 
believe they may be eligible.
4.1.5
Withdrawal from the Study
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to future treatment (withdrawal of consent). At the time of 
withdrawing consent, subjects will be asked about the reason(s) for withdrawing and the 
presence of any AEs. After consent is withdrawn, no further study visits or data collection 
should take place.
4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:
•
Withdrawal of consent from further treatment with investigational product or lost to 
follow-up
•
An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing
•
Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation at study entry and continuing 
investigational product, in the decision of the investigator, might constitute a safety risk
•
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
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including follow-up of any AEs unless consent 
is withdrawn specifically from further study participation (Section 4.1.5), the subject is lost 
to follow-up, the subject starts alternative treatment, or the subject is enrolled in another 
clinical study.


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4.1.7
Replacement of Subjects
Subjects who withdraw from the study will be replaced where possible. A maximum number 
of five subjects may be replaced in each cohort.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject. 
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, 
MedImmune is not obliged to destroy the results of this research.
 
 
 
 
 
 
 
 
 
 
 
 
 




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Table 4.2.1-1
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure/Study Day
Day -60 to Day -2
Medical history, including smoking and alcohol history
X
Physical examination (full) including structured neurological 
examination a
X
Verify eligibility criteria
X
Weight, height, and BMI calculation
X
Demographics
X
12-lead ECG b
X
Vital signs (BP c, heart rate, body temperature, RR)
X
Collect blood for:
    LFTs, CR, and eGFR calculation only
X
    Haematology (FBC)
X
    HbA1c
X
    Calcitonin
X
    HIV-1 and -2 antibodies; hepatitis B and C serology
X
Collect urine for:
      Urinalysis
X
      Drug and alcohol screen
X 
Urine or serum pregnancy test if applicable
X
CGM device demonstration d
X
SC injection self-administration training e
X
Concomitant medications
X
BMI = body mass index; BP = blood pressure; CGM = continuous glucose monitoring; CR = creatinine;
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; FBC = full blood count; HbA1c = 
glycated haemoglobin; HIV = human immunodeficiency virus; LFTs = liver function tests (albumin; alanine 
transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP], and total bilirubin);
RR = respiration rate; SC = subcutaneous; SID = subject identification; V = visit
a
examination is required.
b
A single digital ECG recording should be performed after the subject has rested in the supine position 
for 10 minutes. 
c
Blood pressure should be measured once at heart level in the nondominant arm where possible, after the 
subject has rested in either a seated or supine position for at least 10 minutes.
d
Cohort 1 only; subjects should be shown the device and given an explanation as to how it is worn; 
allocation to Cohort 2 may be preferable for subjects who would rather not use a CGM device during the 
study.
e
Subject’s ability to self-administer investigational product will be verified using normal saline 
subcutaneous injections.


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4.2.2
Randomised Treatment Period
Table 4.2.2-1 and Table 4.2.2-2 show all procedures to be conducted during the treatment 
period for Cohort 1 and Cohort 2, respectively. Assessments should be performed in the 
order shown in the table.
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, and then 
blood draws. The timing of the first 2 assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the exact nominal time. Subjects are expected to fast 
overnight with water permitted only for all study visits.


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Table 4.2.2-1
Schedule of Treatment Period Study Procedures: Cohort 1
Study Period
Inpatient
Inpatient 
or daily 
visits
Outpatient
Inpatient
Outpatient
Inpatient
Outpatient
Study Day
-2
-1
1
2-6
7
15
22
23
29
36
43
49
50
7 to 14 
Days
Post Last 
Dose
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
Procedure
Verify eligibility criteria a
X
Admit to clinical unit b
X
X
X
Discharge from clinical unit c
(X)
X
X
Outpatient visit to clinic c
(X)
X
X
X
X
X
X
Medical and disease history
X
Pregnancy test (if applicable) d
X
X
X
X
Targeted physical examination
X
X
X
X
X
X
X
X
Vital signs (BP, heart rate, body 
temperature, RR) e
X
X
X
X
X
X
X
X
X
X
X
ABPM f
X
X
X
X
X
X
ECG g
X
X
X
X
X
X
X
X
Body weight h
X
X
X
X
X
X
X
X
X
SC injection training using normal 
saline
X
X
X
Randomisation i
X
Subjects required to fast overnight 
for 10 hours j
X
X
X(D6)
X
(D21)
X
(D48
& 49)
IP administration k (SC)
X
X
X
X
X
X
X
X
X
X
Up-titration l
X
X
X






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Table 4.2.2-1
Schedule of Treatment Period Study Procedures: Cohort 1
Study Period
Inpatient
Inpatient 
or daily 
visits
Outpatient
Inpatient
Outpatient
Inpatient
Outpatient
Study Day
-2
-1
1
2-6
7
15
22
23
29
36
43
49
50
7 to 14 
Days
Post Last 
Dose
Visit Number
V2
V3
V4
V5
V6
V7
V8
V9
V10
ADA = anti-drug antibody; AE = adverse event; APBM = ambulatory blood pressure monitoring; BP = blood pressure; CGM = continuous glucose monitoring; 
D = day; ECG = electrocardiogram; GLP-1 = glucagon-like peptide-1; HbA1c = glycated haemoglobin; 
IP = investigational product; min = minutes; MMTT = mixed-meal tolerance test; PD = pharmacodynamic(s); PK = pharmacokinetic(s); RR = respiration rate; 
SAE = serious adverse event; SC = subcutaneous; V = Visit.
Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood 
draws should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (eg, for PK and PD) to occur as close as 
possible to the scheduled time. Ten minutes of supine rest should precede these assessments.
a
The eligibility check should be based on all clinical measurements and blood tests taken during the screening visit (V1) with the exception of eGFR, liver 
function tests, blood pressure, urinary illicit drug, alcohol and pregnancy tests, which should be rechecked on Day -2. A targeted physical examination and 
repeat medical history should also be undertaken to ensure the subject is well enough to commence dosing.  
b
The diet of subjects should not be restricted in any way during the study (including during inpatient stay) unless fasting or a standardised meal is specified.  
c
Subjects who prefer to attend for daily visits during the first week will be discharged home on Day 1 after all assessments are complete. (X) indicates that 
subjects can be inpatients or outpatients at these visits.
d
A serum or urine pregnancy test should be conducted on any female subject of childbearing potential as detailed in the schedule. 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 
(defined as at least 1 year since last menses and having an elevated follicle stimulating hormone laboratory value which is in the postmenopausal range in 
previous laboratory test results). 
e
Vital Signs Schedule (blood pressure, heart rate, respiratory rate, and temperature): on days where ABPM is due to be checked a predose set of vital signs 
should be performed prior to application of the ABPM cuff. Blood pressure should be measured once at heart level in the nondominant arm where possible, 
opposite to the arm where the CGM device is applied, after the subject has rested in either a seated or supine position for at least 10 minutes. For time points 
where ECG recording precedes vital sign measurement, the 10-minute rest in the supine position prior to the ECG suffices for the rest prior to vital sign 
measurement.
o
Day -2; vital signs to be taken prior to fitting the ABPM device; postural (standing and supine) blood pressures should be performed at this time.
o
Day 1; vital signs to be taken; predose (-15 min), 15, 30, and 60 minutes (± 5 min) and 2 hours (± 10 min) postdose


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o
Day 7, 15; 23 no specific time point
o
Day 22, 29, 36, and 43; vital signs to be taken prior to fitting ABPM device
o
Day 49: vital signs to be taken prior to fitting the ABPM device; postural (standing and supine) blood pressures should be performed at this time.
f
Subjects will be fitted with the ABPM device while at the clinical unit, which may involve practice inflations. The ABPM device should be applied on the 
opposite arm to the arm where the CGM device is applied. The subject will then wear the monitor/cuff for approximately 24 hours (including overnight at 
home) and will remove the device at home at the end of the 24-hour period. Subjects will return the device to the clinic. 
g
A single digital ECG recording should be performed predose after the subject has rested for 10 minutes in the supine position on Day 1, 7, 22, and 49. No 
specific time point for other visits.
h
Body weight should be measured in the morning prior to breakfast (predose on Day 1); the subject should take off their shoes and remove bulky clothing. 
Calibrated scales should be used. 
i
Randomisation may occur any time from Day -1 to Day 1 predosing. 
j
Subjects are required to fast overnight on the night of Day -2, -1, 6, 21, 48, and 49. Refer to footnote (s) for additional fasting requirements on Day -2 and 
Day 49 during the day.  
k
Subjects are required to dose at the clinic on Day 1 – 7 as dilution of dose is required by site staff. Subjects are also required to dose at the clinic on study 
day visits when predose assessments are required. See Section 4.5.1.3 for further information.
l
On Day 7, the subject will receive a final 50-μg dose, and should be provided with 7 days of IP supply to dose at the 100-μg dose level and advised to 
commence this dose level on Day 8 while they are at home. On Day 15, subjects will be given a 200-μg dose during their study visit, and should be provided 
with 6 days IP supply for dosing at the 200-μg dose level while at home. Subjects should be given the first 300-μg dose on Day 22 and continue this dose 
level for the remainder of the study.
m
Predose not applicable on Days 7, 29, 36, and 43. An additional blood test for safety (to be taken at any time between Day -3 and Day -7) is not required if 
the screening visit occurs within 7 days of dosing (Day 1); if the screening visit is more than 7 days prior to dosing on Day 1, then additional safety blood 
tests should be taken (as described in Section 4.3.3).
n
PK Sampling Schedule for MEDI0382: 
Day -1; No specific time point
Day 1; Predose
Day 7 and Day 15; Predose
Day 22; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 23: Predose 
Day 29; 36; 43 Predose
Day 49; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 50; Predose 




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Table 4.2.2-2
Schedule of Treatment Period Study Procedures: Cohort 2
Study Period
Inpatient
Inpatient 
or daily 
visits
Inpatient
Inpatient 
or daily 
visits
Inpatien
t
Outpatient
Inpatient
Outpatient
Study Day
-2
-1
1
2-6
7
8
9-13
14
15
29
43
49
50
7 to 14 
Days
Post Last 
Dose
Visit Number
V2
V3
V4
V5
V6
V7
V8
Procedure
Verify eligibility criteria a
X
Admit to clinical unit b
X
X
X
X
Discharge from clinical unit c
(X) (D2)
(X)
X
X
Outpatient visit to clinic c
(X)
(X)
X
X
X
Medical and disease history
X
Pregnancy test (if applicable) d
X
X
X
X
X
Targeted physical examination
X
X
X
X
X
X
Vital signs (BP, heart rate, body 
temperature, RR) e
X
X
X
X
X
X
X
X
X
X
X
ECG f
X
X
X
X
X
X
X
Body weight g
X
X
X
X
X
X
X
SC injection training
X
X
X
Randomisation h
X
Subject required to fast overnight for
10 hours i
X
(D-3
andD
-2)
X
X (D6)
X(D13)
X
X
(D28)
X
(D42)
X
(D48
and 
D49)
IP administration j
X
X
X
X
X
X
X
X
X
X
Uptitration k
X
X
X
Collect blood for:






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c
Subjects who prefer to attend for daily visits will be discharged home on Day 2 and will be readmitted for overnight stays on Day 7 and Day 14.
d
A pregnancy test should be conducted on any female subject of childbearing potential as detailed in the schedule. 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 
(defined as at least 1 year since last menses and having an elevated follicle stimulating hormone laboratory value which is in the postmenopausal range in 
previous laboratory test results).
e
Vital Signs Schedule (blood pressure, heart rate, respiratory rate, and temperature): On Days 1, 7, and 14 vital signs are to be recorded predose (-15 min) 
and at 15, 30, 60, 90 (± 5 min) minutes and 2 hours postdose (± 10 min), and predose (-15 min) at all other times. Vital signs should be performed after 
the subject has rested in either a seated or supine position for at least 10 minutes prior to the measurement. For time points where ECG recording precedes 
vital sign measurement, the 10-minute rest in the supine position prior to the ECG suffices for the rest prior to vital sign measurement.
f
A single digital ECG recording should be performed predose after the subject has rested in the supine position for 10 minutes.
g
Body weight should be measured in the morning prior to breakfast (predose on Day 1); the subject should take off their shoes and remove bulky clothing. 
Calibrated scales should be used.
h
Randomisation may occur on either Day -1 to Day 1 predosing.
i
Subjects are required to fast overnight on the night of Day -3
 -2, -1, 6, 13, 14, 28, 42 48, and 49.
j
Subjects are required to dose at the clinic on Day 1 – 14 as dilution of dose is required by site staff. Subjects are also required to dose at the clinic on study 
day visits when predose assessments are required.
k
On Day 14, the subject will receive a final 50 μg dose; on Day 15 subjects will receive a 100-μg dose of IP, and should be discharged home with adequate 
supply of IP for a further 13 days of dosing at the 100-μg dose level. On Day 29, subjects should receive a 200-μg dose during their study visit, and again 
be discharged with 13 days supply of IP for dosing at the 200-μg dose level. On Day 43, subjects should receive a 300-μg dose during their study visit and 
continue this dose until the end of the study.
l
Predose not applicable on Days 7, 15, 29, and 43. An additional blood test for safety (to be taken at any time between Day -3 and Day  -7) is not required 
if the screening visit occurs within 7 days of dosing (Day 1); if the screening visit is more than 7 days prior to dosing on Day 1 then additional safety 
blood tests should be taken (as described in Section 4.3.3).
m
PK Sampling Schedule for MEDI0382:
Day -1; No specific time point
Day 1; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 2: Predose
Day 7; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 8; Predose (± 15 min)
Day 14; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 15, 29, 43, 49, 50; Predose
n
MMTT Schedule (Type A and Type B): Following a minimum 10-hour fast overnight and 2.5 hours after taking the IP, a blood sample for glucose 
(Type B) or a glucose metabolism panel 
will be taken immediately (within 15 minutes)
prior to the subject drinking 1 entire can of Ensure Plus as a standardised meal (ie, “0 minutes”). Blood samples for glucose metabolism panel will 




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4.2.3
Follow-up Period
Table 4.2.3-1 shows all procedures to be conducted during the follow-up period. 
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, and then 
blood draws. 
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.
Table 4.2.3-1
Schedule of Follow-up Procedures 
Study Period
Follow-up Period
Visit Number
Final
Procedure/Study Day
28 days post last dose (± 3 days)
Targeted physical examination 
X
Weight
X
ECG
X
Vital signs (BP, heart rate, body temperature, RR) a
X
ABPM (Cohort 1 only)
X
Serum chemistry panel
X
Fasting lipid profile
X
Calcitonin c
X
Haematology
X
Urinalysis
X
HbA1c
X
Pregnancy test
X
MEDI0382 ADA d
X
Assessment of AEs/SAEs
X
Concomitant medications
X
ABPM = ambulatory blood pressure monitoring; AE = adverse event; ADA = anti-drug antibody; BP = blood 
pressure; ECG = electrocardiogram; HbA1c = glycated haemoglobin; min = minute; RR = respiration rate; 
SAE = serious adverse event; ULN = upper limit of normal
a
Blood pressure should be measured once at heart level in the nondominant arm where possible, after the 
subject has rested in either a seated or supine position for at least 10 minutes.
b
Subjects should fast for > 10 hours the night before; in the morning,  a baseline blood test for glucose 
and insulin should be taken alongside a baseline measurement of expired CO2 just prior to administration 
of C13- octanoate in conjunction with a standardised solid meal. Subjects will be expected to consume 
the meal within less than 5 minutes. Blood sampling of glucose and insulin should be performed at t = 0 


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Table 4.2.3-1
Schedule of Follow-up Procedures 
Study Period
Follow-up Period
Visit Number
Final
Procedure/Study Day
28 days post last dose (± 3 days)
(baseline), t = 30 min, t = 60 min, t = 120 min and t = 240 min (±5 min) after taking the standardised 
meal. Concurrent sampling of expired CO2 should occur as described in the detailed methods section.
c
Only to be repeated if the calcitonin level was > ULN in the sample taken at the end of dosing
d
If this sample is ADA positive, the subject will be asked to return to provide another sample at 
approximately 3 months after the end-of-study visit (post-study sample). If the sample taken at 3 months 
is ADA positive, the subject will be asked to return to provide a sample in another 3 months
4.2.3.1
Early Discontinuation Visit or Unscheduled Study Visit
The following study procedures should be conducted for subjects who prematurely 
discontinue from the study or for subjects who require an unscheduled study visit. 
Assessments may be performed in any order:
•
Targeted physical examination 
•
ECG
•
Vital signs
•
Body weight
•
PK for MEDI0382
•
Blood tests: Chemistry and haematology panel
•
ADA
•
Assessment of AEs/serious adverse events (SAEs)
•
Concomitant medications
•
Pregnancy test (if applicable)
4.3
Description of Study Procedures
4.3.1
Efficacy…..
4.3.1.1
Mixed-meal Tolerance Tests
Following a minimum 10-hour fast the subject will undergo an MMTT which will involve 
the consumption of a standardised liquid meal (Ensure Plus, a nutritional supplement 
containing the components of fat, carbohydrate, and protein, which make up a standard 
MMTT) within 5 minutes, and timed serial blood samples will be obtained for measurement 
of glucose and parameters related to glucose metabolism through 240 minutes after 


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consumption of the standardised meal (with no additional food intake during this time). The 
MMTT procedures will be performed at the time points specified in the schedules of 
procedures by cohort.
For Cohort 1 blood will be drawn within 15 minutes before consuming the standardised 
liquid meal (ie, “0 minutes”), and at 15, 30, 45, 60, 90, 120, 180, and 240 minutes 
(± 5 minutes) after consumption. Blood sampling should occur as close as possible to the 
specified times for the MMTT. Sampling ± 5 minutes of the specified time will not be 
considered a protocol deviation but the exact time of sampling should be recorded.
For Cohort 2, blood will be drawn within 15 minutes before consuming the standardised 
liquid meal (ie, “0 minutes”), and at 5, 10, 15, 30, 45, 60, 90, 120, 180, and 240 minutes 
(± 5 minutes) after consumption. 
For clarity, MMTTs have been subdivided into Types A, B, and C; according to the timing of 
the test, and differences in blood sampling schedules.
Ingestion of standardised liquid meals/Ensure as part of an MMTT Type A or B, where 
relevant, should occur after blood sampling for PK, 2.5 hours after investigational product 
administration and PD sampling should be arranged in accordance with this schedule.
Mixed-meal Tolerance Test Type A (Cohorts 1 and 2)
 
 
Glucose measurements from these pre- and post-MMTT samples will be 
used for the primary efficacy assessment and secondary endpoints including fasting glucose 
and AUC glucose 7 days at the 50 μg dose level. All MMTT test results will be used to 
generate PD profiles.
Mixed-meal Tolerance Test Type B (Cohorts 1 and 2)
All timings and procedures are identical to MMTT Type A except for PD sampling which 
should be for collection of blood glucose samples only.
Mixed-meal Tolerance Test Type C – Cohort 1 only
For subjects in Cohort 1 a standardised liquid meal (Ensure Plus, a nutritional supplement 
containing the components of fat, carbohydrate, and protein) will be administered on Day -1 


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at 1800 and also Day 49 at 1800. The subject should consume the Ensure Plus within 
5 minutes. The subject will be expected to fast from 1400 hours prior to the test, and to 
consume water only during this period up until 2000 hours. The subject should be wearing
their CGM sensor before, after, and during the test. As the CGM sensor will record 
interstitial glucose levels, there is no need to perform concurrent blood sampling during this 
test. From 2000 hours onwards the subject may eat and drink normally. If the subject is 
required to fast for the next day assessments, fasting should commence from mid-night.
4.3.1.2
Weight…..
Weight will be measured at the time points specified in the schedules of procedures by 
cohort(s), after the subject has toileted and removed bulky clothing including shoes. 
Whenever possible, the same (properly calibrated) scale should be used for each 
measurement for any given subject.
4.3.2
Safety Assessments
4.3.2.1
Medical History and Physical Examination
Complete medical history will include history and current medical conditions, past or present 
cardiovascular disorders, respiratory, GI, renal, hepatic, neurological, endocrine, lymphatic, 
haematologic, immunologic, dermatological, psychiatric, genitourinary, drug and surgical 
history, or any other diseases or disorders.
Physical examinations will be performed by a physician or qualified designee and will 
include examination of the following body systems: immunologic/allergy; head, ears, eyes, 
nose, throat; respiratory; cardiovascular; GI; musculoskeletal; neurological (structured 
neurological examination to encompass mental status; cranial nerves; nystagmus; motor 
system - muscle strength; sensory system - sensation; bowel and bladder function; deep 
tendon reflexes; gait; station; coordination; fundoscopy; and cerebellar function); psychiatric 
(to the extent of determining whether or not the subject is willing and able to cooperate with 
the required study procedures in the investigator’s judgment); dermatological, 
haematologic/lymphatic; and endocrine.
Any focal deficit identified at baseline should be documented in the eCRF.
The full physical examination including structured neurological examination is required at 
screening. Targeted examinations (evaluation of selective body systems at the judgment of 
the physician or qualified designee based on subject presentation) are sufficient for the 
remaining time points.


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Clinically significant abnormal findings will be recorded. Physical examinations will be 
performed at the time points specified in the schedules of procedures. Height will be 
measured at screening. 
4.3.2.2
Assessment of the Injection Site
Site staff will check the injection site for injection site reactions during study visits as 
required. Injection site reactions may include (but are not limited to) local erythema, pain, 
tenderness, induration, swelling, pruritus, ulceration, and pigmentation.
4.3.2.3
Electrocardiograms
At the visits specified in Table 4.2.1-1, Table 4.2.2-1, and Table 4.2.2-2, ECGs will be 
obtained after 10 minutes supine rest. Only a single ECG will be required at the specified 
time points. Only the overall evaluation will be recorded in the eCRF.
The same recorder will be used for each subject at each time point, if possible. Date and time 
settings should be checked at the start of each study day and aligned with an official 
timekeeper for all machines used in the study.
Skin preparation should be thorough and electrode positions should be according to standard 
12-lead ECG placement. 
In this study lead V2 will be analysed and reported as primary. Lead V5 will be analysed, for 
all visits, as backup for the individual where analysis in lead V2 is not deemed possible for 
predose or significant parts of whole visits or whole visits.
The following variables will be reported: heart rate, RR, PR, QRS, and QT intervals from the 
primary lead of the digital 12-lead ECG. The investigator may add extra 12-lead ECG safety 
assessments if there are any abnormal findings or if the investigator considers it is required 
for any other safety reason.
4.3.2.4
Vital Signs
Vital sign measurements (BP, heart rate, body temperature, and respiration rate) will be 
obtained after the subject has rested in either a seated or supine position for at least 
10 minutes at the time points specified in the schedules of procedures for each cohort (for 
time points where ECG recording precedes vital sign measurement, the 10-minute rest in the 
supine position prior to the ECG suffices for the rest prior to vital sign measurement). Route 
of body temperature measurement will be according to local protocols. Where indicated at 
Days -2 and 49, postural BPs (standing and supine) should be performed.


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4.3.3
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. 
Clinical laboratory safety tests will be performed in a licensed central or licensed local 
clinical laboratory. Abnormal laboratory results considered to be clinically significant should 
be repeated as soon as possible (preferably within 24 to 48 hours). 
The following clinical laboratory tests will be performed (refer to time points in the 
schedules of procedures by cohorts): 
Serum Chemistry Panel for Safety To Be Taken At Any Time From Day -7 to 
Day -3 Only
•
eGFR
•
Alkaline phosphatase (ALP)
•
Potassium
•
Total bilirubin
•
Sodium
•
Creatinine
•
AST
•
Blood urea
•
ALT
•
Albumin
Hematology Panel for Safety To Be Taken at Any Time From Day -7 to Day -3 
Only
•
White blood cell count with differential
•
Platelet count
•
Red blood cell count
•
Mean corpuscular volume
•
Haematocrit
•
Mean corpuscular haemoglobin concentration
•
Haemoglobin


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Serum Chemistry Panel
•
Calcium
•
Alkaline phosphatase (ALP)
•
Chloride
•
Total bilirubin
•
Potassium
•
Creatinine
•
Sodium
•
Blood urea
•
Bicarbonate*
•
Albumin
•
AST
•
Magnesium
•
ALT
Notes:
Liver function tests = AST, ALT, ALP, total bilirubin, and albumin
Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently and assessed concurrently.
* may be measured via serum chemistry sample of blood gas analyser per local procedures.
Hematology Panel
•
White blood cell count with differential
•
Platelet count
•
Red blood cell count
•
Mean corpuscular volume
•
Haematocrit
•
Mean corpuscular haemoglobin concentration
•
Haemoglobin
Urinalysis
•
Protein
•
Urine drug screen*  (screening and Day -2 for 
both cohorts
•
Glucose
•
Ketones
•
Blood
Note: Urinalysis for protein, glucose, ketones, and blood may be performed at the site using a licensed test 
(dipstick).
*Illicit drug panel will test for the following drugs; Amphetamines, barbituates, benzodiazepines, cocaine, 
opiates (morphine, heroin), methamphetamine, cannabinoids (marijuana), methodone, phencyclidene, 
methylenedioxy-methamphetamine (ecstasy), propoxyphene, tricyclic antidepressants. Subjects who use 
tricyclic antidepressants or benzodiazepines for an established clinical indication may be permitted to enter the 
study based upon the judgement of the investigator.
Other Tests
•
Calcitonin
•
Alcohol screening test (breath or urine based test)
•
Pancreatic amylase, lipase
•
•
Uric acid
•
•
HbA1c
•
Anti-drug antibodies




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“bridging” assay using electrochemiluminescence. Any positive samples will be tested in a 
confirmatory assay whereby the specificity of the ADA response will be confirmed as either 
positive or negative with respect to MEDI0382. Cross-reactivity of ADA-positive samples to 
GLP-1 and glucagon may also be assessed in the confirmatory assay. Titre evaluation will be 
performed on samples that are confirmed positive for ADA.
positive ADA result, 
 
At the end of study visit, if a subject’s sample is confirmed ADA positive, the subject will be 
asked to return to provide another sample in approximately 3 months to evaluate whether or 
not ADAs persist. If the sample taken in 3 months is ADA positive, the subject will be asked 
to return to provide a sample in another 3 months (ie, 6 months after the end of study visit). If 
the sample is ADA positive at 6 months, the investigator and the medical monitor will 
discuss what further action will be taken. 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. See Section 10.7 for further details.
4.3.6
Pharmacodynamic Evaluation and Methods
 
 
 
 
 
 
 
 
 
 
 


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4.3.6.2
Training for Application and Wearing of CGM Sensor
A Freestyle Libre® Pro CGM device will be used to measure interstitial glucose levels during 
the study. The Freestyle Libre® Pro CGM device measures interstitial glucose levels every 
15 minutes for 2 weeks continuously, and does not require any calibration or periodic 
near-touch/ blue-tooth connections with the device to perform this function. The Freestyle 
Libre® Pro CGM device does not permit flash glucose measurements. Study site staff and 
investigators should avoid periodic reviews of interstitial glucose levels during the study to 
avoid the risk of unblinding. However, should a subject experience an AE or SAE, and the 
investigator deems information acquired by CGM to be useful in the subject’s ongoing 
management, interstitial glucose readings may be reviewed by the investigator as described 
in the manual, and should avoid review of baseline readings taken on Day-2 and Day -1. The 
CGM sensor, which is a small plastic circular device of 35 mm diameter and 5 mm depth, 
should be applied to the back of the upper arm, taking into account subject preference and the 
side where the ABPM device will be sited. The selected site should be shaved where 
necessary, and a sterile alcohol wipe supplied with the kit used to clean the site prior to 
application. Study site staff should refer to the training materials and manual for application 
of the CGM sensor. Subjects will be expected to wear the CGM sensor continuously up until 
the time of a sensor change, which should occur within 14 days, and are to be advised that 
they may bathe and shower, and swim in up to 3 m depth for up to 30 minutes while wearing 
the CGM sensor. The CGM sensor should be removed at the specified times in the schedule 
of assessments (CGM sensor change). At this time the site should be inspected and cleaned; 
and a new CGM sensor may be reapplied ideally close to the original site, but taking into 
account the subject’s preference on site. CGM sensors are single-use only and cannot be 
reapplied once removed and may only be applied to the upper arm and not to any other site in 
the body. It should be noted that monitors should remain at the study site and not be provided 
to subjects to take home.
If a subject is unable to tolerate wearing the CGM sensor for the entire duration of the study, 
the sensor should be removed; but the subject should remain in the study with or without 
continued CGM.


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4.3.6.3
Training for Application and Wearing of ABPM Device
Subjects will be given training at their local study site about how to set up and apply the 
ABPM device. In brief, an appropriate size cuff encircling 80% to 100% of the arm will be 
selected and the device will be fitted to the nondominant arm of the subject, with the bladder 
placed over the artery and an initial test reading performed. The subjects will be advised that 
for the first reading the device will inflate to a pressure of 180 mm Hg, and thereafter the 
device will adapt to inflate to a pressure just above the last recorded BP. The subject will be 
advised to undergo normal daily activities while wearing the cuff, and he/she will be advised 
to avoid any strenuous form of activity, bathing, or showering while wearing the cuff. The 
subject will be advised to remain still during a measurement with the arm relaxed at heart 
level. The subject will also be given advice on how to wear the device during the day and at 
night while sleeping, and what to expect in terms of frequency of readings during the day 
(every 15 minutes) and overnight (every 30 minutes). During ABPM, systolic BP, diastolic 
BP, heart rate pressure, heart rate, and mean arterial pressure readings will be recorded over a 
period of 24 hours.
 
 
 
 
 
4.3.7.2
Storage, Re-use, and Destruction of Pharmacodynamic 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 any investigation will be reported 
either in the clinical study report itself or as an addendum, or separately in a scientific report 
or publication.
4.3.8
Estimate of Volume of Blood to Be Collected
The estimated volume of blood to be collected from each subject over the entire course of 
their participation in the study is 342 mL for Cohort 1 and 439 mL for Cohort 2. Additional 


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blood samples may be collected at the discretion of the investigator in the event of abnormal 
laboratory findings or an AE.
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include but are not limited 
to the following: 
•
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects (eg, drug-related SAEs, anaphylactic reaction, hepatic enzyme 
alterations meeting Hy’s law, signs of renal toxicity, QT interval prolongation).
•
Subject enrollment is unsatisfactory.
•
Noncompliance might significantly jeopardise the validity or integrity of the study.
•
Sponsor decided to terminate development.
•
Sponsor decided to terminate the study.
If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Independent Ethics Committee (IEC) promptly and provide the reason(s) for the 
suspension/termination. If the study is suspended for safety reasons and it is deemed 
appropriate by the sponsor to resume the study, approval from the relevant regulatory 
authorities (and IECs when applicable) will be obtained prior to resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Products
MedImmune will provide the investigator(s) with investigational product (Table 4.5.1-1) 
using designated distribution centers. 


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Table 4.5.1-1
Identification of Investigational Products
Investigational Product
Manufacturer
Concentration and Formulation as 
Supplied
MEDI0382
MedImmune
2 mg/mL liquid formulation
Matched placebo
MedImmune
Solution
Normal saline
NA
9 g/L NaCl solution
NA = not applicable; NaCl = sodium chloride
Note: Diluent (solution manufactured by MedImmune) will be provided to sites for use in the event that a dose 
level requires dilution. The diluent solution is the same as the matched placebo, and diluent and matched 
placebo are provided in the same vials. Matched placebo will be used for dilution for the 50 μg doses only. 
 
 
  
 
 
Investigational product will be supplied to the site in blinded kits each containing 1 vial.
Each kit has a unique number that is printed on all labels within the kit (ie, the outer carton 
label and the label of the vial within the carton). When supplying the investigational product 
for at-home dosing, the 1-vial kits will be supplied in an additional take-home carton.
4.5.1.1
Investigational Product Dose Preparation
In-clinic Investigational Product Handling
Investigational product should be stored at 2°C to 8°C in the original container. 
Investigational products do not contain preservatives and any unused portion must be 
discarded. Preparation of syringes for dose administration is to be performed aseptically. 
Total in-use storage time from needle puncture of the investigational product vial to start of 
administration should not exceed 4 hours. If storage time exceeds these limits, a new dose 
must be prepared from new vials.
At-home Investigational Product Handling
The entire carton of investigational product should be stored in the refrigerator. Subjects 
should be asked to ensure they have a normal domestic refrigerator at home, which should be 
between 2°C and 8°C.


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The subject is to remove from the refrigerator only the 1-vial kit required for their daily dose. 
All other kits are to be kept in the outer carton in the refrigerator until required. The subject 
is to avoid the risk of freezing the investigational product by carefully placing the 
investigational product within their refrigerator, and should not use investigational product if 
it has been frozen. The subject is not to administer investigational product if the time outside 
of the refrigerator has exceeded 24 hours; if storage time exceeds this limit, a new dose must 
be prepared from a new vial. After use, the subject is to retain the vial during the at-home 
self-administration period for return to the site (along with any unused vials) for 
accountability at the weekly visit. The subject should be instructed not to re-use the vial
(vials are single-use only) after administration of a single dose. Investigational product
should be protected from heat and light. The needle should always be removed and safely 
discarded after each use.
4.5.1.2
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. MEDI0382 is supplied as a 
liquid solution at a concentration of 2 mg/mL.
If there are any defects noted with the investigational product, the investigator and site 
Monitor should be notified immediately. Refer to the Product Complaint section for further 
instructions (Section 4.5.1.6).
4.5.1.3
Dose Preparation Steps
The final delivery volume and concentration for each dose level and the syringe sizes to be 
used for preparation are described in Table 4.5.1.3-1.
Table 4.5.1.3-1
MEDI0382 and Placebo Dose Preparation
Dose Level
Formulation Stock 
Concentration (mg/mL)
Volume of 
Injection (mL)
Number of 
Units b
Syringe Size 
50 μg or placebo
0.2
0.25 a
NA
1 mL
100 μg or placebo
2.0
0.05
5
0.3 mL
200 μg or placebo
2.0
0.1
10
0.3 mL
300 μg or placebo
2.0
0.15
15
0.3 mL
a
For the 50 μg dose, the stock concentration will be achieved by dilution in the clinic.
b
The 0.3-mL syringe is marked in “units” where each unit = 0.01 mL and 0.15 mL = 15 units.
No incompatibilities between MEDI0382 and plastics passing compatibility tests (ie, 
polyolefin or polyvinylchloride syringes) have been observed.


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1. Investigational product is supplied in 3-mL glass vials at a nominal concentration of
2 mg/mL.  
2. Determine from Table 4.5.1.3-1 the correct dose level and injection volume.
3. For doses of 50 ug a 10-fold diluted stock concentration of 0.2 mg/mL will be prepared
by site staff at the clinical unit, prior to administration.
4. To make a 10-fold diluted MEDI0382, it is recommended to take 0.1 mL of MEDI0382
investigational product using a needle and 1-mL syringe, add it into a sterile empty vial, 
followed by addition of 0.9 mL of diluent into the same vial using a needle and 1-mL 
syringe. The vial should be mixed by swirling gently to make a homogenous final 
admixture. Do not shake. The diluted dose should be administered using a 1-mL syringe.
The 100-μg, 200-μg, and 300-μg doses do not require a dilution step and should be 
administered using a 0.3-mL syringe. For the 50 μg dose, dilution steps will need to be 
carried out by site staff at the clinical unit.
At-home Dose Preparation Steps
No dilution steps for preparation of investigational product will be performed by the subject 
at home; all dilution steps will be performed at the study site. The 50-μg dose is always 
administered in the clinic.
4.5.1.4
Treatment Administration
If diluent is required: investigational product should be removed from the refrigerator and
kept at room temperature for at least 30 minutes and a maximum of 2 hours for temperature 
equilibration. If no diluent is required, 15 minutes is recommended for temperature 
equilibration.
In-clinic Treatment Administration
The first day of dosing is considered Day 1. On the day of each dose, investigational product
will be administered according to the schedule of procedures. On study days where fasting is 
required for an additional assessment, the investigational product should be taken 2.5 hours 
prior to any MMTT
 Investigational product will be 
administered by SC injection in the lower abdomen utilising either a 0.3-mL or a 1-mL
insulin syringe according to the dose level. Refer to the Investigational product manual.
At-home Treatment Administration
Investigational product should be removed from the refrigerator for at least 15 minutes for 
temperature equilibration.


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A once-daily dose is to be self-administered by SC injection using a 0.3-mL insulin syringe
as soon as practicable upon waking each morning prior to breakfast. The investigational 
product is packaged in a carton with sufficient vial kits. Each vial contains 1 mL of liquid 
product with adequate overfill. The carton must be stored in the refrigerator. Refer to the 
home dosing instructions.
If a dose of MEDI0382 or placebo is missed, subjects should take the dose 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 study drug at the next regularly scheduled time.
4.5.1.5
Monitoring of Dose Administration
As with any exogenous peptide delivered subcutaneously, allergic reactions to dose 
administration are possible. In prior experience with MEDI0382 there has been one injection 
site reaction and no anaphylactoid reactions. During visits to the clinical unit, the site of 
administration will be checked for signs of injection site reaction as required
(Section 4.3.2.2).
4.5.1.6
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone: +1-301-398-2105
+1-877-MEDI-411 (+1-877-633-4411)
Fax:
+1-301-398-8800
Mail:
MedImmune, LLC
Attn: Product Complaint Department
One MedImmune Way,
Gaithersburg, MD USA 20878


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4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Labeling…..…..
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. The label will fulfill GMP 
Annex 13 requirements for labeling. Label text will be translated into local languages, as 
required.
4.5.4
Storage…..
Store investigational product at the clinical site at 2°C to 8°C. Investigational product taken 
home by the subject must be stored in a refrigerator and must not exceed 25°C.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor 
compliance.
4.5.6
Accountability…..
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to
MedImmune. All unused investigational product will be returned to a MedImmune-
authorised depot or disposed of upon authorisation by MedImmune.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An interactive web response system (IWRS) will be used for randomisation to a treatment 
group and assignment of blinded investigational product kit numbers. A subject is considered 
randomised into the study when the investigator notifies the IWRS that the subject meets 
eligibility criteria and the IWRS provides the assignment of blinded investigational product 
kit numbers to the subject.
4.6.1.1
Cohort 1…..
Subjects will be randomised using a ratio of 2:1 to one of 2 treatment arms to receive either 
MEDI0382 titrated up to 300 μg or placebo. Sufficient subjects will be invited to participate 


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in the study such that a maximum of 26 will complete dosing in the active arm and 13 will 
complete dosing in the placebo arm.
4.6.1.2
Cohort 2…..
Subjects will be randomised using a ratio of 3:1 to receive either MEDI0382 titrated up to 
300 μg or placebo respectively. Sufficient subjects will be invited to participate in the study 
such that a maximum of 18 will complete dosing in the active arm and 6 will complete 
dosing in the placebo arm.
4.6.2
Methods for Ensuring Blinding
This is a double-blind study in which MEDI0382 and placebo are identically labeled and 
indistinguishable in appearance. As such, neither the subject nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects will be 
aware of the treatment received (ICH E9). (See Section 4.6.3.2 for unblinding related to the 
interim analysis.) In the event that treatment allocation for a subject becomes known to the 
investigator or other study staff involved in the management of study subjects, the sponsor 
must be notified immediately. 
4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IXRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
subject having received investigational product. In the majority of cases, the management of 
a medical emergency would be the same whether or not investigational product was received 
by the subject. If this was the case, the investigational product allocation should not be 
unblinded.
MedImmune retains the right to unblind the treatment allocation for SAEs that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities.
4.6.3.2
Unblinding for Interim Analysis Purposes
An interim analysis is planned for this study after the last subject has received their last dose 
as described in Section 4.8.6. Only the study team pharmacokineticist will be unblinded and 
only descriptive PK analyses will be performed. The unblinded pharmacokineticist will stop 


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day-to-day work on the study and other pre-selected personnel will take over these roles for 
the remainder of the trial.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the study (final study visit). Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.7.2. Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, 
antiemetics, anti-diarrhoeals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines.
4.7.2
Prohibited Concomitant Medications
Other than the medications described above, use of concomitant medications including over-
the-counter medications, herbal supplements, vitamin, etc at the times specified in the list 
below is not permitted. Subjects must be instructed not to take any medications, including 
over-the-counter products, without first consulting with the investigator.
Subjects should not be initiated on any new medications to control blood glucose levels 
during the dosing and follow-up period unless it is deemed necessary by the investigator for 
safety and following discussion with the medical monitor. Refer to Section 3.1.4.3 for further 
details.
•
Concurrent or previous use of a GLP-1 analogue containing preparation within the last 
30 days or 5 half-lives of the drug, whichever is longest, prior to the start of screening 
(Visit 1)
•
Concurrent use of any herbal preparations or medicinal products licensed for control of 
body weight or appetite and within 1 week prior to the start of the study (Visit 2)
•
Concurrent or previous use of drugs approved for weight loss (eg, orlistat, 
bupropion-naltrexone, phentermine-topiramate, phentermine, lorcaserin) and within the 
last 30 days or 5 half-lives of the drug, whichever is longest, prior to the start of the study 
(Visit 2)




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4.8.3
Efficacy…..
4.8.3.1
Primary Efficacy Analysis
The efficacy analysis will be based on the ITT population. The coprimary efficacy endpoints 
of percentage glucose AUC change and percentage weight change from baseline to 49 days 
(Section 2.1) will be compared between MEDI0382 and placebo arms, using an analysis of 
covariance (ANCOVA) model, adjusting for treatment and measurement at baseline.
4.8.3.2
Secondary Efficacy Analyses
For analyses of the secondary endpoints (Section 2.2), an ANCOVA model similar to the 
primary efficacy analysis will be used for continuous endpoints. For proportion-related 
endpoints, a logistic regression model will be used with fixed effects of treatment and 
baseline measurement. For the secondary endpoint evaluating glucose AUC reduction at the 
50 μg dose level, only glucose readings taken at 0, 15, 30, 45, 60, 90, 120, 180, and 
240 minutes will be used in this analysis.
4.8.3.3
Exploratory Analyses
For analyses of the exploratory endpoints (Section 2.3), an ANCOVA model similar to the 
primary efficacy analysis will be used for continuous endpoints. For proportion-related 
endpoints, a logistic regression model will be used with fixed effects of treatment and 
baseline measurement.
4.8.4
Safety…..
AEs and SAEs will be coded by the most updated version of Medical Dictionary for 
Regulatory Activities (MedDRA), and the type, incidence, severity, and relationship to study 
investigational product will be summarised by MedDRA System Organ Class and Preferred 


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Term and by treatment. AEs leading to discontinuation, AEs leading to death, and deaths will 
also be summarised and will be marked in the listings or will be in a separate listing. 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. 
4.8.4.1
Analysis of Clinical Laboratory Parameters
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. 
Mean ambulatory BP and heart rate measurements recorded over 24 hours at different time
points will be analysed using an ANCOVA model, adjusting for treatment and measurement 
at baseline. ADA incidence rate and titre will be tabulated for each treatment.
4.8.5
Analysis of Immunogenicity/Pharmacokinetics 
Pharmacokinetic parameters such as MEDI0382 Cmax, Tmax, AUC, and T1/2 will be estimated 
if data allow, from plasma concentration time data for MEDI0382 at the 50 and 300 μg dose 
level separately. 
Descriptive statistics will be generated for PK parameters for the MEDI0382 group in each 
cohort. Subjects who have at least one measurable concentration time point of investigational 
product will be used for this analysis.
The incidence and impact of ADA to MEDI0382 will be evaluated. The number and 
percentage of subjects with confirmed positive serum antibodies to MEDI0382 will be 
reported by dose level. Data on titres and cross-reactivity to GLP-1 and glucagon (where 
applicable) will be listed. If warranted by the data, the association of ADA positive with 
observed PK data may be explored.
4.8.6
Interim Analysis
An interim database lock for analysis of PK data only will be performed just after last subject 
last dose. Only the study team pharmacokineticist will be unblinded at this stage and will use 
the data to perform descriptive PK analyses. All other analyses will take place after final 
database lock. 


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5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for GCP E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. The term disease progression should not be reported as an AE or SAE;
however, medically significant individual events and/or laboratory abnormalities associated 
with disease progression (see definition of disease progression below) that fulfill the AE or 
SAE definition should be reported. An abnormal laboratory finding (including ECG finding) 
that requires medical intervention by the investigator, or a finding judged by the investigator 
as medically significant should be reported as an AE. If clinical sequelae are associated with 
a laboratory abnormality, the diagnosis or medical condition should be reported (eg, renal 
failure, hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood 
cell count increased). Abnormal laboratory values that are not, in the investigator's opinion, 
medically significant and do not require intervention should not be reported as AEs.
Adverse events may be treatment-emergent (ie, occurring after initial receipt of 
investigational product) or non-treatment emergent. A non-treatment-emergent AE is any 
new sign or symptom, disease, or other untoward medical event that begins after written 
informed consent has been obtained but before the subject has received investigational 
product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
5.2
Definition of Serious Adverse Events
An SAE is any AE that:


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•
Results in death
•
Is immediately life-threatening
•
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
•
Results in persistent or significant disability/incapacity 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalisations; or development of drug 
dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the investigational product and may require close monitoring and 
collecting additional information by the investigator and reporting to the sponsor. An AESI 
may be serious or nonserious. The rapid reporting of AESIs allows ongoing surveillance of 
these events in order to characterise and understand them in association with the use of this 
investigational product.
All AESIs should be recorded in the eCRF within 24 hours. In addition, AESIs that are also 
SAEs should be reported to the appropriate sponsor representative within 24 hours. 
Instructions to the site on how to record (in the eCRF) and report an AESI are provided in 
Section 5.3.1 and Section 10.5, respectively. The AESIs for this study are defined below. 
5.3.1
Hepatic Function Abnormalities
Refer to Section 5.6.2 and Section 10.5 for the definition and follow-up for liver 
abnormalities. There are no other AESIs in this study.
5.4
Recording of Adverse Events
Adverse events will be recorded on the eCRF using a recognised medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible aetiologies, and whether the 
event meets criteria of an SAE and therefore requires immediate notification to the sponsor 


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(Section 5.5). See Section 5.2 for the definition of SAEs and Section 10.3 for guidelines for 
assessment of severity and relationship. If an AE evolves into a condition that meets the 
regulatory definition of “serious,” it will be reported in the eCRF.
5.4.1
Time Period for Collection of Adverse Events
All AEs will be collected from the time of admission to the clinical unit (Day -2 for Cohort 1 
and Day -2 
 for Cohort 2) throughout 
the treatment period and including the follow-up period (7 to 14 days after the last dose of 
investigational product; Visit 10 for Cohort 1 [Table 4.2.2-1] and Visit 8 [Table 4.2.2-2] for 
Cohort 2). Additionally, all SAEs will be collected from time of signature of informed 
consent throughout the treatment period and including the follow-up period as described 
above. 
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
MedImmune retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. Updates regarding SAEs that were 
ongoing at the time of the subject’s completion of study participation should be submitted to 
the study representative using a paper SAE follow-up form.
5.5
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered casually related to the 
investigational product, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs during the course of the study, the investigator or other site personnel will 
inform the appropriate sponsor representative(s) within 1 day; ie, immediately but no later 
than 24 hours of when he or she becomes aware of the event.
The designated sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel will inform 
sponsor representatives of any follow-up information on a previously reported SAE within 


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1 calendar day; ie, immediately but no later than 24 hours of when he or she becomes aware 
of the event.
Once the investigator or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
representative(s).
If the EDC system is not available, then the investigator or other study site personnel report 
the SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose…..
An overdose in this study is defined as a subject receiving a dose of investigational product 
that is greater than the dose that was intended to be given:
•
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
•
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose with a MedImmune investigational product occurs during the course of the 
study, then the investigator or other site personnel inform appropriate sponsor representatives 
immediately, or no later than 24 hours after becoming aware of the event.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see 
Section 5.5. For other overdoses, reporting must occur within 30 days.
5.6.2
Hepatic Function Abnormality
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may 
need to be reported as SAEs. Refer to Section 10.5 for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s law.


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5.6.3
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.6.3.1
Maternal Exposure
Women of childbearing potential in this study who are sexually active with a nonsterilized 
male partner are required to use 1 form of contraception as described in the inclusion criteria. 
Pregnancy should be avoided for at least 28 days after receiving investigational product or 
until the subject completes participation in the study, whichever is longer. If a subject 
becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be 
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 inform the appropriate sponsor representatives within 1 day; ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided within 1 or 5 calendar days for SAEs (Section 5.5) and within 
30 days for all other pregnancies.
The same timelines apply when outcome information is available.
Any subject who becomes pregnant during the course of the study will be followed so that 
pregnancy outcome can be determined and reported to the sponsor and the regulatory 
authorities.
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 


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investigational staff and also train them in any study-specific procedures and system(s) 
utilised.
The principal investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:
•
Provide information and support to the investigator(s)
•
Confirm that facilities remain acceptable
•
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual, and that study drug accountability checks are 
being performed
•
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts).
•
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The principal investigator at each centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 


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terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between MedImmune and the principal investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through the last protocol-specified visit/assessment, regardless of the number of 
doses of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (Sections 4.1.5 and 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last subject in the study. 
6.4
Data Management 
Data management will be performed by MedImmune Data Management staff according to 
the Data Management Plan.
A web based data capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 


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emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the principal investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc will only be collected with the subject’s informed consent. The informed consent 
form (ICF) will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that describes how subject data will be collected, used, and 
distributed in compliance with relevant data protection and privacy legislation.
 
 
 
7.2
Ethics and Regulatory Review
The IEC responsible for each site must review and approve the final study protocol, 
including the final version of the ICF and any other written information and/or materials to 
be provided to the subjects. The IEC must also approve all advertising used to recruit 
subjects for the study. The investigator or representative is responsible for submitting these 
documents to the applicable IEC and distributing them to the study site staff.
The opinion of the IEC should be given in writing. The investigator should submit the written 
approval to MedImmune before enrolment of any subject into the study. 
The IEC should approve all advertising used to recruit subjects for the study.
MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the IEC annually.


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Before the study is initiated, MedImmune will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. 
MedImmune will provide safety updates/reports according to local requirements, including 
suspected unexpected serious adverse reactions where relevant, to regulatory authorities, 
IEC, and principal investigators.
Each principal investigator is responsible for providing the IEC with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with the 
investigational product. MedImmune will provide this information to the principal 
investigator so that he/she can meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. MedImmune will develop a core 
ICF for use by all investigators in the clinical study. MedImmune must approve any 
modifications to the ICF that are needed to meet local requirements.
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 they are free to discontinue from the study at any time
•
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
•
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study
•
Ensure the original, signed 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 IEC
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the principal
investigator and MedImmune.
Substantial changes must be documented in a study protocol amendment. MedImmune will 
distribute amended versions of the protocol to the principal investigator(s). Before 


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implementation, amended protocols must be approved by relevant IEC (Section 7.2) and
according to local requirements, the national regulatory authority approval. The IEC must 
also approve revisions to the ICF, advertising, and any other written information and/or 
materials resulting from the change to the protocol.
If local regulations require, any administrative change will be communicated to or approved 
by each IEC.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IEC 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 protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements. The investigator will contact MedImmune 
immediately if contacted by a regulatory agency about an inspection at the site.


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8
REFERENCES
Bagger et al, 2015
Bagger JI, Holst JJ, Hartmann B, Andersen B, Knop FK, Vilsbøll T. Effect of 
oxyntomodulin, glucagon, GLP-1, and combined glucagon +GLP-1 infusion on food intake, 
appetite, and resting energy expenditure. J Clin Endocrinol Metab. 2015;100(12):4541-52. 
CDER, 2005
Center for Drug Evaluation and Research. Byetta Pharmacology Review. 2005.9
Exenatide, 2016
Exenatide SmPc. Saxenda Prescribing Information. 2016. Available from: URL: 
http://www.novo-pi.com/saxenda.pdf.
Gagliardi et al, 2009
Gagliardi AC, Miname MH, Santos RD. Uric acid: a marker of increased cardiovascular risk. 
Atherosclerosis. 2009 Jan;202(1):11-7.
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. 
Keller and Shulman, 1979
Keller U, Shulman G. Effect of glucagon on hepatic fatty acid oxidation and ketogenesis in 
conscious dogs. Am J Physiol. 1979 Aug;237(2):E121-9.
 
 
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. 




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9
CHANGES TO THE PROTOCOL
9.1
Protocol Amendment 2, 17Oct2017
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. Key changes to the protocol are summarized in the table below. 
Table 9.1-1
Summary of Revisions to the Protocol
Key Details of Amendment
Reason for Amendment
Amendment 2 / 17Oct2017
Table 4.2.2-1 (Schedule of Treatment Period Study 
Procedures: Cohort 1)
Footnote “u” amended to clarify that a new CGM 
can be applied at any time on Day 36, and that the 
CGM sensor should be removed after 0800 hours on 
Day 50.
Table 4.2.1-1 (Schedule of Screening Procedures), 
Table 4.2.2-1 (Schedule of Treatment Period Study 
Procedures: Cohort 1), Table 4.2.2-2 (Schedule of 
Treatment Period Study Procedures: Cohort 2), 
Table 4.2.3-1 (Schudule of Follow-up Procedures) 
and Section 4.3.2.4 (Vital Signs)
Table footnotes and text in Section 4.3.2.4 amended 
to clarify that vital signs can be taken after a subject 
has rested for 10 minutes in a seated or supine 
position.
Table 4.2.2-1 (Schedule of Treatment Period Study 
Procedures: Cohort 1) and Table 4.2.2-2 (Schedule 
of Treatment Period Study Procedures: Cohort 2) 
Text added to clarify that the additional blood test for 
safety should be taken at any time between Day -7 
and Day -3, if required.
Table 4.2.2-2 (Schedule of Treatment Period Study 
Procedures: Cohort 2)
The instruction to fast on the night of Day 7 was 
removed from footnote “i” to correct a previous 
oversight.
Table 4.2.3-1 (Schedule of Follow-up Procedures)
Text referring to a postdose sample in footnote “b” 
was removed to correct a previous oversight.
Section 4.2.3.1 (Early Discontinuation Visit or 
Unscheduled Study Visit)
Text was edited to allow flexibility around the order 
of assessments based on site feedback.
Section 4.3.1.1 (Mixed-meal Tolerance Tests)
The timeframe to consume a standardised liquid 
meal was changed from “15 minutes” to “5 minutes” 
to correct a previous oversight.
Section 5.4.1 (Time Period for Collection of Adverse 
Events)
The timeframe of SAE collection was updated for 
consistency with internal MedImmune processes. 
Section 5.6.3.1 (Maternal Exposure)
Text was amended to state that women of 
childbearing potential in this study who are sexually 
active with a nonsterilized male partner are required 
to use 1 form of contraception. This change was 
made to correct a previous oversight and for
consistency with the inclusion criteria. 
Section 10.2 (Appendix 2-Contraception Guidance)
Text in bold added to the definition of 
postmenopausal to correct a previous oversight: 
“defined as at least 1 year since last menses and/or
having an elevated follicle-stimulating hormone level 
in the postmenopausal range in previous laboratory 
test results.”




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Table 9.2-1
Summary of Revisions to the Protocol
Key Details of Amendment
Reason for Amendment
sections of the protocol. The uptitration schedule 
was also corrected from Day 14 to Day 15.
Footnote describing timings for MMTT Type A and 
Type B was corrected to be consistent with other 
sections of the protocol.
Correction of typographical errors.
Screening blood samples were added at the request 
of the ethics committee.
Section 4.3.1.1 Mixed-meal Tolerance Tests
Text describing the timing of consumption of Ensure 
Plus (within 15 minutes) was clarified to be 
consistent with other sections of the protocol.
Correction of typographical error.
Section 4.3.2.4 Vital Signs
Corrected to state that vital signs measurements will 
be taken with the subject in a seated position.
Correction of typographical error.
Table 4.5.1.3-1 MEDI0382 and Placebo Dose 
Preparation
The number of units for the 300 μg dose was 
corrected to 15.
The example given for units calculation has been 
changed to be consistent with the table for clarity.
Correction of typographical error.
Section 4.5.1.4 Treatment Administration
Clarification that investigational product will be 
administered by SC injection in the lower abdomen 
utilising either a 0.3-mL or a 1-mL insulin syringe 
according to the dose level.
Correction of typographical error.
Section 4.3.8 Blood Volumes
Total blood volumes to be drawn in both cohorts 
have been reduced. 
Section 4.7.2 Prohibited Concomitant Medication
Additional guidance around the allowed use of 
concomitant medications to control blood glucose 
were added at the request of the ethics committee.
Section 4.8.2 Sample Size and Power Calculations
The overall power for both primary endpoints was 
added at the request of the ethics committee.
Table 10.2-1 Highly Effective Methods of 
Contraception
The table has been modified to remove reference to 
oral contraceptives at the request of the ethics 
committee.


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10 APPENDICES
10.1
Appendix 1 - Signatures
Sponsor Signature(s)
A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, 
Safety, Tolerability, and Pharmacokinetics of Different Doses of MEDI0382 in Overweight 
and Obese Subjects with Type 2 Diabetes Mellitus
I agree to the terms of this protocol.
Signature and date: 
Electronic signature attached
One MedImmune Way, Gaithersburg MD, 20878, USA


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Signature of Principal Investigator
A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, 
Safety, Tolerability, and Pharmacokinetics of Different Doses of MEDI0382 in Overweight 
and Obese Subjects with Type 2 Diabetes Mellitus
I, the undersigned, have reviewed this protocol and all amendments, and I agree to conduct 
this protocol in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and are consistent with the ICH guidelines on Good Clinical Practice (GCP), any 
applicable laws and requirements, and any conditions required by a regulatory authority 
and/or Independent Ethics Committee (IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and IEC, 
and must be approved by the IEC prior to implementation except when necessary to 
eliminate immediate hazards to the subjects or when the change(s), as deemed by the 
sponsor, involves only logistical or administrative changes. Documentation of IEC approval 
must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:  
Address including postal code: 
  
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.


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10.2
Appendix 2 – Contraception Guidance
For females of childbearing potential:
•
Females of childbearing potential are defined as those who are not surgically sterile (ie, 
surgical sterilisation includes bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or those who are not postmenopausal (defined as at least 1 year since last 
menses and/or having an elevated follicle-stimulating hormone level in the 
postmenopausal range in previous laboratory test results).
A highly effective method of contraception is defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly. The acceptable methods of 
contraception are described in Table 10.2-1.
Female subjects must refrain from egg cell donation while in study and for 28 days after the 
final dose of investigational product.
Table 10.2-1
Highly Effective Methods of Contraception
•
Tubal occlusion
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system (eg, Mirena®)
•
Medroxyprogesterone injections (eg, Depo-Provera®)
•
Etonogestrel implants (eg, Implanon®, Norplan®)
•
Norelgestromin/ethinyl estradiol transdermal system
•
Intravaginal device (eg, NuvaRing®)


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10.3
Appendix 3 - Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from 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 edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result 
in death, hospitalisation, disability or incapacity but may jeopardize the subject or may 
require medical intervention to prevent one or more outcomes listed in the definition of 
serious. These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; 
medical judgment must be used.
Examples of such events are:
•
Angioedema not severe enough to require intubation but requiring intravenous 
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) or convulsions 
that do not result in hospitalisation
•
Development of drug dependency or drug abuse


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


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


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10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases
and Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Disease (NAID) and Food Allergy and 
Anaphylaxis Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid 
in onset and may cause death. They recognise 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis 
(for all 3 categories). 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalised hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxaemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, swollen 
lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxaemia)
c.
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline


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10.5
Appendix 5 - Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law. It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) 
criteria are met. HL criteria are met if there is no alternative explanation for the elevations in 
liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the investigational 
product. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting adverse events (AE) and serious adverse events (SAE) according to the outcome of 
the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase or ALT ≥ 3 × upper limit of normal (ULN) together with total 
bilirubin (TBL) ≥ 2 × ULN at any point during the study following the start of investigational
product irrespective of an increase in alkaline phosphatase (ALP).
Hy’s Law (HL)
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no 
other reason, other than the investigational product, can be found to explain the combination 
of increases; eg, elevated ALP indicating cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on 
the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.


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Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:
•
ALT ≥ 3 × ULN
•
AST ≥ 3 × ULN
•
TBL ≥ 2 × ULN
The investigator will without delay review each new laboratory report and if the 
identification criteria are met will:
•
Notify the sponsor study representative
•
Determine whether the subject meets PHL criteria by reviewing laboratory reports from 
all previous visits
•
Promptly enter the laboratory data into the laboratory eCRF
Follow-up
Potential Hy’s Law Criteria Are Not Met
If the subject does not meet PHL criteria the investigator will:
•
Inform the sponsor representative that the subject has not met PHL criteria
•
Perform follow-up on subsequent laboratory results according to the guidance provided 
in the Clinical Study Protocol.
Potential Hy’s Law Criteria Are Met
If the subject does meet PHL criteria the investigator will notify the sponsor study 
representative who will then inform the central study team. The Study Physician contacts the 
investigator, to provide guidance, discuss and agree an approach for the study subjects’ 
follow-up and the continuous review of data. Subsequent to this contact the investigator will:
•
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated 
•
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician 


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•
Complete the Liver eCRF Modules as information becomes available 
•
If at any time (in consultation with the Medical Monitor) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Medical 
Monitor will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
investigational product. The Clinical Medical Monitor and Global Safety Physician will also 
be involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
•
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF
•
If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF accordingly 
and follow the sponsor standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:
•
Report an SAE (report term ‘Hy’s Law’) according to sponsor standard processes. 
◦
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply
◦
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:


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•
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above
•
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM174090.pdf


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10.7
Appendix 7 Biological Samples
Storage, Re-use and Destruction of Biological Samples
Biological 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 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 study drug to generate hypotheses 
to be tested in future research. ADA samples will be stored for up to 2 years after marketing 
approval.
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).
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with MedImmune and appropriate 
labelling, shipment and containment provisions are approved.
Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The principal investigator at each study site keeps full traceability of collected biological 
samples from the subjects while in storage at the study site 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.
MedImmune 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 Translational Sciences Biorepository
during the entire life cycle.



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Statistical Analysis Plan 
A Phase 2, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy, Safety, Tolerability, and Pharmacokinetics of Different Doses of MEDI0382 in 
Overweight and Obese Subjects with Type 2 Diabetes Mellitus 
 
Protocol Number: D5670C00011 
 
 


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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 
2.1.3Exploratory Study Objectives .......................................................................5 
2.2 
Study Design .........................................................................................................6 
2.3 
Treatment Assignment and Blinding ....................................................................7 
2.4 
Sample Size...........................................................................................................7 
3 
STATISTICAL METHODS ...........................................................................................8 
3.1 
General Considerations .........................................................................................8 
3.2 
Analysis Populations.............................................................................................8 
3.3 
Study Subjects.......................................................................................................9 
3.3.1Subject Disposition and Completion Status .................................................9 
3.3.2Demographics and Baseline Characteristics .................................................9 
3.3.3Study Drug Exposure ....................................................................................9 
3.3.4Concomitant Medications .............................................................................9 
3.4 
Efficacy Analyses ...............................................................................................10 
3.4.1Primary Efficacy Endpoint(s) and Analyses ...............................................10 
3.4.1.1 
Primary Efficacy Endpoint(s) ...................................................10 
3.4.1.2 
Primary Efficacy Analysis ........................................................10 
3.4.2Secondary Efficacy Endpoint(s) and Analyses ...........................................10 
3.4.2.1 
Secondary Efficacy Endpoint(s) ...............................................10 
3.4.2.2 
Secondary Efficacy Analyses ...................................................10 
3.4.3Other Efficacy Analyses .............................................................................11 
3.5 
Exploratory Pharmacodynamic Endpoint(s) and Analyses ................................11 
3.5.1.1 
Pharmacodynamic Endpoint(s) .................................................11 
3.5.1.2 
Analysis of Pharmacodynamic Endpoint(s) .............................12 
3.6 
Safety Analyses...................................................................................................13 
3.6.1Adverse Events and Serious Adverse Events .............................................13 
3.6.2Adverse Events of Special Interest .............................................................14 
3.6.3Deaths and Treatment Discontinuations due to Adverse Events ................14 
3.6.4Clinical Laboratory Evaluations .................................................................14 
3.6.5Vital Signs ..................................................................................................14 
3.6.6Electrocardiogram .......................................................................................15 
3.7 
Immunogenicity ..................................................................................................15 
3.8 
Pharmacokinetics ................................................................................................16 


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4 
INTERIM ANALYSIS..................................................................................................17 
5 
VERSION HISTORY ...................................................................................................17 
 
LIST OF FIGURES AND TABLES 
Figure 2.2-1 
Study Flow Diagram ..............................................................................6 
Table 3.2-1 
Analysis Populations ..............................................................................8 
 


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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
ABPM
Ambulatory blood pressure monitoring
ADA
Anti-drug antibody
AE
Adverse event
ANCOVA
Analysis of covariance
ATC
Anatomical Therapeutic Chemical
AUC
Area under the concentration-time curve
BMI
Body mass index
CGM
Continuous glucose monitoring
CV
Coefficient of variation (standard deviation/mean)
eCRF
electronic Case Report Form
ECG
Electrocardiogram
FFA
free fatty acids
GLP-1
Glucagon-like peptide-1
hr
hours
IM
Immunogenicity
ITT
Intent-to-Treat
IWRS
Interactive web response system
LOCF
Last observation carried forward
MMTT
Mixed-meal tolerance test
msec
milliseconds
PD
Pharmacodynamics
PK
Pharmacokinetics
PT
Preferred Term
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SID
Subject identification number
SOC
System Organ Class
SPP
Statistical programming plan
T2DM
Type 2 diabetes mellitus
ULN
Upper limit of normal reference range


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1
INTRODUCTION
This document describes the statistical analysis methodology for protocol D5670C00011, a 
phase 2a study to evaluate the efficacy, safety, tolerability, and pharmacokinetics (PK) of 
different doses of MEDI0382 in overweight and obese subjects with Type 2 Diabetes 
Mellitus. The main portion of this document details the statistical summaries relating to each 
study objective and describes the general conventions and definitions that will be used. In 
addition, a set of table templates and specifications will be included in a statistical 
programming plan (SPP) to complement this document.
2
STUDY OVERVIEW
2.1
Study Objectives
2.1.1
Primary Study Objective(s)
To assess the effects of MEDI0382 titrated up to a dose level of 300 μg on glucose control 
and body weight versus placebo after 49 days of treatment (Cohort 1 only).

2.1.2
Secondary Study Objectives
x
To assess the effects of MEDI0382 titrated up to a dose level of 300 μg on additional 
measures of glucose control and body weight versus placebo after 49 days of 
treatment (Cohort 1 only).
x
To characterize the safety profile and tolerability of MEDI0382 titrated up to a dose 
level of 300 μg during dosing and follow-up (Cohorts 1 and 2).
x
To characterize the PK profile and immunogenicity of 50 and 300 μg of MEDI0382 
(Cohorts 1 and 2).
x
To characterize the effect of 50 μg of MEDI0382 on glucose lowering versus placebo 
after 7 days (Cohorts 1 and 2).
2.1.3
Exploratory Study Objectives
x
x
To assess gastrointestinal tolerability across different titration schedules (Cohorts 1
and 2).
x
To assess the effect of MEDI0382 on glucose lowering during different meals and 
times of the day as measured by continuous glucose monitoring (CGM) (Cohort 1 
only).
x
To characterize the effect of MEDI0382 on glucose lowering and weight versus 
placebo after 7, 14 and 49 days (Cohort 2 only).
x
To assess the effect of MEDI0382 on pancreatic and incretin hormone profiles at 
baseline and during the mixed-meal tolerance test (MMTT) (Cohorts 1 and 2).
x
To assess the effect of MEDI0382 on ketone bodies, amino acids, and free fatty acid 
(FFA) levels over 49 days of treatment (Cohort 1 only).


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x
To assess the effect of MEDI0382 on uric acid 
(Cohort 
1 only).
2.2
Study Design
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, 
tolerability, and PK profile of 50 and 300 μg of MEDI0382 in overweight and obese subjects 
with T2DM. Up to 63 subjects are planned to be enrolled across multiple study sites. The 
study is divided into 2 cohorts that will be recruited in parallel; for both cohorts, subjects will 
be consented, screened for suitability, and randomized within 60 days if eligible. A total of
39 subjects will be randomized to Cohort 1, and 24 subjects will be randomized to Cohort 2. 
Cohort 1 will evaluate the efficacy, safety, tolerability, and PK of MEDI0382 when titrated 
up in weekly intervals from 50 to 300 μg and administered over 49 days. Cohort 2 will 
explore an alternative 2-week titration schedule, and will provide additional information on
the PK profile and glucose-lowering efficacy of 50 μg MEDI0382 
. Each dose is administered as an SC injection 
each morning according to the dosing schedule is presented below:
Figure 2.2-1
Study Flow Diagram


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2.3
Treatment Assignment and Blinding
An interactive web response system (IWRS) will be used for randomization to a treatment
group and assignment of blinded investigational product kit numbers. A subject is considered
randomized when the IWRS provides the assignment of blinded investigational product kit 
numbers for the subject.

In Cohort 1, subjects will be randomized using a ratio of 2:1 to one of 2 treatment arms to 
receive either MEDI0382, titrated from 50 μg up to 300 μg according to a fixed schedule, or
placebo for 49 days.
In Cohort 2, subjects will be randomized using a ratio of 3:1 to receive either MEDI0382,
titrated from 50 μg up to 300 μg according to a different fixed schedule, or placebo for 49 
days. 
This is a double-blind study in which MEDI0382 and placebo are identically labeled and 
indistinguishable in appearance so that neither the subject nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects or data 
analysis will be aware of the treatment received (ICH E9).
2.4
Sample Size
For Cohort 1, 26 subjects in the MEDI0382 arm and 13 subjects in the placebo arm will 
provide 97% power to detect 28% glucose AUC change-from-baseline difference between 
MEDI0382 300 μg and placebo, assuming a standard deviation of 20%. It will also provide 
85% power to detect 2.3% difference of percentage change of body weight versus placebo, 
assuming a standard deviation of 2.2%. From the two cohorts, the combined 44 subjects in 


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the MEDI0382 arms and 19 subjects in the placebo arms can also provide 80% power to 
detect 12% glucose AUC change-from-baseline difference between MEDI0382 50 μg and 
placebo at Day 7.
3
STATISTICAL METHODS
3.1
General Considerations
Data will be presented in data listings sorted by cohort and treatment, subject number and 
date collected, where appropriate. Tabular summaries will be presented by cohort and 
treatment group. Categorical data will be summarized by the number and percentage of 
subjects within each category. In general, continuous variables will be summarized by 
descriptive statistics including mean, standard deviation, median, minimum, and maximum. 
The last observation carried forward (LOCF) will be used in efficacy and pharmacodynamics 
(PD) endpoints analyses unless otherwise specified. Baseline values will be defined as the 
last valid assessment prior to the first administration of study treatment unless otherwise 
specified.
All statistical tests will be 2-sided at an alpha = 0.1 significance level unless stated otherwise.
There will be no adjustment for multiplicity.
Data analyses will be performed using SAS
® version 9.3 or higher (SAS Institute Inc., Cary, 
NC).
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 investigational product will be included in the ITT 
population and subjects will be analyzed according to their randomized treatment group.
As-treated
population
Subjects who receive any study investigational product will be included in the as-treated 
population will be analyzed according to the treatment they received.
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 with a value above the lower limit of 
quantitation.
PD population
The PD population includes all subjects who received at least one dose of investigational 
product and had at least one post-baseline PD sample or PD evaluation 


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3.3 
Study Subjects 
3.3.1 
Subject Disposition and Completion Status 
A summary of subject eligibility and randomization as well as treatment group received 
(including summary of subjects randomized but not treated) will be provided. In addition, 
disposition of subjects throughout the study with respect to completion of treatment and 
follow-up will be provided. 
3.3.2 
Demographics and Baseline Characteristics 
Demographic information and baseline characteristics will be summarized by cohort and by 
treatment group. Demographic information will include: gender, age (years), ethnicity, race, 
weight (kg), height (cm), and body mass index (BMI) (kg/m2). A summary of baseline 
characteristics may include but not limited to eGFR, HbA1c, glucose, insulin, blood pressure, 
and pulse rate etc. 
BMI= weight (kg) / [height (m)]2 
All summaries of continuous characteristics will be based on non-missing observations. For 
categorical characteristics, percentage will be calculated, and the denominator for each 
percentage is the number of subjects with non-missing data for that demographic or baseline 
parameter. 
No statistical test will be performed for comparison of any baseline measurement among 
treatment groups. 
3.3.3 
Study Drug Exposure 
The number of doses and total dose received will be summarized for each investigational product 
(MEDI0382 or Placebo) by descriptive statistics and by frequency. 
3.3.4 
Concomitant Medications 
Concomitant medications will be coded using current WHO Drug Dictionary. The number 
and percentage of subjects who took concomitant medications will be summarized by the highest 
anatomical therapeutic chemical (ATC) class and preferred term by treatment group for each 
cohort for the As-treated Population. The summary of concomitant medications will include all 
concomitant medications taken on or after the date of first dose of investigational product or any 
concomitant medication started prior to first dose of investigational product that continued 
beyond the date of first dose of investigational product. 


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3.4 
Efficacy Analyses 
3.4.1 
Primary Efficacy Endpoint(s) and Analyses 
3.4.1.1 
Primary Efficacy Endpoint(s) 
The co-primary endpoints for this trial are: 
1. Percentage change in plasma glucose AUC0-4hr as measured by a standardized MMTT 
from baseline (Day -1) to the end of 49 days of treatment (Day 49) 
2. Percentage change in body weight from baseline (Day 1) to the end of 49 days of 
treatment (Day 50) 
3.4.1.2 
Primary Efficacy Analysis 
The percent change in the MMTT plasma glucose AUC0-4mmtt from the baseline (Day -1) 
evaluation to the Day 49 evaluation will be analyzed with an analysis of covariance 
(ANCOVA) with an effect for treatment (MED0382 or Placebo) and the baseline MMTT 
glucose AUC0-4hr value used as a covariate (Cohort 1). 
The percent change in body weight from baseline (Day 1) to the Day 50 evaluation will also 
be analyzed with an ANCOVA with an effect for treatment (MED0382 or Placebo) and the 
baseline body weight used as a covariate (Cohort 1). 
Both comparisons will be performed at the 0.05 significance level (2-sided).   
3.4.2 
Secondary Efficacy Endpoint(s) and Analyses 
3.4.2.1 
Secondary Efficacy Endpoint(s) 
1. Change in HbA1c from baseline (Day -1) to the end of 49 days of treatment (Day 49) 
(Cohort 1) 
2. Change in fasting plasma glucose (Day -1) from baseline to the end of 49 days of 
treatment (Day 49) (Cohort 1) 
3. Change in body weight (kg) from baseline (Day 1) to the end of 49 days of treatment 
(Day 50) (Cohort 1) 
4. Proportion of subjects achieving > 5% body weight loss from baseline (Day 1) after 
49 days of treatment (Day 50) (Cohort 1) 
5. Percent change in MMTT plasma glucose AUC0-4hr from baseline (Day -1) to Day 7 
(Cohorts 1 and 2 combined) 
3.4.2.2 
Secondary Efficacy Analyses 
All analyses will be performed at the 0.05 (2-tailed) significance level unless otherwise 
specified. 


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The changes from baseline in HbA1c, fasting plasma glucose, and body weight will be 
analyzed using an ANCOVA with an effect for treatment and the corresponding baseline 
measure as a covariate.  The pre-meal plasma glucose values from the MMTT are used for 
the fasting plasma glucose values. The proportion of subjects who have a >5% decrease in 
body weight will be analyzed with logistic regression with treatment effect and the baseline 
weight as a covariate.
The percent change in MMTT glucose AUC from baseline to Day 7, including data from 
both cohorts, will be analyzed with an ANCOVA with treatment effect and the baseline value 
used as a covariate.
3.4.3
Other Efficacy Analyses
For Cohort 2 data, the percent change in the MMTT plasma glucose AUC0-4hr from the 
baseline (Day -1) evaluation to the Day 7, Day 14, and Day 49 evaluations will be 
summarized by visit and analyzed for the end-of-treatment measure at Day 49 only with a 
similar ANCOVA model as that in the primary analysis.
Similar summary and analysis will be also applied to the change in fasting plasma glucose
from baseline (Day -1) to the Day 7, Day 14, and Day 49 evaluations (Cohort 2 only), the 
change and percent change in body weight from baseline (Day 1) to the Day 8, Day 15, and
Day 50 evaluations (Cohort 2 only), and the change in HbA1c from baseline (Day -1) to the
Day 49 evaluations.
3.5
Exploratory Pharmacodynamic Endpoint(s) and Analyses
3.5.1.1
Pharmacodynamic Endpoint(s)
x
x
Change in CGM glucose AUC0-24h from baseline (Day -1) to the end of each dosing 
level for titration and treatment (Cohort 1 only)
x
Change in coefficient of variation (CV) (ratio of standard deviation: mean) of CGM 
glucose values over 24 hours from baseline (Day -1) to the end of each dosing level 
for titration and treatment (Cohort 1 only)
x
CV of CGM glucose values over 7 days at each dose level (Days 1 to 7, Days 8 to 14, 
Days 15 to 21, and Days 22 to 28) (Cohort 1 only)
x
Change in percentage of time in hyperglycemia (defined as > 7.8 mmol/l or > 140 
mg/dl as measured by CGM) over 24 hours from baseline (Day -1) to the end of each 
dosing level for titration and treatment periods (Cohort 1 only)
x
Change in percentage of time in hypoglycemia (defined as < 3 mmol/l or < 54 mg/dl
as measured by CGM) over 24 hours from baseline (Day -1) to the end of each dosing 
level for titration and treatment periods (Cohort 1 only)


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x
Percentage of time in hyperglycemia (defined as > 7.8 mmol/l or > 140 mg/dl as 
measured by CGM) over 7 days at each dose level (Days 1 to 7, Days 8 to 14, Days 
15 to 21, and Days 22 to 28) (Cohort 1 only)
x
Percentage of time in hypoglycemia (defined as < 3 mmol/l or < 54 mg/dl as 
measured by CGM) over 7 days at each dose level (Days 1 to 7, Days 8 to 14, Days 
15 to 21, and Days 22 to 28) (Cohort 1 only)
x
CGM glucose AUC0-4hr during MMTT (type A) on baseline (Day -1) and Day 49 and 
during MMTT (type B) on Day 7 (Cohort 1 only)
x
CGM glucose AUC0-2hr during morning MMTT (type A) on baseline (Day -1) and
Day 49 (Cohort 1 only)
x
CGM glucose AUC0-2hr during evening MMTT (type C) on baseline (Day -1) and 
Day 49 (Cohort 1 only)
x
The change in insulin AUC0-4hr, glucagon AUC0-4hr, and active and total (the sum of 
active and inactive GLP-1) GLP-1 AUC0-4hr from baseline (Day -1) to Day 49 
(Cohort 1 and 2)
x
The change in pre-meal (i.e., time 0 basal/fasting) values of insulin, glucagon, and 
active and total (the sum of active and inactive GLP-1) GLP-1 from baseline (Day -1)
to Day 49 (Cohort 1 and 2)
For Cohort 1 only, the fasting plasma insulin value on Day 7 will also be summarized
x
The change in fasting C-peptide from baseline (Day -1) to Day 7 and Day 49 (Cohort 
1 only)
x
The change in serum beta-hydroxybutyrate concentration from baseline (Day -1) to 
Days 22 and 49 (pre-dose and 4 hr post-dose) (Cohort 1 only)
x
The change in capillary blood ketone concentration from baseline (Day -1) to Days 
22 and 49 (pre-dose and 4 hr post-dose) (Cohort 1 only)
x
The change in free fatty acids from baseline (Day -1) to Day 49 (Cohort 1 only)
x
The change in fasting amino acids from baseline (Day -1) to Day 49 (Cohort 1 only)
x
The change in uric acid from baseline (Day -1) to Day 49 (Cohort 1 only)
x
3.5.1.2
Analysis of Pharmacodynamic Endpoint(s)
All of the PD measures will be summarized by scheduled visits. Except for the analyses 
specified in the following of this section, all of the other PD endpoints will be analyzed for 
the end-of-treatment measure only using similar ANCOVA model as that in the primary 
analysis. Treatment effect and baseline value (if available) will be added in the model.  
The CV of CGM glucose values over 7 days at each dose level will be analyzed with a 2-
sample t-test (assuming equal variance).
The change in percentage of time in hyperglycemia and hypoglycemia over 24 hours from 
baseline (Day -1) to Day 49 will be analyzed with the Wilcoxon rank sum test.


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The percentage of time in hyperglycemia and hypoglycemia over 7 days at each dose level 
will be analyzed with the Wilcoxon rank sum test.
The morning (type A) and evening (type C) MMTT CGM glucose AUC0-2hr on baseline (Day 
-1) and Day 49, will be summarized. Their difference and agreement will be analyzed by the 
paired t-test and the concordance correlation coefficient, respectively. The CGM glucose 
AUC0-4hr during MMTT on baseline (Day -1), Day 7, and Day 49, and the corresponding 
plasma glucose AUC0-4hr will be summarized and analyzed in a similar manner.
3.6
Safety Analyses
The analyses will be based on the As-treated population. All safety summaries will be 
presented by treatment group for each cohort, unless otherwise specified.
3.6.1
Adverse Events and Serious Adverse Events
Adverse events (AE) will be coded by MedDRA version 20.0 or higher. Analysis of adverse 
events will include the type, incidence, severity and relationship to study investigational 
product summarized by MedDRA System Organ Class (SOC) and Preferred Term (PT) by 
treatment group for each cohort as well as for overall treatments. The AEs summaries will 
include only treatment-emergent AEs, i.e., those occurring after initial receipt of 
investigational product. Subjects will be counted once for specific PT or MedDRA SOC
when calculating incidence. If the same AE Preferred Term occurs multiple times within a 
subject, the highest severity and level of relationship observed will be reported. Non
treatment-emergent AEs/serious adverse events (SAEs) will be presented in the listings.
The number and percentage of subjects with nausea, vomiting, and either nausea or vomiting
will be summarized daily for first 7 days of treatment. For MEDI0382 only, the above three 
endpoints over the first 7 days for two cohorts combined will be summarized. In addition, 
two-sided 80% confidence intervals of the percentages will also be reported using exact 
method.


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3.6.2 
Adverse Events of Special Interest 
Hepatic function abnormality meeting the definition of Hy’s law is considered an adverse 
events of special interest.  Number and proportion of subjects who meet Hy’s law criteria: 
AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN will be summarized by 
treatment and cohort. 
3.6.3 
Deaths and Treatment Discontinuations due to Adverse Events 
Death and AEs resulting in permanent discontinuation from the study drug will be 
summarized by treatment and cohort. The summary includes overall, categorized by 
MedDRA system organ class, and preferred term. 
3.6.4 
Clinical Laboratory Evaluations 
Hematology, serum chemistry, and urinalysis laboratory evaluations will be performed 
during the study. The hematology and serum chemistry (including calcitonin, lipase, and 
amylase) parameters as well as their changes from baseline will be summarized with 
descriptive statistics (number of subjects, mean, and standard deviation, median, minimum 
and maximum) by treatment group at each of the time points specified in Treatment and 
Follow-up Period Study Procedures in the protocol. The urinalysis results will be listed. The 
hematology and serum chemistry results will also be classified as low, normal, or high. The 
urinalysis results will be classified as normal or abnormal. The shift from baseline 
hematology, serum chemistry, and urinalysis results will be summarized by treatment group 
at each of specified time points. 
3.6.5 
Vital Signs 
Vital signs including pulse rate (beats/min), systolic and diastolic blood pressure (mmHg), 
temperature (oC), weight (kg), and respiratory rate (breaths/min), as well as the change from 
baseline for each of those parameters will be descriptively summarized by treatment group at 
each of the specified time points in the protocol. 
The 24-hour average ambulatory blood pressure monitoring (ABPM) pulse rate (beats/min) 
and systolic and diastolic blood pressure (mm Hg) from the ABPM will be summarized by 
treatment group at each visit (Days -2, 22, 29, 36, 43, and 49) performed. The change from 
baseline (Day -2) for the 24-hour average pulse rate and systolic and diastolic blood pressure 
at each post-baseline visit will be analyzed with an ANCOVA with an effect for treatment 
and the baseline value as the covariate. The above summary and analyses will also be 
conducted for PR, SBP and DBP during asleep and awake periods.  


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3.6.6 
Electrocardiogram 
Electrocardiogram parameters will be assessed using standard 12-lead electrocardiography. 
The following ECG parameters as well as the change from baseline for each of those 
parameters will be reported and descriptively summarized by treatment group at each of the 
specified time points: Heart rate (beats/min), RR (msec), PR (msec), QRS (msec), and QT 
(msec) intervals and the QT corrected interval. 
The normality/abnormality of the ECG evaluation will be summarized using frequency tables 
of the number of subjects with a normal/abnormal ECG evaluation at each scheduled visit. A 
listing of subjects will be produced which will display all ECG findings in subjects with 
abnormal ECGs. 
 
3.7 
Immunogenicity 
All subjects in the safety analysis set with reported anti-drug antibody (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. 
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 


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Similar summary will be performed for ADA cross-reactivity to GLP-1 and/or glucagon (as 
data allows and if applicable). 
The association of ADA status with PK, PD endpoints, efficacy, and safety may be evaluated 
if data allows and if applicable.  
3.8 
Pharmacokinetics 
The analysis of the PK data is described below. 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. 
For subjects in each active treatment group the following pharmacokinetic parameters will be 
determined from the plasma concentration-time data for MEDI0382 if data allow. The 
pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using Phoenix WinNonlin 6.3 or equivalent. All 
calculations of non-compartmental parameters will be based on actual sampling times. 
The following PK parameters of MEDI0382 will be determined if data allow for each subject 
from the plasma concentration–time data: 
1. Cmax: The first occurrence of the maximum observed plasma concentration 
determined directly from the raw concentration-time data 
2. tmax: The first time at which Cmax is observed will be determined directly from the raw 
concentration-time data. 
3. CW: trough concentrations from the plasma concentration-time data at the end of the 
dosing interval (i.e. 24 hours). 
4. t half: The apparent terminal elimination half-life (t1/2) obtained as the ratio of ln2/Oz, 
where Oz is the terminal phase rate constant estimated by linear regression analysis of 
the log transformed concentration-time data 
5. AUCτ: Area under the plasma concentration time curve at the end of the dosage 
interval τ. 
6. Ro: observed accumulation ratio will be calculated using both the AUC and Ctrough 
methods, where data allows, as follows: Ro = AUCWdayi/AUCWday1 and Ro = 
CWdayi/CWday1. 
All the derived parameters described above will be listed. For each of these parameters, 
except tmax, the following summary statistics will be calculated for each active treatment 
group: median, maximum, minimum, arithmetic mean, standard deviation, CV, geometric 
mean. For tmax  median, maximum, minimum, arithmetic mean.  


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Individual Ctrough will be listed by cohort, treatment and day and will be summarized as 
maximum, minimum, arithmetic mean and geometric mean. 
4 
INTERIM ANALYSIS 
The analysis of the PK data will be conducted after the last subject has completed his/her last 
dose and all pharmacokinetic samples have been collected. The PK scientist will be 
unblinded and create descriptive summaries of the PK data, and once being unblinded the PK 
scientist will not be involved in the day-to-day study work until the final data base lock. 
5 
VERSION HISTORY 
Version 
Date 
Summary of Changes 
Reason for Change 
1.0 
08Sep2017 
Initial document 
Initial document