Clinical trial NCT03555994
Conditions: Type 2 Diabetes Mellitus
Keywords: 0382, T2DM, Cotadutide, Overweight, Obese, MEDI0382
Sponsor: MedImmune LLC
Start date: 2018-05-31; Completion date: 2021-04-14
Enrollment: 51 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A phase 2 study in two parts (A \& B) designed to evaluate the effect of MEDI0382 on Hepatic Glycogen Metabolism in subjects with Type 2 Diabetes Mellitus (T2DM). Approximately 20 subjects will be enrolled in Part A and approximately 30 subjects in Part B.

Detailed description:
This is a 2-part exploratory Phase 2 study.

Part A is a randomised, double-blind, placebo-controlled study to evaluate the effect of MEDI0382 (also known as Cotadutide) administered once daily subcutaneously (SC) for 28 days on hepatic glycogen metabolism in overweight and obese subjects with T2DM. Part A is planned to randomise up to 20 subjects. Subjects from Part A will not be re-enrolled in Part B.

Part B is an exploratory Phase 2 randomised, double-blind, placebo-controlled and open-label active comparator study to evaluate the effect of MEDI0382 on hepatic glycogen metabolism in overweight and obese subjects with T2DM. Part B is planned to randomise approximately 30 subjects (not to exceed a maximum of 35 subjects). Subjects in Part B will be randomised to receive double-blind MEDI0382 or placebo, or open-label liraglutide once daily for 35 days.

Arms: arm 1: MEDI0382 administered subcutaneously (Part A) arm 2: Placebo comparator administered subcutaneously (Part A) arm 3: Active comparator administered subcutaneously (Part B) arm 4: MEDI0382 administered subcutaneously (Part B) arm 5: Placebo comparator administered subcutaneously (Part B)
Interventions: intervention 1: MEDI0382 intervention 2: Placebo intervention 3: Liraglutide
Intervention descriptions: intervention 1: MEDI0382 administered subcutaneously intervention 2: Placebo administered subcutaneously intervention 3: Liraglutide administered subcutaneously

Protocol documents:
Prot_000.pdf: 
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An Exploratory Phase 2, Randomised, Double-blind, 
Placebo-controlled, and Open-label Active Comparator Study to 
Evaluate the Effect of MEDI0382 on Hepatic Glycogen 
Metabolism in Overweight and Obese Subjects with Type 2 
Diabetes Mellitus
Sponsor Protocol Number: D5670C00022
Application Number:
EudraCT number 2017-005081-22
Investigational Product: 
MEDI0382
Sponsor:
 
 
 
Medical Monitor:
Contract Research Organisation: Covance, Inc.
Protocol History, Date:
Original Protocol, 29Jan2018
Protocol Amendment 1, 27Mar2018
Protocol Amendment 2, 29Mar2018
Protocol Amendment 3, 08May2018
Protocol Amendment 4, 24Sep2018
Protocol Amendment 5, 03May2019
Protocol Amendment 6, 15Jul2020
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 An Exploratory Phase 2, Randomised, Double-blind, Placebo-controlled, and Open-label Active 
Comparator Study to Evaluate the Effect of MEDI0382 on Hepatic Glycogen Metabolism in Overweight and 
Obese Subjects with Type 2 Diabetes Mellitus
HYPOTHESES  
Primary Hypothesis:
Administration of MEDI0382 once daily subcutaneously (SC) titrated up to a dose level of 300 µg will result 
in a reduction in postprandial hepatic glycogen levels versus placebo after 28 days of treatment in overweight 
and obese subjects with type 2 diabetes mellitus (T2DM). (Part A only). 
Administration of MEDI0382 once daily SC titrated up to a dose level of 300 µg will result in a reduction in 
fasting hepatic glycogen levels versus placebo after 35 days of treatment in overweight and obese subjects 
with T2DM (Part B only). 
Secondary Hypothesis:
•
Administration of MEDI0382 once daily SC titrated up to a dose level of 300 µg will result in a 
reduction in fasting hepatic glycogen levels versus liraglutide 1.8 mg administered SC once daily after 
35 days of treatment in overweight and obese subjects with T2DM (Part B only).
•
Administration of MEDI0382 once daily SC titrated up to a dose level of 300 µg once daily SC will 
result in a reduction in hepatic fat fraction versus placebo after 35 days of treatment in overweight and 
obese subjects with T2DM (Part B only).
•
Administration of MEDI0382 once daily SC titrated up to a dose level of 300 µg will be well tolerated in 
overweight and obese subjects with T2DM.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the effect of MEDI0382 on hepatic 
glycogen levels versus placebo after 28 days
(Part A) and 35 days (Part B) of treatment
•
Change in hepatic glycogen concentration adjusted for 
liver volume as measured by magnetic resonance 
spectroscopy (MRS) at Time (T) = 4 hours post 
standardised morning meal from baseline (Day -1) to 
the end of 28 days of treatment (Part A)
•
Percentage change in fasting hepatic glycogen 
concentration adjusted for liver volume as measured by 
magnetic resonance spectroscopy (MRS) at Time 
(T) = 24 hours post standardised morning meal from 
baseline (Day 1) to the end of 35 days of treatment
(Day 36) (Part B)
Secondary
To assess the effect of MEDI0382 on hepatic 
glycogen levels versus liraglutide after 
35 days of treatment (Part B only)
Percentage change in fasting hepatic glycogen concentration 
adjusted for liver volume as measured by MRS at T = 24 
hours post standardised morning meal from baseline 
(Day 1) to the end of 35 days of treatment (Day 36) (Part B 
only)
To assess the effect of MEDI0382 on hepatic 
fat fraction versus placebo after 35 days of 
treatment (Part B only)
Change in hepatic fat fraction from baseline as measured by 
magnetic resonance imaging (Day -1) to the end of 35 days 
of treatment (Part B only)




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STUDY DESIGN
This is a 2-part (Part A and Part B) exploratory Phase 2 study. 
Part A is a randomised, double-blind, placebo-controlled study to evaluate the effect of MEDI0382 
administered once daily SC for 28 days on hepatic glycogen metabolism in overweight and obese subjects 
with T2DM. Part A is planned to randomise up to 20 subjects. Subjects will be consented, screened for 
suitability, and randomised within 60 days if eligible. Subjects from Part A will not be re-enrolled in Part B.
Part B is an exploratory Phase 2 randomised, double-blind, placebo-controlled and an open-label active 
comparator study to evaluate the effect of MEDI0382 on hepatic glycogen metabolism in overweight and 
obese subjects with T2DM. Part B is planned to randomise approximately 30 subjects (not to exceed a 
maximum of 35 subjects). Subjects in Part B will be randomised to receive double-blind MEDI0382 
 or placebo, or open-label liraglutide titrated from 0.6 to 1.8 mg once daily for 35 days.
The study will involve measurement of hepatic glycogen content using a carbon (C)-13 MRS based technique 
before and after completion of the treatment period. In Part A, MEDI0382 will be
 
 in comparison to placebo. In Part B MEDI0382 will be titrated 
 
and compared to placebo and liraglutide at a dose of 1.8 mg once daily titrated from 0.6 mg to 
1.8 mg in 7-day intervals. 
In Parts A and B subjects will undergo a 5-day washout period where metformin therapy will be suspended at 
the beginning of the study starting from Day -4 (metformin dosing to resume on Day 2). This washout is 
repeated at the end of the treatment period starting from Day 24 in Part A and Day 32 in Part B.
Across Part A of the study (up to 126 days in total including screening) subjects will have a total of 6 study 
visits, 6 nights of inpatient stay and will undergo a total of 10 MRS scans alongside additional assessments 
and blood sampling. In Part B, subjects will participate in the study for approximately 133 days and will have 
a total of 7 study visits (including 2 remote contacts), 6 nights of inpatient stay and will undergo a total of 
8 MRS scans alongside additional assessments and blood sampling. The duration of MRS scans will be 
approximately 40 minutes with the exception of the baseline and end of treatment scans used for liver fat 
evaluation (Part B only) which will be prolonged and up to 1 hour 45 minutes in duration. Subjects will also 
be given the option to stay overnight prior to study visits if more convenient for them. 


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From Day -2 to Day 1 (and again on Day 8 to Day 15, Day 27 to Day 29 [Part A] and Day 34 to Day 36
[Part B] subjects will be asked to provide a stool sample for microbiome research purposes; this component of 
the study is optional.
On Day -3 in both parts of the study, subjects will be admitted to the clinical unit for 3 nights inpatient stay 
and will undergo initial safety assessments and receive training in SC injection administration. On Day -3 and 
Day -2, subjects will be provided with standardised solid meals (balanced with respect to nutrient content, but 
not calorie restricted) for breakfast, lunch, and evening meal and be expected to consume the entire meal and 
abstain from consumption of additional meals during this period. On the evening of Day -2, subjects will 
undergo a baseline blood test for 2H-glucose prior to consuming deuterated water (2H2O) divided into two 
aliquots and separated by a 4-hour interval. Subjects will be expected to fast for 14 hours overnight (except 
for drinks of deuterated water).
On Day -1 subjects will undergo a baseline MRS scan to measure liver volume and glycogen (and liver fat in 
part B only) and will have blood samples collected for 2H-glucose and baseline assessments prior to 
undergoing a standardised mixed-meal tolerance test (MMTT). The MMTT will consist of a liquid meal 
(400 mL Ensure Plus milkshake) (at Time [T] = 0). Blood will then be collected at specified time points to 
measure glucose levels. In Part A, at T = 4 hours after the MMTT a repeat MRS scan will be performed to 
measure liver volume and glycogen. For the remainder of the day serial MRS scans will be performed and 
blood samples will be collected at T = 9, and 14 hours and subjects will be given standardised solid meals for 
lunch and evening meal. In Part B, a repeat MRS scan to measure liver volume, fat and glycogen will be taken 
at T= 5 hours after the MMTT. A further MRS scan will be performed, and blood samples will be collected at 
T = 14 and subjects will be given standardised solid meals for lunch and evening meal. 
On the morning of Day 1, following an overnight fast of at least 14 hours, subjects will have a final MRS scan 
performed (T = 24 hours) and blood sampling. On Day -1 or Day 1, eligibility criteria will be verified (the 
final eligibility check may occur at any time from Day -3 to Day 1) and subjects will be randomised to receive 
investigational product (MEDI0382 or placebo in Part A or MEDI0382, placebo, or liraglutide in Part B). 
Following predose safety measures, the subjects will receive their first dose of investigational product via SC 
injection and will be discharged from the clinical unit with a sufficient supply of investigational product to 
self-administer once daily by SC injection at home in the morning. 
In Part A subjects will return for an outpatient visit at weekly intervals (Day 8 and Day 15) for safety 
assessments, dose up-titration until a dose of 300 µg MEDI0382 is reached in Part A. . Subjects will receive 
sufficient supply of investigational product at each outpatient visit.
On Day 26 subjects will be re-admitted to the clinical unit for a further 3 nights inpatient stay and as before 
will receive standardised solid meals during this period. On the evening of Day 27, subjects will fast and be 
given 2H2O water to drink at 2 times during the overnight period. On Day 28, following an MRS scan and 
blood sampling, subjects will receive an SC dose of investigational product and then undergo a MMTT as 
before at T = 0 and serial MRS scans and blood samples will be collected at T = 4, 9, and 14 hours. On 
Day 29, following an overnight fast, a final MRS scan will be performed alongside a blood test at
T = 24 hours. 
In Part B subjects will return for an outpatient visit on Day 8 for safety assessments, dose up-titration, and 
will receive an adequate supply of investigational product. On Days 14/15 and 21/22 remote contacts will be 
performed to advise on further dose uptitration as required and to collect AE/serious adverse events (SAEs)
and concomitant medication information.
On Day 33 subjects will be re-admitted to the clinical unit for a further 3 nights inpatient stay and as before 
will receive standardised solid meals during this period. On the evening of Day 34, subjects will fast and be 
given 2H2O water to drink at 2 times during the overnight period. On Day 35, following an MRS scan and 
blood sampling, subjects will receive an SC dose of investigational product and then undergo a MMTT as 




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treatment (Day 36) will be compared between MEDI0382 and placebo. A similar comparison between the 
MEDI0382 and liraglutide groups will be made as a secondary efficacy analysis.
Safety analyses:
The safety analyses will be based on the as-treated population. Treatment-emergent AEs and SAEs will be 
summarised by type, incidence, severity and relationship to investigational product by system organ class and 
preferred term. Other safety data, such as vital signs, clinical laboratory data, and electrocardiogram findings 
will be descriptively summarised at each time point. Change from baseline to each postbaseline time point in 
these data will also be summarised, where appropriate.
Pharmacokinetic analysis: 
The MEDI0382 pharmacokinetic (PK) population includes all subjects who received at least one dose of 
MEDI0382 and had at least one PK blood sample taken that is above the lower limit of quantitation. Plasma 
Ctrough concentrations of MEDI0382 will be summarised by dose level and by day in Part A and Part B 
separately. 
Immunogenicity analysis:
The number and percentage of subjects with confirmed positive ADA against MEDI0382 and titre (if 
confirmed positive) will be reported.
Interim analysis:
An interim analysis will be performed after the last subject completes their last visit in Part A of the study.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ......................................................................................................2
LIST OF ABBREVIATIONS..............................................................................................13
1
INTRODUCTION ............................................................................................15
1.1
Disease Background..........................................................................................15
1.2
MEDI0382 Background ....................................................................................15
1.3
Summary of Nonclinical Experience .................................................................15
1.4
Summary of Clinical Experience.......................................................................16
1.5
Rationale for Conducting the Study...................................................................16
1.6
Benefit-Risk and Ethical Assessment ................................................................18
1.7
Research Hypotheses.........................................................................................18
1.7.1
Primary Hypothesis...........................................................................................18
1.7.2
Secondary Hypotheses ......................................................................................19
2
OBJECTIVES AND ENDPOINTS ...................................................................20
2.1
Primary Objective and Associated Endpoint......................................................20
2.2
Secondary Objectives and Associated Endpoints...............................................20
2.3
Exploratory Objectives and Associated Endpoints.............................................21
3
STUDY DESIGN..............................................................................................23
3.1
Description of the Study....................................................................................23
3.1.1
Overview ..........................................................................................................23
3.1.2
Treatment..........................................................................................................27
3.1.3
Dose Escalation.................................................................................................28
3.1.4
Management of Study Medication Related Toxicities........................................28
3.1.4.1
Tolerability .......................................................................................................28
3.1.4.2
Hypoglycaemia .................................................................................................28
3.1.4.3
Hyperglycaemia ................................................................................................28
3.2
Rationale for Dose, Population, and Endpoints..................................................29
3.2.1
Dose Rationale..................................................................................................29
3.2.2
Rationale for Study Population..........................................................................30
3.2.3
Rationale for Endpoints.....................................................................................30
3.2.3.1
Primary Endpoint ..............................................................................................30
3.2.3.2
Secondary Endpoints.........................................................................................31
3.2.3.3
Exploratory Endpoints.......................................................................................31
4
MATERIALS AND METHODS.......................................................................32
4.1
Subjects.............................................................................................................32
4.1.1
Number of Subjects...........................................................................................32
4.1.2
Inclusion Criteria...............................................................................................32
4.1.3
Exclusion Criteria .............................................................................................33
4.1.4
Subject Enrolment and Randomisation..............................................................35
4.1.5
Withdrawal from the Study ...............................................................................36


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4.1.6
Discontinuation of Investigational Product........................................................36
4.1.7
Replacement of Subjects ...................................................................................36
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples ...................36
4.2
Schedule of Study Procedures ...........................................................................38
4.2.1
Enrolment/Screening Period..............................................................................38
4.2.2
Randomised Treatment Period (Part A and Part B)............................................39
4.2.3
Follow-up Period...............................................................................................56
4.2.3.1
Early Discontinuation Visit or Unscheduled Study Visit....................................57
4.3
Description of Study Procedures .......................................................................57
4.3.1
Efficacy.............................................................................................................57
4.3.1.1
Mixed-meal Tolerance Tests .............................................................................57
4.3.1.2
Magnetic Resonance Spectroscopy Scans..........................................................58
4.3.2
Safety Assessments ...........................................................................................58
4.3.2.1
Medical History and Physical Examination .......................................................58
4.3.2.2
Assessment of the Injection Site........................................................................59
4.3.2.3
Electrocardiograms ...........................................................................................59
4.3.2.4
Vital Signs ........................................................................................................60
4.3.2.5
Weight, Height, and Body Mass Index Calculation............................................60
4.3.3
Clinical Laboratory Tests ..................................................................................60
4.3.3.1
Glucose Meter Measured Capillary Plasma Glucose Readings ..........................61
4.3.4
Pharmacodynamic Evaluation and Measures .....................................................62
4.3.5
Pharmacokinetic Evaluation and Methods .........................................................62
4.3.6
Immunogenicity Evaluation and Methods..........................................................63
4.3.7
Biomarker Evaluation and Methods...................................................................63
4.3.8
Storage, Re-use, and Destruction of Biological Samples....................................63
4.3.9
Estimate of Volume of Blood to Be Collected ...................................................64
4.4
Study Suspension or Termination......................................................................64
4.5
Investigational Products ....................................................................................65
4.5.1
Identity of Investigational Product(s).................................................................65
4.5.1.1
Investigational Product Handling ......................................................................66
4.5.1.2
Investigational Product Inspection.....................................................................67
4.5.1.3
Treatment Administration .................................................................................68
4.5.1.4
Monitoring of Dose Administration...................................................................69
4.5.1.5
Reporting Product Complaints...........................................................................69
4.5.2
Additional Study Medications ...........................................................................70
4.5.3
Labelling...........................................................................................................70
4.5.4
Storage..............................................................................................................70
4.5.5
Treatment Compliance ......................................................................................70
4.5.6
Accountability...................................................................................................70
4.6
Treatment Assignment and Blinding .................................................................71
4.6.1
Methods for Assigning Treatment Groups.........................................................71
4.6.2
Methods to Ensure Blinding ..............................................................................71
4.6.3
Methods for Unblinding ....................................................................................72
4.6.3.1
Unblinding in the Event of a Medical Emergency..............................................72
4.7
Restrictions During the Study and Concomitant Treatment(s)............................72


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4.7.1
Permitted Concomitant Medications..................................................................72
4.7.2
Prohibited Concomitant Medications.................................................................72
4.8
Statistical Evaluation.........................................................................................73
4.8.1
General Considerations .....................................................................................73
4.8.1.1
Analysis Populations.........................................................................................73
4.8.2
Sample Size ......................................................................................................74
4.8.3
Efficacy.............................................................................................................74
4.8.3.1
Primary Efficacy Analysis.................................................................................74
4.8.3.2
Secondary Efficacy Analyses ............................................................................74
4.8.3.3
Exploratory Analyses ........................................................................................75
4.8.4
Safety……… ....................................................................................................75
4.8.4.1
Analysis of Adverse Events...............................................................................75
4.8.4.2
Analysis of Clinical Laboratory Parameters.......................................................75
4.8.5
Analysis of Pharmacokinetics............................................................................75
4.8.6
Analysis of Immunogenicity..............................................................................75
4.8.7
Interim Analysis................................................................................................75
5
ASSESSMENT OF SAFETY............................................................................76
5.1
Definition of Adverse Events ............................................................................76
5.2
Definition of Serious Adverse Events................................................................76
5.2.1
Hepatic Function Abnormalities........................................................................77
5.3
Recording of Adverse Events ............................................................................77
5.3.1
Time Period for Collection of Adverse Events...................................................77
5.3.2
Follow-up of Unresolved Adverse Events .........................................................77
5.4
Reporting of Serious Adverse Events ................................................................77
5.5
Other Events Requiring Immediate Reporting ...................................................78
5.5.1
Overdose...........................................................................................................78
5.5.2
Hepatic Function Abnormality ..........................................................................79
5.5.3
Pregnancy .........................................................................................................79
5.5.3.1
Maternal Exposure ............................................................................................79
6
STUDY AND DATA MANAGEMENT...........................................................80
6.1
Training of Study Site Personnel.......................................................................80
6.2
Monitoring of the Study ....................................................................................80
6.2.1
Source Data.......................................................................................................80
6.2.2
Study Agreements.............................................................................................80
6.2.3
Archiving of Study Documents .........................................................................81
6.3
Study Timetable and End of Study ....................................................................81
6.4
Data Management .............................................................................................81
6.5
Medical Monitor Coverage................................................................................81
7
ETHICAL AND REGULATORY REQUIREMENTS......................................82
7.1
Subject Data Protection.....................................................................................82
7.2
Ethics and Regulatory Review...........................................................................82
7.3
Informed Consent..............................................................................................83


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7.4
Changes to the Protocol and Informed Consent Form........................................83
7.5
Audits and Inspections ......................................................................................84
8
REFERENCES .................................................................................................85
9
CHANGES TO THE PROTOCOL....................................................................87
9.1
Protocol Amendment 6, 15Jul2020....................................................................87
9.2
Protocol Amendment 5, 03May2019 .................................................................88
9.3
Protocol Amendment 4, 24Sep2018 ..................................................................89
9.4
Protocol Amendment 3, 08May2018 .................................................................90
9.5
Protocol Amendment 2, 29Mar2018..................................................................91
9.6
Protocol Amendment 1, 27Mar2018..................................................................92
10
APPENDICES ..................................................................................................93
10.1
Appendix 1 - Signatures....................................................................................93
10.2
Appendix 2 – Contraception Guidance ..............................................................94
10.3
Appendix 3 - Additional Safety Guidance .........................................................94
10.4
Appendix 4 - National Institute of Allergy and Infectious Disease and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis...........98
10.5
Appendix 5 - Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law..............................................................................99
10.5.1
Introduction.......................................................................................................99
10.5.2
Definitions ........................................................................................................99
10.5.2.1
Potential Hy’s Law............................................................................................99
10.5.2.2
Hy’s Law ..........................................................................................................99
10.5.3
Identification of Potential Hy’s Law Cases......................................................100
10.5.4
Follow-up........................................................................................................100
10.5.4.1
Potential Hy’s Law Criteria Are Not Met ........................................................100
10.5.4.2
Potential Hy’s Law Criteria Are Met...............................................................100
10.5.5
Review and Assessment of Potential Hy’s Law Cases .....................................101
10.5.6
Laboratory Tests .............................................................................................102
10.5.7
References ......................................................................................................103
10.6
Appendix 6 - Genetic Research .......................................................................104
10.7
Appendix 7 - Biological Samples ....................................................................107
10.8
Appendix 8 – Example Timetable for In-clinic Standardised Meals, 
Deuterated Water, MMTTs, and Serial MRS Scans (Study Part A)..................108
LIST OF TABLES
Table 1
Fasting Glucose and Liver Glycogen Content at Termination (Day 14) 
in DIO Mice, Group Means ± SEM..........................................................17
Table 2
Primary Objective and Associated Endpoint.............................................20
Table 3
Secondary Objectives and Associated Endpoints......................................20


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Table 4
Exploratory Objectives and Associated Endpoints....................................21
Table 5
Proposed Study Doses and Predicted Safety Margins Based on 
Cynomolgus Monkey Data.......................................................................30
Table 6
Schedule of Screening Procedures............................................................38
Table 7
Schedule of Treatment Period Study Procedures (Day -4 through 
Day 15) (Part A).......................................................................................40
Table 8
Schedule of Treatment Period Study Procedures (Day 25 through 
Day 29) (Part A).......................................................................................45
Table 9
Schedule of Treatment Period Study Procedures (Day -4 through 
Day 22) (Part B).......................................................................................48
Table 10
Schedule of Treatment Period Study Procedures (Day 32 through 
Day 36) (Part B).......................................................................................53
Table 11
Schedule of Follow-up Procedures ...........................................................56
Table 12
Identification of Investigational Products .................................................65
Table 13
Highly Effective Methods of Contraception .............................................94
Table 14
Example Time Table for In-clinic Standardised Meals, Deuterated 
water, MMTTs, and Serial MRS Scans (Part A).....................................108
LIST OF IN-TEXT FIGURES
Figure 1
Study Flow Diagram Part A .....................................................................26
Figure 2
Study Flow Diagram Part B......................................................................27


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialised Term
Definition
AE
adverse event
ADA
Anti-drug antibody/antibodies
ALT
alanine transaminase
ANCOVA
analysis of covariance
AST
aspartate transaminase
AUC
area under the concentration-time curve
BMI
body mass index
BP
blood pressure
C
carbon
C2
carbon 2
C5
carbon 5
C6
carbon 6
CI
confidence interval
Cmax
maximal plasma concentration
COVID-19
coronavirus disease
Ctrough
Trough plasma concentration, measured at the end of a dosing interval taken 
directly before next administration
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
GI
gastrointestinal
2H
deuterium 
2H2O
deuterated (heavy) water
HbA1c
glycated haemoglobin
GLP-1
glucagon-like peptide-1
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IFU
instructions for use


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Abbreviation or 
Specialised Term
Definition
ITT
intent-to-treat
IXRS
interactive voice/web response system
MedDRA
medical dictionary for regulatory activities
MMTT
mixed-meal tolerance test
MRI
Magnetic resonance imaging
MRS
magnetic resonance spectroscopy
NASH
non-alcoholic steatohepatitis
NOAEL
no-observed-adverse-effect level
PK
pharmacokinetic(s)
SAE
serious adverse event
SC
subcutaneous
SID
subject identification
SOC
system organ class
T
Time
T2DM
type 2 diabetes mellitus
ULN
upper limit of normal


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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 loss.
1.2
MEDI0382 Background
MEDI0382 is a synthetic peptide with both glucagon-like peptide-1 (GLP-1) and glucagon 
receptor agonist activity which is under development for the treatment of T2DM and 
non-alcoholic steatohepatitis (NASH). GLP-1 receptor agonists are established treatments for 
T2DM that improve glycaemic control, delay gastric emptying, 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 gastric emptying and 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
 
 
 
 
 
 
 
 
 
 
 
 


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1.4
Summary of Clinical Experience
Prior clinical studies with MEDI0382 have included a single ascending dose study 
(D5670C00001) in healthy subjects, and a multiple ascending dose and a Phase 2a study 
(D5670C00002) conducted in obese and overweight subjects with T2DM. In the Phase 2a 
study (Cohort 4 of Study D5670C00002), treatment with MEDI0382 at 200 µg (uptitrated 
from a starting 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] -4.5, -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. While a 
reduction in blood glucose area under the concentration-time curve (AUC) is also anticipated 
in this study, given the difference in baseline subject characteristics (eg, metformin washout) 
and the higher carbohydrate content of the mixed-meal tolerance test (MMTT) assessment in 
this study, it is expected that the magnitude of AUC glucose reduction will be different.
MEDI0382 was also shown to have an acceptable safety profile in Study D5670C00002. 
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%) subjects; however, 
the number of events diminished in frequency with up-titration (N = 19 at 100 μg, N = 10 at 
150 μg, and N = 11 at 200 μg). The rates of nausea and vomiting were further reduced by 
lengthening the interval between titration steps to 5 days in Cohorts 5 and 6 of the same 
study dosing up to a dose level of 300 µg.
Refer to the current MEDI0382 IB for a complete summary of clinical information.
1.5
Rationale for Conducting the Study
MEDI0382, a GLP-1 receptor and glucagon receptor co-agonist is under development for the 
treatment of T2DM and NASH. Clinical studies to date have shown significant reductions in 
blood glucose levels in treated subjects, despite the known action of glucagon receptor 
agonists to increase blood glucose levels. The study of glucose and glycogen metabolism is 
therefore important to gain an increased understanding of the mechanism of action of 
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Glucagon primarily raises blood glucose levels via increased hepatic glucose output. This is 
initially achieved via an increase in glycogenolysis, and later enhanced gluconeogenesis 
(Cherrington et al, 1981). In contrast, GLP-1 promotes glucose-dependent insulin release 
which both suppresses gluconeogenesis and promotes glycogen synthesis and hepatic glucose 
uptake. However, the relative contribution of each of these counter-regulatory mechanisms to 
hepatic glucose and glycogen metabolism in the setting of dual glucagon and GLP-1 receptor 
agonism is at present unclear. Furthermore, an added level of complexity is that subjects with 
T2DM exhibit dysregulated hepatic glucose production in the fasted state, with an imbalance 
towards heightened gluconeogenesis over glycogenolysis in contrast to healthy subjects 
(Savage et al, 2007). Finally, as hepatic expression of the glucagon receptor is far greater 
than that of the GLP-1 receptor, results obtained in this study may provide evidence of target 
engagement of MEDI0382 with the glucagon receptor, and could serve to differentiate 
MEDI0382 from GLP-1 receptor mono-agonists (Uhlén et al, 2015).
 
 
 
Table 1
Fasting Glucose and Liver Glycogen Content at Termination 
(Day 14) in DIO Mice, Group Means ± SEM
 
 
 
 
 
DIO = diet-induced obesity; eqv = equivalent; SEM = standard error of the mean
*p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001
N = 6 female mice/group
Source: Study AZM110628-01-18
In prior clinical studies in overweight and obese subjects with T2DM dosed with MEDI0382 
for 41 days, marked reductions in both fasting and postprandial blood glucose levels were 
observed; however, measures of hepatic glycogen content were not performed.
The main aim of this study is to establish if the glucagon-receptor agonist component of 
MEDI0382 has a measurable impact on hepatic glycogen levels in subjects with T2DM 
across a 24-hour period in comparison to placebo in Part A, and to placebo and liraglutide (a 
GLP-1 receptor mono agonist) in Part B. This study will also determine if MEDI0382 
modulates the ratio of hepatic gluconeogenesis to glycogenolysis via incorporation of 


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deuterium (2H) into glucose at a different position in the molecule across a 24-hour period, 
and to ascertain if this differs with respect to placebo in Part A, and to placebo and liraglutide 
in Part B.
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 on Harmonisation 
(ICH)/Good Clinical Practice, and applicable regulatory requirements.
MEDI0382 is a GLP-1 receptor and glucagon receptor co-agonist that 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 anticipated to be 
a useful therapy for T2DM. However, it should be noted that given the short treatment 
duration in this study little direct benefit to the patient’s underlying T2DM should be 
expected.
Nausea and vomiting events have been observed in other clinical studies with MEDI0382. 
The study protocol includes strategies to manage gastrointestinal AEs if they arise, including 
reduction of meal sizes and maintaining adequate hydration. As clinical data for MEDI0382 
is still limited, potential risks for MEDI0382 are based on published data for GLP-1 receptor 
agonists and glucagon receptor co-agonists in addition to available nonclinical data and 
clinical data for MEDI0382. According to the latest version of the IB, potential risks for 
MEDI0382 include an increase in heart rate, alterations in blood pressure, QT interval 
prolongation, anaphylactic-type reactions, injection site reactions, skin rash, pancreatitis, 
pancreatic carcinoma, and thyroid cancer. 
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 SC injection administration as well as 
use of any devices. Subjects with contraindications to magnetic resonance imaging (MRI)
scanning are excluded from the study.
Refer to Section 1.4 and the current IB for further 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 SC titrated up to a dose level of 
 will 
result in a reduction in postprandial hepatic glycogen levels versus placebo after 28 days 
of treatment in overweight and obese subjects with T2DM (Part A only). 


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
Administration of MEDI0382 once daily SC titrated up to a dose level of 
 will 
result in a reduction in fasting hepatic glycogen levels versus placebo after 35 days of 
treatment in overweight and obese subjects with T2DM (Part B only). 
1.7.2
Secondary Hypotheses

Administration of MEDI0382 once daily SC titrated up to a dose level of 
 will 
result in a reduction in fasting hepatic glycogen levels versus liraglutide 1.8 mg once 
daily SC after 35 days of treatment in overweight and obese subjects with T2DM (Part B 
only).

Administration of MEDI0382 once daily SC titrated up to a dose level of 
 once 
daily SC will result in a reduction in hepatic fat fraction versus placebo after 35 days of 
treatment in overweight and obese subjects with T2DM (Part B only).

Administration of MEDI0382 once daily SC titrated up to a dose level of 
 will be 
well tolerated in overweight and obese subjects with T2DM.


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2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoint
Table 2
Primary Objective and Associated Endpoint
Type
Objective
Endpoint
Efficacy
To assess the effect of MEDI0382 
on hepatic glycogen levels versus 
placebo after 28 days (Part A) and 
35 days (Part B) of treatment
•
Change in hepatic glycogen concentration 
adjusted for liver volume as measured by 
MRS at T = 4 hours post standardised 
morning meal from baseline (Day -1) to the 
end of 28 days of treatment (Part A only)
•
Percentage change in fasting hepatic 
glycogen concentration adjusted for liver 
volume as measured by MRS at T = 24 hours 
post standardised morning meal from 
baseline (Day 1) to the end of 35 days of 
treatment (Day 36) (Part B)
MRS= magnetic resonance spectroscopy; T = time.
2.2
Secondary Objectives and Associated Endpoints
Table 3
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
Efficacy
To assess the effect of MEDI0382 
on hepatic glycogen levels versus 
liraglutide after 35 days of 
treatment (Part B only)
Percentage change in fasting hepatic glycogen 
concentration adjusted for liver volume as 
measured by MRS at T = 24 hours post 
standardised morning meal from baseline (Day 1) 
to the end of 35 days of treatment (Day 36, Part B 
only)
Efficacy
To assess the effect of MEDI0382 
on hepatic fat fraction versus 
placebo after 35 days of treatment 
(Part B only)
Change in hepatic fat fraction from baseline as 
measured by magnetic resonance imaging (Day -1) 
to the end of 35 days of treatment (Part B only)
Safety
To evaluate the safety and 
tolerability of MEDI0382 titrated 
up to a dose level of 300 μg 
Measures of safety and tolerability (vital signs, 
ECGs, laboratory test results, AEs)
Immunogenicity
To characterise the 
immunogenicity profile of 
MEDI0382 titrated up to a dose 
level of 300 μg 
Development of ADA and titre (if confirmed 
positive)
AE = adverse event; ADA = anti-drug antibodies; ECG = electrocardiogram; MRS = magnetic resonance 
spectroscopy; T = time.






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3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
This is a 2-part (Part A and Part B) exploratory Phase 2 study. 
Part A is a randomised, double-blind, placebo-controlled study to evaluate the effect of 
MEDI0382 administered once daily SC for 28 days on hepatic glycogen metabolism in 
overweight and obese subjects with T2DM. Part A is planned to randomise up to 20 subjects 
(Figure 1). Subjects will be consented, screened for suitability, and randomised within 
60 days if eligible. Subjects from Part A will not be re-enrolled in Part B.
Part B is an exploratory Phase 2 randomised, double-blind, placebo-controlled and 
open-label active comparator study to evaluate the effect of MEDI0382 on hepatic glycogen 
metabolism in overweight and obese subjects with T2DM (Figure 2). In Part B it is planned 
to randomise approximately 30 subjects (not to exceed a maximum of 35 subjects). Subjects 
in Part B will be randomised to receive double-blind MEDI0382 
 
or placebo, or open-label liraglutide titrated from 0.6 to 1.8 mg once daily for 35 days. 
Part A:
Subjects will undergo a 5-day washout period where metformin therapy will be suspended at 
the beginning of the study starting from Day -4 (metformin dosing to resume on Day 2) and 
the end of the study starting from Day 25 (metformin dosing to resume on Day 30). Across 
the course of the study (up to 126 days in total including screening) subjects will have a total 
of 6 study visits, 6 nights of inpatient stay and will undergo a total of 10 MRS scans 
alongside additional assessments and blood sampling. Subjects will be given the option to 
stay overnight prior to study visits if more convenient for them. From Day -2 to Day 1 (and 
again on Day 8 to Day 15 and Day 27 to Day 29)
 
On Day -3 subjects will be admitted to the clinical unit for 3 nights of inpatient stay and will 
undergo initial safety assessments and receive training in SC injection administration. On 
Day -3 and Day -2, subjects will be provided with standardised solid meals (balanced with 
respect to nutrient content, but not calorie restricted) for breakfast, lunch, and evening meal 
and be expected to consume the entire meal and abstain from consumption of additional 
meals during this period. 
On the evening of Day -2, subjects will undergo a baseline blood test for 2H-glucose prior to 
consuming deuterated water (2H2O) divided into two aliquots and separated by a 4-hour 
interval. Subjects will be expected to fast for 14 hours overnight (except for drinks of 2H2O). 
The volume of each drink of 2H2O will be 2.3 mL per kg of body water (body water is 


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calculated as 50% of total body weight for women and 60% of total body weight for men) 
and should ideally be consumed within 15 minutes. 
On Day -1, subjects will undergo a baseline MRS scan to measure liver volume, hepatic 
glycogen, and fat fraction (the latter in Part B only). After the MRS scan, subjects will 
undergo a standardised mixed-meal tolerance test (MMTT). Prior to consumption of a liquid 
meal (400 ml Ensure Plus milkshake) while subjects are still fasted, blood samples will be 
collected for baseline assessments including 2H enriched glucose and non-enriched glucose, 
energy-related and gluconeogenic substrates, pharmacokinetic (PK), and nongenetic future 
research. Following these blood sample collections, the Ensure Plus milkshake will be 
administered (at Time [T] = 0). Blood samples will then be collected at specified time points 
to measure glucose levels and at T = 220 minutes, additional blood samples for 2H labelled 
glucose and nongenetic samples will be collected at the same time. After the MMTT at T = 4 
hours, a repeat MRS scan will be performed. For the remainder of the day serial MRS scans 
and blood sample collections for 2H labelled glucose and non-genetic research will be 
performed at T = 9 and 14 hours and subjects will be given standardised solid meals for 
lunch and evening meal. 
On the morning of Day 1, following an overnight fast of at least 14 hours, subjects will have 
a final MRS scan and blood sampling performed (T = 24 hours). On Day -1 or Day 1, 
eligibility criteria will be verified (the final eligibility check may occur at any time from Day 
-3 to Day 1) and subjects will be randomised to receive investigational product (MEDI0382 
or placebo). Following predose safety measures after the final MRS scan, the subjects will 
receive the first dose of investigational product via SC injection and be discharged from the 
clinical unit with sufficient supply of investigational product to self-administer once daily by 
SC injection at home in the morning. 
Subjects will return for an outpatient visit at weekly intervals (Day 8 and Day 15) for safety 
assessments, dose up-titration until a dose of 300 µg. Sufficient drug supply for home dosing 
will be provided at each visit.
On Day 26 subjects will be re-admitted to the clinical unit for a further 3 nights inpatient stay 
and as before will receive standardised solid meals during this period. On the evening of 
Day 27, subjects will fast and be given 2H2O to drink at 2 times during the overnight period. 
On Day 28, following an MRS scan and blood sampling, subjects will be administered an SC 
dose of investigational product and then undergo an MMTT as before at T = 0 with serial 
blood samples collected as before and MRS scans performed at T = 9 and 14 hours. 
On Day 29, following an overnight fast, a final MRS scan and blood sampling will be 
performed at T = 24 hours. A follow up visit will be performed 28 days after the last dose of 
investigational product for safety assessments.


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Part B:
In Part B a comparison will be made between MEDI0382, 
 
, placebo and liraglutide 1.8 mg once daily titrated from 0.6 to 1.8 mg in 7-day 
intervals. The treatment duration will be 35 days in each treatment group, with subjects 
randomised to liraglutide spending 21 days at 1.8 mg, in contrast subjects randomised to 
MEDI0382 will spend 14 days at the top dose of 300 μg. 
The procedures for subjects who go through to the completion of the visit on Day 8, are 
identical to Part A; aside from the MRS scanning and related activities that will occur at
baseline prior to treatment, then at T = 0, 5, 14, and 24 hours and at the end of the 35 day 
treatment period as detailed in the schedule of events. The duration of MRS scans will be 
approximately 40 minutes with the exception of the baseline and end of treatment scans used 
for liver fat evaluation which will be prolonged and up to 1 hour 45 minutes in duration. 
Subjects will undergo a 5-day washout period where metformin therapy will be suspended at 
the beginning of the study starting from Day 4 (metformin dosing to resume on Day 2) and 
the end of the study starting from Day 32 (metformin dosing to resume on Day 37). 
Subjects will leave the clinical unit on Day 8 with sufficient investigational product to dose 
themselves every day until returning to the clinical unit on Day 33. Site staff will make 
remote contact with subjects on Days 14 or 15 and 21 or 22 to remind them to make an 
uptitration step if required per randomisation and to collect information regarding adverse 
events and concomitant medications. Contact may be made the day prior to the titration step 
being made to serve as a reminder, ideally by telephone, but any means of contact where 
confirmation of information receipt is acceptable and should be made prior to the time that 
the dose is scheduled on Days 15 and 22.
On Day 33 subjects will be re-admitted to the clinical unit for a further 3 night inpatient stay 
and as before will receive standardised solid meals during this period. On the evening of 
Day 34, subjects will fast and be given 2H2O to drink at 2 timepoints during the overnight 
period. On Day 35, following an MRS scan and blood sampling, subjects will administer 
their final SC dose of investigational product and then undergo an MMTT as before at T = 0 
with serial blood samples collected as before and MRS scans performed at T = 5 and 
14 hours. 
On Day 36, following an overnight fast, a final MRS scan and blood sampling will be 
performed at T = 24 hours. A follow up visit will be performed 28 days after the last dose of 
investigational product for safety assessments.






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3.1.3
Dose Escalation
Part A: Doses will escalate from an initial dose of 
 for the 
MEDI0382 and placebo arms. Dose reduction is not permitted in this study.
Part B: Doses will escalate from an initial dose of 
 for the 
MEDI0382 and placebo arms. Doses will escalate from an initial dose of 0.6 to 1.8 mg in 
7-day intervals for the liraglutide arm. Dose reduction is not permitted in this study.
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 which may 
affect gastric emptying, 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 
treatment and is uncommon with liraglutide and metformin co-administration. Clinically 
significant hypoglycaemia is therefore unlikely to occur in this study. All subjects will be 
provided with a diary and a glucose meter and will be advised to check their capillary plasma 
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 to be clinically 
significant hypoglycaemia and should be reported by investigators as an AE, regardless of 
whether subjects have symptoms or not. 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) or capillary plasma glucose readings (eg, 
3 readings > 260 mg/dL [14.4 mmol/L] within one week), the investigator should perform 
additional fasting blood glucose levels as necessary. If 2 or more laboratory plasma fasting 


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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
Rationale for Dose, Population, and Endpoints
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. Based on PK/pharmacodynamic (PD) modelling conducted using available clinical 
data and from a literature review of GLP-1 receptor and glucagon receptor modulators, the 
maximal clinically efficacious dose for glucose control of MEDI0382 was predicted to be in 
the range of 50 to 300 µg/day.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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The primary endpoint of % change in fasting glycogen adjusted for liver volume has been 
selected for Part B as a statistically significant reduction in fasting glycogen (at both T = 0 
and T = 24 hours) was observed in Part A and variability at these time-points was lower than 
other time-points permitting a smaller sample size. The T = 24 hour fasting time-point has 
been selected rather than the T = 0 hour time point to perform the analysis as this is optimal 
from an operational perspective.
3.2.3.2
Secondary Endpoints
Hepatic Glycogen Concentrations
Estimations of hepatic glycogen concentration will be measured by MRS and adjusted for 
liver volume at multiple time points across the study to establish the effects of MEDI0382 on 
glycogen in the fasted and postprandial state, and at different time points in the day. 
Safety, Tolerability, and Immunogenicity
As MEDI0382 remains under development in Phase 2 with limited exposure to date; safety, 
tolerability, and immunogenicity will be assessed throughout this study.
3.2.3.3
 
 
 
 
 
 
 
 
 


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Measures of MEDI0382 Exposure and Immunogenicity
Trough plasma concentrations (Ctrough) of MEDI0382 at 200 and 300 µg in Part A will be 
measured at the end of a dosing interval to check that subjects have been exposed to the drug. 
Anti-drug antibody (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 may be utilised for further characterisation of the ADA 
response.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Part A: Enrolment of up to 20 subjects across one or more study sites is planned.
Part B: Enrolment of approximately 30 subjects (maximum 35 subjects) across three or more 
study sites is planned.
Overall, approximately 50 subjects will be enrolled in the study (Part A and Part B, 
inclusive).
4.1.2
Inclusion Criteria
Subjects must meet all the following criteria:
1
Male and female subjects aged ≥ 18 years at screening


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2
Provision of signed and dated written informed consent (except for consent for genetic 
research and stool sample microbiome research) prior to any study-specific procedures 
3
Body mass index (BMI) ≥27 and ≤ 40 kg/m2 (inclusive) at screening
4
Glycated haemoglobin (HbA1c) ≤8.0% 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
Female subjects of childbearing potential must have a negative pregnancy test at 
screening and randomisation, and must not be lactating
7
Female subjects of childbearing potential who are sexually active with a non-sterilised 
male partner must be using at least one highly effective method of contraception from 
screening and up to 4 weeks after the last dose of investigational product. 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 (see Section 10.2 for 
definition of females of childbearing potential and for a description of highly effective 
methods of contraception).
*Subjects may be re-tested 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:
1
History of, or any existing condition that, in the opinion of the investigator, would 
interfere with evaluation of the investigational product, put the subject at risk, influence 
the subject’s ability to participate or affect the interpretation of the results of the study 
and/or any subject unable or unwilling to follow study procedures. Specific examples 
include: dislike/unable to eat any of the standardised meals that will be used during the 
study and poor venous access.
2
Any subject who has received another investigational product as part of a clinical study 
or a GLP-1 analogue-containing preparation within the last 30 days or 5 half-lives of the 
drug (whichever is longer) at the time of screening
3
Any subject who has received any of the following medications within the specified time 
frame prior to the start of the study as detailed in Section 4.7.2 .

Herbal preparations or drugs licensed for control of body weight or appetite (eg, 
orlistat, bupropion naltrexone, phentermine-topiramate, phentermine, lorcaserin) 

Opiates, domperidone, metoclopramide or other drugs known to alter gastric 
emptying

Glucagon


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
Warfarin
4
Concurrent participation in another study with an investigational product and repeat 
randomisation in this study is prohibited; subjects randomised into Part A of the study 
may not be randomised into Part B of the study
5
Severe allergy/hypersensitivity to any of the proposed study treatments, excipients, C-13 
labelled glucose, deuterated water (2H2O), or ingredients of standardised meals
6
Any contraindication to magnetic resonance imaging/MRS scanning including 
claustrophobia or dislike of confined spaces
7
Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight 
loss), a history of type 1 diabetes mellitus (T1DM) or diabetic ketoacidosis, or if the 
subject has been treated with daily SC insulin within 90 days prior to screening
8
Recurrent unexplained hypoglycaemic episodes (defined as glucose < 3.0 mmol/L or 
< 54 mg/dL on more than 2 occasions in 6 months prior to screening)
9
Significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery 
affecting the upper GI tract (including weight-reducing surgery and procedures) which 
may affect gastric emptying or could affect the interpretation of safety and tolerability 
data
10 Acute or chronic pancreatitis
11 Significant hepatic disease (except for NASH or nonalcoholic fatty liver disease without 
portal hypertension or cirrhosis) and/or subjects with any of the following results at 
screening:

Aspartate transaminase (AST) ≥3 × upper limit of normal (ULN)

Alanine transaminase (ALT) ≥3 × ULN

Total bilirubin ≥2 × ULN
12 Impaired renal function defined as estimated glomerular filtration rate (eGFR) 
< 30 mL/minute/1.73m2 at screening (glomerular filtration rate estimated according to 
Modification of Diet in Renal Disease (MDRD) using MDRD Study Equation 
IDMS-traceable (International System of Units [SI] units)
13 Poorly controlled hypertension defined as:

Systolic blood pressure (BP) > 180 mm Hg

Diastolic BP > 105 mm Hg
14 After 10 minutes of supine rest and confirmed by repeated measurement at screening. 
Subjects who fail BP screening criteria may be considered for 24-hour ambulatory blood 
pressure monitoring at the discretion of the investigator. Subjects who maintain a mean 
24-hour BP ≤ 180/105 mm Hg with a preserved nocturnal dip of > 15% will be 
considered eligible.


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15 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
16 Severe congestive heart failure (New York Heart Association Class III or IV)
17 Basal calcitonin level > 50 ng/L at screening or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia
18 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
19 Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody 
and human immunodeficiency virus (HIV) antibody
20 Substance dependence or history of alcohol abuse and/or excess alcohol intake (defined 
as > 21 units per week for a male subject, and >14 units per week for a female subject). 
Subjects must have a negative alcohol test result at screening and prior to randomisation.
21 Involvement of any AstraZeneca, MedImmune, contract research organisation, or study 
site employee or their close relatives
4.1.4
Subject Enrolment and Randomisation
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Thereafter, 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.
Subjects who fail to meet the eligibility criteria (ie, screening failures) should not be 
randomised or receive investigational product. 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 for Part B if they were found to be eligible for Part A but were 
unable to participate in the study and were not randomised. Otherwise, subjects may be 
rescreened once if, in the opinion of the investigator, there is a reason to believe they may be 
eligible.


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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 (applies for both Part A and Part B of the study):

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 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.
4.1.7
Replacement of Subjects
Subjects who withdraw from the study will be replaced where possible. Up to a maximum of 
3 subjects will be replaced in Part A and 5 subjects in Part B. 
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 a 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. 


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Plasma and Serum Samples Obtained for Future Non-genetic Research 
Plasma and serum samples obtained for future non-genetic research will be used for 
hypothesis-driven metabolomic studies and may also be analysed for exploratory biomarkers 
to assess correlations with disease activity, effects of MEDI0382, clinical outcomes, and 
toxicity according to the results obtained for the main study. Study data are protected by the 
use of a 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. 
Blood Samples Obtained for Future Genetic Research 
 
 
Plasma and serum samples obtained for future genetic research or 
 
 
earch will be labelled with a sample identification number linked to the 
SID number but will not be labelled with personal identifiers such as the subject’s name. If 
the subject withdraws consent for participating in the genetic research 
 
, the sponsor will locate the subject’s sample and destroy it. The coding of samples 
and results is to ensure that these research results are kept confidential by keeping the 
subject’s identity and these results separate.
If the subject consents to have his/her samples used for genetic research or future 
microbiome research, this additional research may not start immediately and may start at any 
time during the storage period. The subject’s sample(s) including any specimens of extracted 
deoxyribonucleic acid will be stored by the sponsor with similar samples from other subjects 
at a secure central laboratory. The subject’s samples will not be kept for more than 15 years 
after the end of the study in which they were collected. If the subject chooses not to allow 
his/her study samples to be used for genetic research or 
, the 
samples will be destroyed by the sponsor once they are no longer required for the main study.
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the sponsor for genetic research or 
 the investigator will 
arrange to have it destroyed. If consent is withdrawn after the subject’s sample(s) have been 
sent to the sponsor for genetic research or 
, the sponsor and the 
investigator will ensure that these sample(s) are destroyed unless the sample identification 
number has been removed and the subject can no longer be linked to any sample(s). 
However, if the subject’s samples have already been used for research, the sponsor is not 
required to destroy results of this research. In this case only the remaining sample(s) will be 
destroyed.


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4.2
Schedule of Study Procedures
The coronavirus disease (COVID-19) pandemic and associated guidelines, recommendations, 
national laws, and local restrictions are constantly evolving. Thus, where possible, other 
measures for carrying out protocol-related activities, such as but not limited to home nursing, 
may be required to ensure the safety of subjects.
4.2.1
Enrolment/Screening Period
Table 6 shows all study procedures to be conducted at the screening visit. 
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the blood draws should occur last. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, pharmacokinetics [PK] blood sample) to occur at the proper 
nominal time.
Table 6
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -65 to Day -5
Written informed consent/assignment of SID number
X
Optional informed consent for sample for future genetic 
research
X
Optional informed consent for stool samples for future 
microbiome research
X
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 (BPc, pulse, body temperature, respiratory rate)
X
Collect blood samples for:
    LFTs, Cr and eGFR calculation only
X
    HbA1c
X
    Calcitonin
X


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Table 6
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -65 to Day -5
    HIV-1 and -2 antibodies; hepatitis B and C serology
X
Collect urine samples for:
      Urinalysis
X
      Urine drug screen and alcohol breath screen
X 
Urine or serum pregnancy test (females of childbearing 
potential only)
X
SC self-injection training (including priming and dosing 
instruction for the pen in Part B) d
X
Concomitant medications
X
BMI = body mass index; BP = blood pressure; 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, aspartate transaminase; 
alkaline phosphatase and total bilirubin); SID = subject identification; SC = subcutaneous.
a
Only the screening physical examination will be a full examination including a structured neurological 
examination. For all time points thereafter, only an abbreviated physical examination is required.
b
A single digital ECG recording should be performed after the subject has rested for 10 minutes.
c
Blood pressure should be measured once at heart level in the non-dominant arm where possible, with the 
subject supine and rested for 10 minutes prior to the measurement.
d
Subject’s ability to self-administer investigational product will be verified using normal saline SC 
injections.
4.2.2
Randomised Treatment Period (Part A and Part B)
Table 7, Table 8, Table 9, and Table 10 show all procedures to be conducted during the 
treatment period. 
In addition, an example timetable for standardised meals, 2H2O administration, MMTTs, and 
serial MRS scans is included in Section 10.8. 
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, blood draws should occur last. The timing of the first 2 assessments should be such that 
it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time. 


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Table 7
Schedule of Treatment Period Study Procedures (Day -4 through Day 15)
(Part A)
Study Period
Outpatient
Baseline Measurements
Treatment Phase
Visit Number
V2
V3
V4
Inpatient
Outpatient
Procedure / Study Day
Day -4
Day -3
Day -2
Day -1
Day 1a
Day 8
Day 15
Metformin washout for 5 days b
X
X
X
X
X
Admission to clinical unit
X
Discharge from clinical unit
X
Outpatient visit to clinical unit
X
X
Fasting overnight required c
X
X
X (Day 7)
Physical examination (abbreviated)
X
Weight
X
X
X
ECG
X
Vital signs (BP, pulse, body temperature, respiratory rate)
X
X
X
X
Collect blood samples for: a
Serum chemistry 
X
X
X
Haematology
X
X
Serum calcitonin, amylase, and lipase
X
Fasting amino acids, FFAs, lipids, BHB, acetoacetate, and 
lactate
X
Optional blood sample for future genetic research d
X


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Table 7
Schedule of Treatment Period Study Procedures (Day -4 through Day 15)
(Part A)
Study Period
Outpatient
Baseline Measurements
Treatment Phase
Visit Number
V2
V3
V4
Inpatient
Outpatient
Procedure / Study Day
Day -4
Day -3
Day -2
Day -1
Day 1a
Day 8
Day 15
Blood samples for non-genetic future research e
X
X
X
MEDI0382 Pharmacokinetics f
X
X
Immunogenicity (ADA)
X
X
2H labelled glucose samples g
X
X
X
X
X
Urinalysis
X
Urine or serum pregnancy test (females of child bearing potential 
only)
X
X
Alcohol and illicit drug test
X
Standardised meals i
X
X
X
Deuterated water (2H2O) administration j 
X
MMTT and serial blood sampling for glucose levels k 
X
Serial MRS scans l
X
X
Assessment of AEs/SAEs m 
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
SC self-injection training n
X
Verify eligibility criteria
X
X
X
X


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Table 7
Schedule of Treatment Period Study Procedures (Day -4 through Day 15)
(Part A)
Study Period
Outpatient
Baseline Measurements
Treatment Phase
Visit Number
V2
V3
V4
Inpatient
Outpatient
Procedure / Study Day
Day -4
Day -3
Day -2
Day -1
Day 1a
Day 8
Day 15
Randomisation o
X
X
Glucose meter and diary provision p
X
Investigational product administration in clinic q
X
X
X
Dispense investigational product r
X
X
X
Dose up-titration
X
X 
ADA = anti-drug antibody; AE = adverse event; BHB = beta hydroxybutyrate; BP = blood pressure; C = carbon; SC = subcutaneous; 
ECG = electrocardiogram; FFAs = fasting free fatty acids; hr = hours; min = minutes; MMTT = mixed-meal tolerance test; MRS = magnetic resonance 
spectroscopy; PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; T = time; V = Visit.
a
All blood samples (including blood samples for PK) collected on Day 1 should be collected prior to investigational product administration.
b
Subjects should only commence washout of metformin if eligibility has been confirmed at Visit 1 and may resume taking metformin on Day 2. If the 
subject fails to meet inclusion/exclusion criteria between Day -3 and the final eligibility check (which may take place at any time from Day -3 to 
Day 1(predose)) the subject should re-commence the metformin with immediate effect. The site should inform the subject to ensure that they stop 
taking metformin from the morning of Day -4.
c
For the overnight fast on Day -2, subjects should fast for 14 hr with no solids or liquids (including water); they are permitted to drinks sips of 
deuterated water during this period. On Day -1, subjects should again fast for 14 hr overnight but they are permitted to drink clear liquids during this 
time. On Day 7 prior to their outpatient visit, subjects should be asked to fast for at least 8 hr.
d
Separate consents for collection of optional blood samples for genetic research and stool samples must be obtained before these samples are collected.
e
Blood samples for non-genetic testing should be collected from subjects on Day -1 and Day 1 at the same time as blood samples are collected for 2H 
labelled glucose at T = 0, 220 min (± 5 min), 9 hr (± 30 min), 14 hr (± 30 min) and 24 hr (± 30 min) post morning standardised liquid meal 
administered at 0800 on Day -1. Note that the time of blood sampling may be adjusted to 1 hr before or 1 hr after provided all other related procedures 
are performed at the same time intervals. A single sample will be taken at Day 8 (Visit 3).
f
PK blood sample is to be collected from subjects predose on Day 1 and Day 15. 
g
Blood samples for measurement of 2H labelled glucose should be collected from subjects just prior to deuterated water administration on Day -2 at 
1800 (± 10 min). Further blood samples for measurement of 2H labelled glucose will then be collected at the same time as the blood samples for 
nongenetic testing (see footnote e) following the morning (0800 ± 15 min) standardised liquid meal at T = 0, 220 min (± 5 min), 9 hr (± 30 min), 14 hr 
(± 30 min) and 24 hr. Note that the time of blood sampling may be adjusted to 1 hr before or 1 hr after provided all other related procedures are 
performed at the same time intervals.




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Table 7
Schedule of Treatment Period Study Procedures (Day -4 through Day 15)
(Part A)
Study Period
Outpatient
Baseline Measurements
Treatment Phase
Visit Number
V2
V3
V4
Inpatient
Outpatient
Procedure / Study Day
Day -4
Day -3
Day -2
Day -1
Day 1a
Day 8
Day 15
q
Investigational product administration should occur in the clinic on Day 1 (Visit 2) after the final MRS scan and blood sample collection (Day 1 first 
dose of MEDI0382 100 µg Daily investigational product administration should then be performed by the subject at home on Day 2 through Day 7 
(Day 7 is the last dose of MEDI0382 at a dosage level of 100 µg. The subject will receive the first dose of MEDI0382 200 µg in clinic on Day 8 (Visit 
3) at any time in the morning during the clinic visit. The subject will then self-administer investigational product at home daily on Day 9 through 
Day 14 (Day 14 is the last dose of MEDI0382 at a dose level of 200 µg. The subject will receive the first dose of MEDI0382 300 µg in the clinic on 
Day 15 (Visit 4) at any time in the morning after blood sampling for PK. The subject will then dose at home daily on Day 16 through to Day 25. 
MEDI0382 300 µg will be administered in the clinic at on Days 26, 27 and 28; the final dose is on Day 28 (Visit 5).
r
MEDI0382 or placebo will be dispensed on Days 1, 8, and 15.


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Table 8
Schedule of Treatment Period Study Procedures (Day 25 through Day 29) (Part A)
Study Period
Outpatient
Treatment Phase
Visit Number
V5
Inpatient
Procedure / Study Day
Day 25
Day 26
Day 27
Day 28 a
Day 29
Metformin washout for 5 days b
X
X
X
X
X
Admission to the clinical unit
X
Assessment of AE/SAEs c and review of concomitant 
medications
X
X
X
X
Discharge from the clinical unit
X
Fasting overnight for a minimum of 14 hours required 
X
X
Physical examination (abbreviated), ECG, and urine (or serum) 
pregnancy test
X
Weight and urinalysis
X
Vital signs (BP, pulse, body temperature, respiratory rate)
X
X
Collection of blood samples for: a
Serum chemistry, haematology, HbA1c, serum calcitonin, 
amylase, and lipase
X
Fasting amino acids, FFAs, lipids, BHB, acetoacetate and 
lactate
X
MEDI0382 Pharmacokinetics d
X
Immunogenicity (ADA) a
X
Blood samples for non-genetic future research e 
X
X
Blood samples for 2H labelled glucose f 
X
X
X
X






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Table 9
Schedule of Treatment Period Study Procedures (Day -4 through Day 22) (Part B)
Study Period
Outpatient
Baseline Measurements
Treatment Phase
Visit Number
V2
V3
V4
V5
Inpatient
Outpatient
Procedure / Study Day
Day -4
Day -3
Day -2
Day -1
Day 1a
Day 8
Day 14/ 
15
Day 
21/22
Metformin washout for 5 days b
X
X
X
X
X
Admission to clinical unit
X
Discharge from clinical unit
X
Outpatient visit to clinical unit
X
Remote contact
X
X
Fasting overnight required c
X
X
X 
(Day 7)
Physical examination (abbreviated)
X
Weight
X
X
ECG
X
Vital signs (BP, pulse, body temperature, respiratory rate)
X
X
X
Collect blood samples for: a
Serum chemistry 
X
X
X
Haematology
X
X
Serum calcitonin, amylase, and lipase
X
Fasting amino acids, FFAs, lipids, BHB, 
acetoacetate, and lactate
X
Optional blood sample for future genetic research d
X
Blood samples for non-genetic future research e
X
X
X


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Table 9
Schedule of Treatment Period Study Procedures (Day -4 through Day 22) (Part B)
Study Period
Outpatient
Baseline Measurements
Treatment Phase
Visit Number
V2
V3
V4
V5
Inpatient
Outpatient
Procedure / Study Day
Day -4
Day -3
Day -2
Day -1
Day 1a
Day 8
Day 14/ 
15
Day 
21/22
MEDI0382 Pharmacokinetics f
X
Immunogenicity (ADA) f
X
2H labelled glucose samples g
X
X
X
 
 
X
X
Urinalysis
X
Urine or serum pregnancy test (females of child bearing 
potential only)
X
X
Alcohol and illicit drug test
X
Standardised meals i 
X
X
X
Deuterated water (2H2O) administration j
X
MMTT and serial blood sampling for glucose levels k
X
Serial MRS scans l
X
X
Assessment of AEs/SAEs m
X
X
X
X
X
X
X


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Table 9
Schedule of Treatment Period Study Procedures (Day -4 through Day 22) (Part B)
Study Period
Outpatient
Baseline Measurements
Treatment Phase
Visit Number
V2
V3
V4
V5
Inpatient
Outpatient
Procedure / Study Day
Day -4
Day -3
Day -2
Day -1
Day 1a
Day 8
Day 14/ 
15
Day 
21/22
Concomitant medications
X
X
X
X
X
X
X
Training in use of pen (including priming and dosing 
instructions for the pen) n
X
Verify eligibility criteria
X
X
X
X
Randomisation o
X
X
Glucose meter and diary provision p
X
Investigational product administration in clinic q
X
X
Dispense investigational product r
X
X
Dose up-titration s
X
X 
X#
ADA = anti-drug antibody; AE = adverse event; BHB = beta hydroxybutyrate; BP = blood pressure; C = carbon; SC = subcutaneous; 
ECG = electrocardiogram; FFAs = fasting free fatty acids; hr = hours; min = minutes; MMTT = mixed-meal tolerance test; MRS = magnetic resonance 
spectroscopy; PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; T = time; V = Visit.
a
All blood samples (including blood samples for PK) collected on Day 1 should be collected prior to investigational product administration.
b
Subjects should only commence washout of metformin if eligibility has been confirmed at Visit 1 and may resume taking metformin on Day 2. If the 
subject fails to meet inclusion/exclusion criteria between Day -3 and the final eligibility check (which may take place at any time from Day -3 to 
Day 1(predose)) the subject should re-commence the metformin with immediate effect. The site should inform the subject to ensure that they stop 
taking metformin from the morning of Day -4.




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Table 9
Schedule of Treatment Period Study Procedures (Day -4 through Day 22) (Part B)
Study Period
Outpatient
Baseline Measurements
Treatment Phase
Visit Number
V2
V3
V4
V5
Inpatient
Outpatient
Procedure / Study Day
Day -4
Day -3
Day -2
Day -1
Day 1a
Day 8
Day 14/ 
15
Day 
21/22
k
Following a minimum 14 hr fast, a MMTT will be performed at 0800 ± 15 min on Day -1; baseline blood samples will be collected at T = 0 (alongside 
samples for other blood tests and 2H labelled glucose); a standardised liquid meal will be given to subjects and consumed in entirety within 5 min. 
Further blood samples for glucose levels will be collected at T = 15, 30, 45, 60, 120, 180 and 220 min (± 5 min). Note that the start time of the MMTT 
may be adjusted to 1 hr before or 1 hr after provided all other related procedures are performed at the same time intervals.
l
MRS scans will be performed on Day -1 at 0700, 1300, 2200 (± 15 min) and on Day 1 at 0800 (24 hours post MMTT) (± 15 min). Note that times may 
be adjusted to 1 hr before or 1 hr after provided all other related procedures are performed at the same time intervals. The MRS scan that will be used 
to evaluate liver fat content should be performed whilst the subject is fasted and may occur on Day -1 or Day 1.
m
AEs will be assessed from the start of investigational product administration; SAEs will be assessed from the time of signed informed consent form.
n
Injection training should be performed with Placebo MEDI0382 pens prior to Day 1 and with the randomised investigational product on Day 1; 
subjects should be provided with as much training as they need to be comfortable with self-injection using the pen device between Day -3 through 
Day 1.
o
On Day -1 or Day 1, subjects will be randomised to receive investigational product: MEDI0382 or placebo or liraglutide. Subjects enrolled in Part A 
will not be re-enrolled in Part B.
p
A glucose meter, test strips, and a diary should be provided to the subject. The subject should be trained in its use and advised to test their capillary 
blood glucose at any time the subject feels unwell or has symptoms of hypoglycaemia (hunger, dizziness, shaking, sweating, or irritability) and they 
should record these symptoms and a capillary plasma glucose level in their diary only when symptomatic. Subjects should do this until their final study 
visit and bring the diary card with them to their next visit if they recorded symptoms or capillary plasma glucose levels while at home.
q
Investigational product administration should occur in the clinic on Day 1 (Visit 2) after the final MRS scan and blood sample collection (Day 1 first 
dose of MEDI0382 50 µg or 0.6 mg liraglutide). Daily investigational product administration should then be performed by the subject at home on 
Day 2 through Day 7 (Day 7 is the last dose of MEDI0382 at a dosage level of 50 µg or liraglutide 0.6 mg). The subject will receive the first dose of 
MEDI0382 100 µg or liraglutide 1.2 mg in clinic on Day 8 (Visit 3) at any time in the morning The subject will then self-administer investigational 
product at home daily on Day 9 through to Day 14 (Day 14 is the last dose of MEDI0382 at a dose level of 100 µg or liraglutide 1.2 mg). On Day 14 or 
the morning of Day 15 prior to dosing, the site will make remote contact with the subject and remind them to make the up-titration in the MEDI0382 
or placebo arms to 200 µg or liraglutide to 1.8 mg and to continue daily dosing at home. On Day 22 subjects in the MEDI0382 or placebo arms will be 
asked to uptitrate to 300 µg and to continue this dose until their next visit. Subjects in the liraglutide arm will be advised to continue at a dose at 1.8 
mg and to continue this dose until their next visit.
r
MEDI0382 or placebo and liraglutide will be dispensed on Days 1 and 8.
s
#Up-titration in blinded arms only


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Table 10
Schedule of Treatment Period Study Procedures (Day 32 through Day 36) (Part B)
Study Period
Outpatient
Treatment Phase
Visit Number
V6
Inpatient
Procedure / Study Day
Day 32
Day 33
Day 34
Day 35 a
Day 36
Metformin washout for 5 days b
X
X
X
X
X
Admission to the clinical unit
X
Assessment of AE/SAEs c and review of concomitant 
medications
X
X
X
X
Discharge from the clinical unit
X
Fasting overnight for a minimum of 14 hours required 
X
X
Physical examination (abbreviated), ECG, and urine (or serum) 
pregnancy test
X
Weight and urinalysis
X
Vital signs (BP, pulse, body temperature, respiratory rate)
X
X
Collection of blood samples for: a
Serum chemistry, haematology, HbA1c, serum calcitonin, 
amylase, and lipase
X
Fasting amino acids, FFAs, lipids, BHB, acetoacetate and 
lactate
X
MEDI0382 Pharmacokinetics d
X
Immunogenicity (ADA) e
X
Blood samples for non-genetic future research f
X
X
Blood samples for 2H labelled glucose g
X
X
X
h
X




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Table 10
Schedule of Treatment Period Study Procedures (Day 32 through Day 36) (Part B)
Study Period
Outpatient
Treatment Phase
Visit Number
V6
Inpatient
Procedure / Study Day
Day 32
Day 33
Day 34
Day 35 a
Day 36
i
Standardised solid meals are to be given to subjects 3 times daily on Day 33 and Day 34 at 0900 (± 30 min), 1300 (± 30 min), and 1700 (± 30 min); 
each meal is to be consumed within 15 minutes. On Day 35, as part of the MMTT, a standardised liquid meal is to be given to subjects in the morning 
at 0800 (± 15 min). Following the MMTT, subjects will be given standardised solid meals for lunch (1400 ± 5 min) and evening meal (1800 ± 5 min). 
Note that the time of standardised meals may be adjusted ± 1 hr provided all other related procedures are performed at the same time intervals. On Day 
35 after the evening meal at 1800 (± 5 min), subjects should remain fasted overnight for 14 hours until after the T=24h MRS scan and predose 
laboratory assessments are performed on Day 36. Subjects are permitted to drink normal water during this period. On Day 36, after the final MRS at 
0800 (± 15 min), the subject may resume their normal diet.
j
Deuterated water should be administered on Day 34 at 1800 and 2200 (± 15 min). The subject should then avoid drinking any additional water until 
0800 the next morning. Subjects are permitted to drink small quantities of deuterated water during the fast if thirsty. Note that the start time of the 
deuterated water administration may be adjusted to 1 hr before or 1 hr after provided all other related procedures are performed at the same time 
intervals.
k
Following a minimum 14-hour fast, a MMTT will be performed at 0800 (± 15 min) on Day 35. Baseline samples will be collected at T = 0 (alongside 
samples for other blood tests and 2H labelled glucose); a standardised liquid meal will be given to subjects and should be consumed in entirety within 
5 min. Further blood samples will be collected at T = 15, 30, 45, 60, 120, 180 and 220 min (± 5 min) for 2H labelled glucose levels. Note that the start 
time of the MMTT may be adjusted ± 1 hr after provided all other related procedures are performed at the same time intervals.
l
MRS scans will be performed on Day 35 at 0700, 1300 and 2200 (± 15 min) and on Day 36 at 0800 (± 15 min). Note that times may be adjusted to 
± 1 hr provided all other related procedures are performed at the same time intervals. The MRS scan that will be used to evaluate liver fat content 
should be performed whilst the subject is fasted and may occur on Day 35 or Day 36.
m
Investigational product administration should occur at home by the subject on Day 9 through 32 and in the clinic at 0800 (± 60 min) on Day 33, 
Day 34, and Day 35. Note that times may be adjusted to ± 1 hr on Day 35 provided all other related procedures are performed at the same time 
intervals. Investigational product should be administered on Day 35 just after blood samples have been collected for PK, ADA, 2H labelled glucose, 
gluconeogenic substrates, and non-genetic research. 
n
Investigational product will be dispensed on Day 33


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4.2.3
Follow-up Period
Table 11 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, blood draws should occur last. The timing of the first 2 assessments should be such that 
it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time.
Table 11
Schedule of Follow-up Procedures
Study Period
Follow-up Period
Visit Number
Final (V6 (Part A) and V7 (Part B)
Procedure / Study Day
28 days post last dose (± 3 days)
Physical examination (abbreviated) 
X
Weight
X
ECG
X
Vital signs (BP, pulse, body temperature, respiratory 
rate) a
X
Serum chemistry panel
X
Calcitonin
X c
Haematology
X
Urinalysis
X
HbA1c
X
Urine or serum pregnancy test (females of child 
bearing potential only)
X
Immunogenicity (ADA) b
X
Assessment of AEs/SAEs
X
Concomitant medications
X
AE = adverse event; ADA = anti-drug antibody; BP = blood pressure; ECG = electrocardiogram; 
HbA1c = glycated haemoglobin, SAE = serious adverse event
a
Blood pressure should be measured once at heart level in the non-dominant arm where possible, with the 
subject supine or seated and rested for 10 minutes prior to the measurement.
b
Only subjects with an ADA titre ≥ 10 at the safety follow-up visit (28 days post last dose) will be asked to 
return to provide another ADA sample at approximately 3 months after the follow-up visit (3-month post-
study sample). Subjects with a 3-month post-study ADA titre ≥ 10 will be asked to return for a sample at 
3-month intervals until the titre is < 10. Subjects assigned to liraglutide do not need to have ADA samples 
collected (Part B only).
c
Only to be repeated if the calcitonin level was > ULN in the sample taken at the end of dosing.


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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, and 
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 a structured neurological examination is required at 
screening (Table 6). Abbreviated physical 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 (ie, randomised treatment and follow-up periods) 
(Table 7, Table 8, Table 9, Table 10, and Table 11).
Clinically significant abnormal findings will be recorded. 
4.3.2.2
Assessment of the Injection Site
Study centre 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 the schedules of procedures, ECGs will be obtained after 10 minutes 
supine rest. Only a single digital ECG recording will be required at the specified time points.
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 or II 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 or II is not deemed 
possible for predose or significant parts of whole visits or whole visits.


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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 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). Blood pressure should be 
measured once at heart level in the non-dominant arm where possible, with the subject seated 
or supine and rested for 10 minutes prior to the measurement. Route of body temperature 
measurement will be according to local protocols. 
4.3.2.5
Weight, Height, and Body Mass Index Calculation
Weight (kg), height (cm), and BMI (kg/m2) will be measured at screening. Weight will be 
measured at all other time points specified in the schedules of study procedures.
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 including serum pregnancy tests will be performed in a 
licensed central or licensed local clinical laboratory. Urine pregnancy tests may be performed 
at the site using a licensed test (dipstick). Abnormal laboratory results 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): 
Haematology Panel
White blood cell count with differential
Platelet count
Red blood cell count
Mean corpuscular volume
Haematocrit
Mean corpuscular haemoglobin concentration
Haemoglobin
Serum Chemistry Panel
Calcium
ALP
Potassium
Total bilirubin


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Sodium
Creatinine
Bicarbonate*
Blood urea
AST
Albumin
ALT
Magnesium
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase.
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.
Urinalysis
Protein
Urine drug screen*  
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 Laboratory Tests
•
Calcitonin
•
Alcohol screening test (breath or urine based test)
•
Pancreatic amylase, lipase
•
HbA1c
•
Anti-drug antibodies (immunogenicity)
•
Serum or urine pregnancy test (for females with childbearing potential only)
•
HBsAg, hepatitis C antibody (screening only)
•
HIV-1, -2 antibodies (screening only)
•
Glucose metabolism panel for MMTT: Timed glucose
•
Fasting lipid profile: high-density lipoprotein, low-density lipoprotein, triglycerides
•
Gluconeogenic substrates: free fatty acids, beta-hydroxybutyrate, acetoacetate, amino acids, and lactate
•
Glucose samples to measure 2H labelled glucose
4.3.3.1
Glucose Meter Measured Capillary Plasma Glucose Readings 
At the start of the study, each subject will be issued a standardised glucose meter, testing 
strips, and a diary. Subjects will be encouraged to perform finger-prick tests if they feel 
unwell and in particular if they feel the symptoms may be due to hypoglycaemia for the 
duration of the study, but they will not be required to test routinely. If the investigator/site 
staff feel that a subject could be experiencing hypo- or hyperglycaemia, capillary plasma
glucose should be tested with a standardised glucose meter. Capillary plasma glucose levels of 
< 3 mmol/L (54 mg/dL) should be recorded as an AE regardless of whether the subject has 
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4.3.4
Pharmacodynamic Evaluation and Measures
Deuterated water (2H2O) assessment
The test should commence approximately 1 hour after the start of the evening standardised 
meal. Subjects will be expected to fast after they have finished the meal until they receive the 
standardised meal the following morning. Subjects should avoid drinking water or other 
liquids during this period, but are permitted to drink 0.5% enriched 2H2O in small quantities if 
required for comfort. Subjects should be advised that 2H20 may occasionally cause mild 
transient tinnitus.
A baseline blood test should be taken just prior to administration of the first dose of 2H2O 
(70%). The first dose of 2H2O is 3.25 g or 3.0mL per kg of body water; body water is 
calculated as 50% of total body weight for women and 60% of total body weight for men and 
should ideally be consumed within 15 minutes. Four hours later a second dose of 2H2O (3.25 g 
or 3.0 mL per kg of body water) should be administered to the subject and consumed within 
15 minutes (Landau et al, 1995).
Example dosing schedule:
90 kg male subject:
1800 hours: First dose 2H2O; 3.0 × 90 × 0.6 = 162 mL 2H2O
2200 hours: Second dose 2H2O; 3.0 × 90 × 0.6 = 162mL 2H2O
Blood tests to be taken as detailed in (Table 7 and Table 8 [Part A] and Table 9 and Table 10
[Part B]) and will be used to measure the following:

Change in estimated percentage gluconeogenesis as measured by the ratio of 2H 
enrichment in C5 or C6 and C2 of glucose at T = 0, 4, 9, 14 and 24 hours from baseline 
(Day -1) to the end of 28 or 35 days of treatment

Change in estimated percentage glycogenolysis as measured by 1- the ratio of 2H 
enrichment in C5 or C6 and C2 of glucose at T = 0, 4, 9, 14 and 24 hours from baseline 
(Day -1) to the end of 28 or 35 days of treatment
Blood samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.
4.3.5
Pharmacokinetic Evaluation and Methods
Blood will be collected at protocol-specified time points to evaluate plasma concentrations of 
MEDI0382 up-titrated to 300 µg (Table 7 and Table 8). Blood sampling within the specified 
window around the specified time will not be considered a protocol deviation but the exact 


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time of blood sampling should be recorded. The PK of MEDI0382 in plasma will be measured 
utilising a validated liquid chromatography-tandem mass spectrometry method. 
Blood samples will be collected to measure plasma Ctrough concentrations of MEDI0382 at 
steady state (Part A, Days 15 and 28, Part B, Days 8 and 35).
Blood samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual. Residual PK samples will be retained until 5 years after completion of the clinical 
study report.
4.3.6
Immunogenicity Evaluation and Methods
Blood samples will be collected at protocol-specified time points to evaluate serum ADA 
responses to MEDI0382 (Table 7, Table 8, Table 9, Table 10, and Table 11). Evaluations will 
be performed using a validated immunoassay. Samples will be analysed for development of 
ADAs and titre (if confirmed positive).
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.
4.3.7
Biomarker Evaluation and Methods
The subject’s consent for provision of 
 is optional. If 
the subject’s consent is obtained, 
will be collected at the beginning, middle 
(Day 8 to 15 [Part A] or Day 8 to 33 [Part B]), and the end of the study as detailed in the 
schedule of treatment period study procedures (Table 7 and Table 8 [Part A] and Table 9 and
Table 10 [Part B]) and will be used to evaluate changes in the gut microbiome following 
treatment with MEDI0382.
In addition, blood samples will be collected for future nongenetic research at the time points 
as detailed in the schedule of treatment period study procedures (Table 7 and Table 8 [Part A] 
and Table 9 and Table 10 [Part B]). The blood samples are part of the main study and will be 
primarily used to perform hypothesis-driven metabolomic studies, and may also be analysed 
for exploratory biomarkers to assess correlations with disease activity, effects of MEDI0382, 
clinical outcomes, and toxicity. See Section 10.7 for further information. 
4.3.8
Storage, Re-use, and Destruction of Biological Samples
Samples will be stored for a maximum of 15 years from the date of the last subject’s last visit, 
after which they will be destroyed. The results of any investigation will be reported either in 
the clinical study report itself or as an addendum, or separately in a scientific report or 
publication.


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4.3.9
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 approximately 404 mL. Additional 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 permanently terminate this study at 
any time during part A or B of the study. The reasons for temporarily suspending or 
permanently 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 enrolment is unsatisfactory

Noncompliance that might significantly jeopardise the validity or integrity of the study 

Sponsor decision to terminate development of the investigational product for this 
indication

Sponsor decision to terminate the study
If MedImmune determines that temporary suspension or permanent termination of the study is 
required, MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the 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. In the 
event that the study is prematurely terminated, biological samples will be retained for up to 
15 years as described previously unless consent is withdrawn as described in Section 4.1.8.






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The entire kit of investigational product (MEDI0382 or placebo or liraglutide) 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. Investigational product should be 
protected from heat and light. Subjects should be instructed to refer to the IFU of 
investigational product. The subject is to avoid the risk of freezing the investigational product 
by carefully placing the investigational product within their refrigerator, and they should not 
use investigational product if it has been frozen.
In Part A of the study, the subject is to remove from the refrigerator only the prefilled syringe 
of MEDI0382 or placebo required for their daily dose. All other syringes are to be kept in the 
refrigerator until required. The prefilled syringe should always be safely discarded after use. 
The subject will return sharps bins with used syringes and any unused prefilled syringes to the 
site for accountability at each outpatient/inpatient visit.
In Part B, subjects randomised to receive MEDI0382 or placebo will remove the multidose 
pen injector required for their daily dose from the refrigerator. Subjects randomised to receive 
open-label liraglutide will remove from the refrigerator the multidose pen injector required for 
their daily dose. The pen should always be safely discarded when empty. The subject will 
return sharps bins with used multidose pen injectors and any unused multidose pen injectors to 
the site for accountability at each outpatient/inpatient visit. 
4.5.1.2
Investigational Product Inspection
For Part A: MEDI0382 is supplied as a sterile liquid solution in a prefilled syringe for single 
use. Each syringe selected for in-clinic treatment administration should be inspected by the 
unblinded investigational product manager or unblinded study personnel prior to injection. 
MEDI0382 is supplied at a concentration of 0.5 mg/mL. The solution should not be cloudy, 
discoloured, or contain any visible particles.
For Part B: MEDI0382 or placebo is supplied as a sterile liquid solution in a multi-dose pen.
Each pen selected for administration should be inspected prior to injection. The solution in the 
cartridge should not be cloudy, discoloured, or contain any visible particles.
Liraglutide is supplied as a 6 mg/mL clear, colourless solution in a prefilled, multidose pen 
injector that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg. The solution in the cartridge of the 
pen should not be cloudy, discoloured, or contain any visible particles (Victoza package 
insert, 2017).
Subjects should be instructed to refer to the IFU for MEDI0382 and placebo and to the PIL for 
liraglutide.


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If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Reporting Product Complaints 
(Section 4.5.1.5) for further instructions. 
4.5.1.3
Treatment Administration
In-clinic Treatment Administration
MEDI0382, placebo, or liraglutide should be stored at 2°C to 8°C in the original container. 
The dose to be administered should be allowed to warm up at room temperature for about 
30 minutes before injection. The first day of dosing with MEDI0382 or placebo (or liraglutide 
Part B only) is considered Day 1. On the day of each dose, investigational product will be
administered according to the schedule of procedures. Investigational product (MEDI0382 or 
placebo) will be administered by SC injection in the lower abdomen.
Doses of liraglutide are to be administered by SC injection in the abdomen, thigh, or upper 
arm. The staff at the clinic should refer to the PIL for liraglutide for additional product 
information. 
At-home Treatment Administration
Investigational product (MEDI0382 or placebo) should be removed from the refrigerator for 
about 30 minutes for temperature equilibration prior to dosing. 
 
 
 
 
 
 
 
 
 
 
 
  


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Subjects should always refer to the IFU document for at-home administration details.
For at-home self-administration of liraglutide, subjects should refer to the label on the carton 
containing the prefilled liraglutide multidose pen injector and to the PIL for liraglutide.
If a dose of MEDI0382, placebo, or liraglutide 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 investigational product at the next regularly scheduled time.
4.5.1.4
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).
4.5.1.5
Reporting Product Complaints
Any defects with the investigational product must be reported immediately (ie, at the first 
opportunity) 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 labelled conditions unless 
otherwise instructed.


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4.5.2
Additional Study Medications
Subjects entering the study must have been treated with daily stable doses of oral, blood 
glucose-lowering therapy with metformin for at least 3 months prior to screening. Metformin 
is not provided by the sponsor.
After screening, eligible subjects on metformin monotherapy will complete two 5-day 
metformin washout periods (at the beginning of the study starting from Day -4 with 
metformin dosing resuming on Day 2 and at the end of the study starting from Day 25 with 
metformin dosing resuming on Day 30). 
4.5.3
Labelling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. Label text will be translated 
into local languages, as required.
4.5.4
Storage
All investigational product should be kept in a secure place under appropriate storage 
conditions. The label on the investigational product kit specifies the appropriate storage.
4.5.5
Treatment Compliance
In-clinic administration
At the clinic, investigational product is administered by study site personnel, who will monitor 
compliance.
At-home administration
Compliance during the at-home dosing period to be monitored via returned prefilled syringes
(Part A), and returned multidose pen injectors (Part B). The distribution of investigational 
product for self-administration should be recorded in the appropriate sections of the eCRF.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records and will account for all investigational 
product dispensed to and returned by the subject. Study-site staff, if applicable, or the site 
monitor delegated to the investigational product management will account for all 
investigational product received at the site, unused investigational product, and for appropriate 
disposition of investigational product in accordance to local procedures. 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.


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In the case of a malfunctioning prefilled syringe or a liraglutide prefilled multidose pen, the 
designated investigational product manager (pharmacist/study nurse) should contact the site 
monitor delegated to investigational product management to initiate a product complaint 
process according to Section 4.5.1.5.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IXRS will be used for randomisation to a treatment group and assignment of 
investigational product kit numbers. A subject is considered randomised into the study when 
the investigator notifies the IXRS that the subject meets eligibility criteria, and the IXRS 
provides the assignment of investigational product kit numbers to the subject.
Eligible subjects will be randomised at a 1:1 ratio following screening to receive either 
MEDI0382 SC or placebo SC (Part A) or randomised at a 1:1:1 ratio following screening to 
receive either MEDI0382 SC, placebo SC, or open-label liraglutide (Part B). The IXRS will 
assign a unique randomisation code and treatment group to the subject at the time of 
randomisation. Subjects who withdraw from the study may be replaced, if deemed necessary 
by the medical monitor, to ensure that safety data are collected on a sufficient number of 
subjects (Section 4.1.7).
4.6.2
Methods to Ensure Blinding
Part A: This is a double-blind study in which MEDI0382 and placebo are not identical in the 
prefilled syringe titration volumes. 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).
The different fill volumes of investigational product (MEDI0382 and placebo) and the relative 
position of the plunger rods will be visually distinct during administration. To maintain the 
blind in Part A, investigational product (MEDI0382 and placebo) prefilled syringes will be 
handled by an unblinded investigational product manager or unblinded study personnel who 
will not be involved in the treatment or clinical evaluation of subjects. An unblinded site 
monitor will perform investigational product accountability, and this will be a different person 
to the blinded site monitor who will oversee other aspects of the study at the clinical site. 
In Part B, the MEDI0382 and placebo multidose pens are indistinguishable. Each subject will
know the volume of investigational product they have been instructed to select and administer, 
the subject and site staff are blinded with respect to whether they are receiving MEDI0382 or 
placebo. Liraglutide used in Part B will be open-label.
The site will maintain a written plan detailing which staff members are blinded/unblinded and 
the process of investigational product administration used to maintain the blind.


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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. 
If a subject’s investigational product allocation is unblinded, the subject should be 
discontinued from investigational product.
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 4.1.3. 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, vitamins, 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 screening, treatment, 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.


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Use of the following concomitant medications is not permitted:

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)

Concurrent use of opiates, domperidone, metoclopramide, or other drugs known to 
alter gastric emptying and within 2 weeks prior to the start of the study (Visit 2) 

Concurrent use of glucagon or glucagon analogues within 4 weeks prior to the start 
of the study (Visit 2)

Concurrent use of warfarin within 4 weeks prior to the start of the study (Visit 2)
4.8
Statistical Evaluation
4.8.1
General Considerations
Tabular summaries will be presented by treatment group. Categorical data will be summarised 
by the number and percentage of subjects in each category. Continuous variables will be 
summarised by descriptive statistics. The study objectives will be evaluated on Part A and Part 
B separately and also on the combined cohorts as appropriate. Additional details of statistical 
analyses will be described in the statistical analysis plan.
4.8.1.1
Analysis Populations
Efficacy Analysis Population
The efficacy analysis will be based on the intent-to-treat (ITT) population, which is defined as 
all subjects that are randomised and received at least one dose of investigational product, and 
subjects will be analysed according to randomised treatment assignments. All efficacy 
analyses will be performed on the ITT population unless otherwise specified.
Safety Analysis Population
The safety analysis will be based on the As-treated population, which includes all subjects 
who receive at least one dose of any investigational product and subjects will be analysed 
according to the treatment they actually received.


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Pharmacokinetic Analysis Population
The PK population includes all subjects who received at least one dose of investigational 
product and had at least one PK blood sample taken that is above the lower limit of 
quantitation.
4.8.2
Sample Size
 
 
 
 
 
 
 
 
 
 
 
.
4.8.3
Efficacy
4.8.3.1
Primary Efficacy Analysis
The primary endpoint, change in glycogen concentration (adjusted for liver volume) as 
measured by MRS at T = 4 hours post standardised morning meal from baseline (Day -1) to 
the end of 28 days of treatment, will be compared between the MEDI0382 and placebo groups 
using an analysis of covariance (ANCOVA) model adjusting for baseline value and treatment 
group (Part A only).
The primary endpoint, percentage change in fasting glycogen concentration (adjusted for liver 
volume) as measured by MRS at T = 24 hours post standardised morning meal from baseline 
(Day -1) to the end of 35 days of treatment, will be compared between the MEDI0382 and 
placebo groups using an analysis of covariance (ANCOVA) model adjusting for baseline 
value and treatment group.
4.8.3.2
Secondary Efficacy Analyses
The secondary endpoints, percentage change in glycogen concentration (adjusted for liver 
volume) as measured by MRS at T = 24 hours post standardised morning meal from baseline 
(Day 1) to the end of 35 days treatment, will be compared between MEDI0382 and liraglutide 
groups using the ANCOVA model adjusting for baseline value and treatment group in Part B 
of the study only. A similar analysis will be applied to measure change in hepatic fat fraction 
CCI


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from baseline (Day -1 or Day 1) to the end of 35 days of treatment (Day 35 or 36) versus 
placebo.
4.8.3.3
Exploratory Analyses 
The exploratory endpoints will be summarised by treatment arms and formal statistical model 
analysis may be performed if deemed necessary.
4.8.4
Safety
4.8.4.1
Analysis of Adverse Events
Treatment-emergent AEs and SAEs will be summarized by type, incidence, severity and 
relationship to investigational product by system organ class (SOC) and preferred term (PT). 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Specific AEs will be counted once for each subject for calculating rates, but will 
be presented in total in subject listings. In addition, if the same AE occurs multiple times 
within a particular subject, the highest severity and level of causality will be reported. If any 
associations of interest between AEs and baseline characteristics are observed, additional 
stratified results may be presented. All treatment-emergent AEs will be summarized overall 
and by MedDRA SOC and PT, by severity and relationship to investigational product. In 
addition, summaries of deaths, SAEs, and treatment discontinuations due to AEs will be 
provided.
4.8.4.2
Analysis of Clinical Laboratory Parameters
Other safety data, such as vital signs and clinical laboratory data, will be descriptively 
summarised at each time point. Change from baseline to each post baseline time point in these 
data will also be summarised, where appropriate. ECG parameters will also be assessed and 
summarised descriptively.
4.8.5
Analysis of Pharmacokinetics
Plasma Ctrough concentrations of MEDI0382 will be summarised by dose level and by day in 
both Part A and Part B.
4.8.6
Analysis of Immunogenicity
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.
4.8.7
Interim Analysis
An interim analysis after the last subject completes their last visit in Part A of the study is 
planned.


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


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
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.
5.2.1
Hepatic Function Abnormalities
Refer to Section 5.5.2 and Section 10.5 for the definition and follow-up for liver 
abnormalities. 
5.3
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 etiologies, and whether the event 
meets criteria of an SAE and therefore requires immediate notification to the sponsor (Section 
5.4). See Section 5.4 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.
5.3.1
Time Period for Collection of Adverse Events
AEs will be collected from the time of start of investigational product throughout the study 
including the follow-up period (28 days after the last dose of investigational product; Visit 6
[Part A] and Visit 7 [Part B]). Additionally, all SAEs will be collected from time of signature 
of informed consent throughout the study including the follow-up period as described above. 
5.3.2
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.
5.4
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.


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If any SAE occurs in the course of the study, then investigators or other site personnel must 
inform the appropriate sponsor representative(s) within 1 day, ie, immediately but no later 
than 24 hours after becoming aware of the event.
The designated sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor’s patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform sponsor 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed. 
5.5
Other Events Requiring Immediate Reporting
5.5.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in this protocol.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on 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 6.5. 
For other overdoses, reporting must occur within 30 days.


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5.5.2
Hepatic Function Abnormality 
Cases where a subject shows elevation in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need 
to be reported as SAEs. Please refer to Section 10.5 (Appendix 5) for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s Law. 
5.5.3
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.5.3.1
Maternal Exposure
Women of childbearing potential who are sexually active with a nonsterilised male partner are 
required to use one 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 during the course of the study, then the investigator or other site 
personnel will inform the appropriate sponsor representatives within 1 day, ie, immediately 
but no later than 24 hours 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 within 1 or 5 calendar 
days for SAEs (see Section 5.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.
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.


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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 protocol and related documents with the 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 of the centres should comply with all the terms, conditions, 
and obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of 


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any inconsistency between this protocol and the Clinical Study Agreement, the terms of 
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 to their last protocol-specified visit/assessment, regardless of the number of 
doses of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.5 and Section 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last subject in the study.
6.4
Data Management 
Data management will be performed by MedImmune Data Management staff according to the 
Data Management Plan.
An electronic data capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded in the eCRFs as specified in the study protocol 
and in accordance with the eCRF instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 


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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 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.
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. MedImmune will not provide individual genotype results 
to subjects, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law.
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 informed consent form (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 is responsible for submitting these documents 
to the applicable IEC and distributing them to the study site staff.
The opinion of the IEC must be given in writing. The investigator must provide a copy of 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 must be re-approved by the IEC annually.
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 


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unexpected serious adverse reactions where relevant, to regulatory authorities, IEC, and 
principal investigators.
Each principal investigator is responsible for providing reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product to the 
IEC. 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 principle investigator(s). Before 
implementation, amended protocols must be approved by relevant IEC (see 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.


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If local regulations require, any unsubstantial changes will be communicated to or approved 
by each IEC.
7.5
Audits and Inspections
Authorised 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
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for estimating rates of gluconeogenesis. Application to the fasted state. J Clin Invest. 1995 
Jan;95(1):172-8.
Leung et al, 1986
Leung NW, Farrant P, and Peters TJ. Liver volume measurement by ultrasonography in 
normal subjects and alcoholic patients. J Hepatol. 1986;2(2):157-64.
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.
Magnusson et al, 1992
Magnusson I, Rothman DL, Katz LD, Shulman RG, and Shulman GI. Increased rate of 
gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin 
Invest. 1992 Oct;90(4):1323-7.


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Moore et al, 2017
Moore MC, Smith MS, Farmer B, Kraft G, Shiota M, Williams PE, Cherrington AD. Priming 
Effect of a Morning Meal on Hepatic Glucose Disposition Later in the Day. Diabetes. 2017 
May;66(5):1136-1145. 
Petersen et al, 2005
Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of non-
alcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight 
reduction in patients with type 2 diabetes. Diabetes. 2005 Mar;54(3):603-8.
Rothman et al, 1991
Rothman DL, Magnusson I, Kat LD, Shulman RG, Shulman GI. Quantitation of hepatic 
glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science. 1991 
Oct 25;254(5031):573-6.
Savage et al, 2007
Savage DB, Petersen KF, Shulman GI. Disordered Lipid Metabolism and the Pathogenesis of 
Insulin Resistance. Physiol Rev. 2007 Apr;87(2):507-20.
Skyder et al, 2017
Skyder JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et al. Differentiation of 
diabetes by pathophysiology, natural history, and prognosis. Diabetes. 2017 Feb;66(2):241-55.
Uhlén et al, 2015
Uhlén M1, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. 
Proteomics. Tissue-based map of the human proteome. Science. 2015 Jan 23;347 (6220): 
1260419. doi: 10.1126/science.1260419.
Victoza package insert, 2017
Victoza package insert. Bagsvaerd, DK: Novo Nordisk A/S, 2017. |
Wynne et al, 2006
Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS. Oxyntomodulin increases 
energy expenditure in addition to decreasing energy intake in overweight and obese humans: a 
randomized controlled trial. Int J Obes. 2006;30(12):1729-36.




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Section Changed
Key Details of the Amendment
“from Day 33 to Day 36” to “from Day 34 to 
Day 36”
Table 11 (Schedule of Follow-up Procedures)
•
Revised immunogenicity (ADA) footnote to
specify that subjects with an ADA titre ≥ 10 at 
the follow-up visit will be asked to return to 
provide another ADA sample at 3-month 
intervals until the titre is < 10
Section 4.3.1.1 (Mixed-meal Tolerance Tests), 
Section 4.3.4 (Pharmacodynamic Evaluation and 
Measures), Section 4.3.7 (Biomarker Evaluation and 
Methods), and Section 5.3.1 (Time Period for 
Collection of Adverse Events)
•
Specified 35-day treatment length and/or Part A 
versus Part B time points as needed throughout 
for clarification
Section 4.5.1 (Identity of Investigational Product[s])
•
Corrected number of days liraglutide to be 
administered for Part B of the study
Section 4.5.1.5 (Reporting Product Complaints)
•
Deleted an obsolete phone number and fax 
number
Section 10.1 (Appendix 1 – Signatures)
•
Updated the sponsor representative name and 
contact information
ADA = anti-drug antibody; COVID-19 = coronavirus disease; MMTT = mixed-meal tolerance test; 
MRS = magnetic resonance spectroscopy; PK = pharmacokinetic
9.2
Protocol Amendment 5, 03May2019
Based on the analysis of data from Part A of this study, changes to Part B have been made to
improve tolerability while still evaluating efficacy. The introduction of a multi-dose pen 
device to administer the investigational product facilitated the introduction of 50 µg starting 
dose but this has had an impact on the duration of dosing. Formatting changes have also been 
made in line with the current process of the sponsor.
Changes relating to Part B of the study have been made in Protocol Amendment 5 and are 
summarized below. Other minor editorial changes have also been made.
Section Changed
Key Details of the Amendment
Amendment 5 / 03May2019
Section 1.7 (Research Hypothesis), Section 2.1 
(Primary Objective and Associated Endpoints), 
Section 2.2 (Secondary Objective and Associated 
Endpoints), Section 2.3 (Exploratory Objective and 
Associated Endpoints), Section 3.2.3.1 (Primary 
Endpoint), 
•
Change in the primary endpoint to % change in 
fasting glycogen (at T = 24 hrs time point)
•
Change in MRS schedule from 0, 4, 9, 14, and 
24 hrs to 0, 5, 14 and 24 hrs
•
Addition of analysis of endpoints are Day 35 for 
Part B
Section 3.1.1 (Overview), Section 3.1.2 (Treatment), 
Section 3.1.3 (Dose Escalation), Table 1, Section 
•
The dosing schedule for MEDI0382 will now 
commence at a lower start dose of 50 µg and 
will be uptitrated in 7-day intervals to 300 µg 


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Section Changed
Key Details of the Amendment
3.2.3.3 (Exploratory Endpoints), Section 4.5 
(Investigational Products), Section 4.8.3 (Efficacy)
across 35 days; the end of treatment assessments 
have been altered to reflect this.
•
The delivery device for MEDI0382 will be a 
pen device rather than PFS
•
Introduction of a 14 hour fast prior to 
measurement of the scans related to the primary 
endpoint
•
Alteration to visits; one less outpatient visit and 
two additional remote contacts to guide dose 
titration and collect AEs/SAEs. 
Section 3.1.1 (Overview), Section 4.1.1 (Number of 
Subjects), Section 4.8.2 (Sample Size)
•
The number of subjects for Part B has increase 
to 30 (maximum 35 subjects)
Table 9 (Schedule of Treatment Period Study 
Procedures (Part B), Table 10 (Schedule of Treatment 
Period Study Procedures (Part B), Section 4.3.5 
(Pharmacokinetic Evaluation and Methods)
•
Tables were added
•
On Day 8, collection of laboratory assessments 
and predose PK and clarification of footnotes.
•
Day 15 is now converted to a remote contact
Section 3.1.1 (Overview), Section 4.3.1.1 (Mixed-
meal Tolerance Test)
•
Removal of optional C13 glucose administration
Section 4.5.1.3 (At Home Administration)
•
Instructions specific to the use of the pen were 
added
Section 4.6.2 (Methods to Ensure Blinding)
•
Blinding instructions for the pen were added.
Section 10.5 (Appendix 5 - Actions Required in 
Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law)
•
Update of Hy’s Law monitoring in line with 
Sponsots current practice
Section 10.9 (Appendix 9 – Summary of Potential 
Risks)
•
This appendix has been removed as the current 
version of the IB should be referenced for this 
information and hold the most up to date 
summary of potential risks.
AE = adverse event; hrs = hours; IB = Investigator’s Brochure; MRS = magnetic resonance spectroscopy, PFS = 
pre-filled syringe; PK = pharmacokinetics; SAE = serious adverse event; T = time
9.3
Protocol Amendment 4, 24Sep2018
Changes have been made in Protocol Amendment 4. Major changes are summarised below. 
Other minor editorial changes have also been made.
Key Details of Amendment
Reason for Amendment
Amendment 4 / 24Sep2018
Synopsis, Section 3.1.1, 3.1.2, and 4.1.1
Increased subject numbers
The number of subjects to be randomised in Part A 
was increased from 16 to 20 in order to ensure that at 
least 16 subjects complete the study. The total 
number of subjects in Part A and Part B therefore 
also increased to 44. 


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Key Details of Amendment
Reason for Amendment
Tables 4.2.2-1 and 4.2.2-2
Correction of typographic errors
Correction of error message for the footnote reference 
on the Serial MRS scans row. Footnote reference “m” 
added.
Correction of timeframe for MMTT procedure and 
administration of standard liquid meal for this test so 
that footnotes match.
Section 10.7 (Appendix 7)
Added clarity
Updates to wording about sample storage as some 
samples will be stored at TS Biorepository and others 
at AZ Biobank in Gothenburg (due to long term 
storage requirements in Sweden)
Section 10.8 (Appendix 8)
Added clarity
Modified to include only Standardised Meals, 
Deuterated water, MMTTs, and Serial MRS Scans 
(removed blood samples except for those taken along 
with the MMTT) 
AZ = AstraZeneca; MMTT = mixed-meal tolerance test; MRS = magnetic resonance spectroscopy; TS = 
Translational Sciences
9.4
Protocol Amendment 3, 08May2018
Key Details of Amendment
Reason for Amendment
Amendment 3 / 08May2018
Protocol Synopsis, Section 3.1.1, Table 4.2.2-1 and 
footnote p to update randomisation time to occur on 
Day -1 or Day 1
Text was amended to provide clarity.
Protocol Synopsis and Section 4.8.7 to reflect Part A 
interim analysis will be done after last subject last 
visit
Text was amended to provide clarity.
Section 4.3.4, revised to reflect that 70% 2H2O will 
be used instead of 100% 2H2O and calculations 
adjusted accordingly
Text was amended to provide clarity.
Tables 4.2.2-1 (footnote g), added to reflect that 
subjects assigned to liraglutide do not need to 
undergo blood tests for ADAs
Text was amended to provide clarity.
Table 4.2.2-2 (footnotes e and n added) to reflect that 
subjects assigned to liraglutide do not need to 
undergo blood tests for ADAs, and to reinforce that 
investigational product (MEDI0382 or placebo) will 
be dispensed on Day 26
Text was amended to provide clarity.
Table 4.2.3-1 (footnote b revised) to reflect that 
subjects assigned to liraglutide do not need to 
undergo blood tests for ADAs
Text was amended to provide clarity.


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Key Details of Amendment
Reason for Amendment
Section 4.3.2.3 to reflect lead II may also be used for 
ECG analysis
Text was amended to provide clarity.
Section 3.2.1 and Section 4.8.2 
Typographic corrections (ie, missing D for D Code 
corrected and addition of 0 to 0.1, respectively)
Section 4.5.1 to remove reference to a take home 
carton. Syringes are pre-packaged into cartons with 
8 syringes.
Text was amended to provide clarity.
Section 4.8.7, revised to: An interim analysis after the 
last subject ‘completes their last visit’
Text was amended to provide clarity.
9.5
Protocol Amendment 2, 29Mar2018
Key Details of Amendment
Reason for Amendment
Amendment 2 / 29Mar2018
Synopsis and Sections 3.1.1, 3.2.3.1 and 4.3.1.1 and 
corresponding footnote k in table 4.2.2.1 and 
footnotes h and j in 4.2.2.2 have been updated to 
reflect that co-administration of C-13 labelled 
glucose to augment the MRS signal may not be 
required and is therefore now an optional component 
to this study.
Update to make a procedure that was previously a 
core part of the main study into an optional 
assessment.


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9.6
Protocol Amendment 1, 27Mar2018
Changes have been made in Protocol Amendment 1 at the request of the Swedish Medical 
Products Agency. A summary of these changes is provided below.
Key Details of Amendment
Reason for Amendment
Amendment 1 / 27Mar2018
Section 1.6 and Appendix 9, more detail has been 
added regarding the benefit risk associated with the 
study.
At the request of the Swedish Medical Products
Agency. 
Section 4.1.3 Exclusion criterion 3 and Section 4.7.2 
have been modified to ensure subjects who take 
warfarin are not enrolled and to clarify that warfarin 
is a prohibited concomitant medication
Sections 4.1.6 and 4.4 have been modified to clarify 
that study suspension applies to both Parts A and B
Synopsis and Section 4.8.1.1 have been modified to 
specify that the efficacy analyses will be performed 
using an ITT population (according to the 
randomised treatment).
ITT = intent=to-treat


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10
APPENDICES
10.1
Appendix 1 - Signatures
Sponsor Signature(s)
An Exploratory Phase 2, Randomised, Double-Blind, Placebo-Controlled and Open-Label 
Active Comparator Study to Evaluate the Effect of MEDI0382 on Hepatic Glycogen 
Metabolism in Overweight and Obese Subjects with Type 2 Diabetes Mellitus
I agree to the terms of this protocol.
Signature and date: 
Electronic signature attached


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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 13.

Female subjects must refrain from egg cell donation and breastfeeding while on study and 
for 28 days after the final dose of investigational product.
Table 13
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®)
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 oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 


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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
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
An event of mild intensity that is usually transient and may 
require only minimal treatment or therapeutic intervention. The 
event does not generally interfere with usual activities of daily 
living.
Grade 2
An event of moderate intensity that is usually alleviated with 
additional specific therapeutic intervention. The event interferes 
with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject.
Grade 3
A severe event that requires intensive therapeutic intervention. 
The event interrupts usual activities of daily living, or 
significantly affects the clinical status of the subject.
Grade 4
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental disabilities 
that affect or limit the ability of the subject to perform activities 
of daily living (eating, ambulation, toileting, etc).


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Grade 5
Death 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:

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:


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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 Disease 
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 recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for 
all 3 categories). 
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, 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
10.5.1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law cases and Hy’s Law cases. 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.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible potential Hy’s Law events.
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.
10.5.2
Definitions
10.5.2.1
Potential Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase.
10.5.2.2
Hy’s Law
AST or ALT ≥ 3 × ULN together with total bilirubin (TBL) ≥ 2 × ULN at any point during the 
study following the start of investigational product irrespective of an increase in alkaline 
phosphatase.


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For potential Hy’s Law and Hy’s Law, 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.
10.5.3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
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 potential Hy’s Law criteria (see Section 10.5.2.2) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
10.5.4
Follow-up
10.5.4.1
Potential Hy’s Law Criteria Are Not Met
If the subject does not meet potential Hy’s Law criteria the investigator will:

Inform the study representative that the subject has not met potential Hy’s Law criteria

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
10.5.4.2
Potential Hy’s Law Criteria Are Met
If the subject does meet potential Hy’s Law criteria the investigator will:

Determine whether potential Hy’s Law criteria were met at any study visit prior to 
starting study treatment

Notify the sponsor study representative who wil then inform the study team.

Within 1 day of potential Hy’s Law criteria being met, the investigator will report the 
case as an SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and 
causality assessment ‘yes/related’ according to clinical study protocol process for SAE 
reporting


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The medical monitor contacts the investigator, to provide guidance, discuss and agree on an 
approach for the study subjects’ follow-up (including any further laboratory testing) and the 
continuous review of data. 
Subsequent to this contact the investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
Complete follow-up SAE form as required.

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the medical monitor 

Complete the relevant eCRF Modules as information becomes available 
10.5.5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law 
criteria are met.
As soon as possible 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 potential Hy’s Law criteria other than DILI 
caused by the investigational product, to ensure timely analysis and reporting to health 
authorities per local requirements from the date potential Hy’s Law criteria were met. The 
medical monitor and Global Safety Physician will also be involved in this review together 
with other subject matter experts as appropriate.
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, update the previously submitted 
potential Hy’s Law SAE and AE CRFs accordingly with the new information 
(reassessing event term; causality and seriousness criteria) following sponsor’s 
standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:


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
Send the updated SAE (report term ‘Hy’s Law’) according to the sponsor’s standard 
processes.

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the Hy’s Law case, a causality assessment 
of ‘related’ should be assigned
If, there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for Hy’s Law, then it is assumed 
that there is no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of Potential Hy’s Law 
(report term now ‘Hy’s Law case’), ensuring causality assessment are related to the 
investigational product and seriousness criteria is medically important, according to 
the clinical study protocol process for SAE reporting

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether Hy’s Law criteria are still met. Update the previously submitted 
potential Hy’s Law SAE report following clinical study protocol process for SAE 
reporting, according to the outcome of the review and amend the reported term if an 
alternative explanation for the liver biochemistry elevations is determined
10.5.6
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgement. If required, for additional 
assistance on which tests could be used to evaluate other potential causes of liver dysfunction,
consult with the Hepatic Safety Knowledge Group. Any test results need to be recorded.


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Hy’s Law lab kit for central laboratories
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgM and IgG anti-HCV
HCV RNA
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
10.5.7
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) 'Drug-induced liver injury: Premarketing 
clinical evaluation'


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10.6
Appendix 6 - Genetic Research
Rationale and Objectives
MedImmune intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. Genetic research samples may be used to perform whole genome 
and whole exome sequencing.
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic Research Plan and Procedures
Selection of genetic research population and study selection record
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit. The subject will 
not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, subjects must fulfill all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and provide informed consent for 
the genetic sampling and analyses.
Exclusion Criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection
Discontinuation of Subjects from this Genetic Research
Specific reasons for discontinuing a subject from this genetic research are:
Withdrawal of consent for genetic research: Subjects may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study. Voluntary discontinuation will not prejudice further treatment. Procedures for 
discontinuation are outlined in Section 4.1.6 of the main Protocol.


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Collection of Samples for Genetic Research
The blood sample for genetic research will be obtained from the subjects at Visit 2 provided 
that the subject has given explicit consent for this. Although DNA variants are a stable 
parameter, early sample collection is preferred to avoid introducing bias through excluding 
subjects who may withdraw due to an AE, such subjects would be important to include in any 
genetic analysis. If for any reason the sample is not collected at Visit 2, it may be taken at any 
visit until the last study visit. Only one sample should be collected per subject for genetic 
research during the study. Samples will be collected, labelled, stored and shipped as detailed 
in the Laboratory Manual.
Coding and Storage of DNA Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last subject last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable by the second, unique number only. This number is used to identify the sample 
and corresponding data at the MedImmune genetics laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(MedImmune employee or designated organisations working with the DNA).
The link between the subject randomisation code and the second number will be maintained 
and stored in a secure environment, with restricted access at MedImmune or designated 
organisations. The link will be used to identify the relevant DNA samples for analysis, 
facilitate correlation of genotypic results with clinical data, allow regulatory audit, and trace 
samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 7.2 of the main Protocol.
Informed Consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre. The 
principal investigator(s) is responsible for ensuring that consent is given freely and that the 


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subject understands that they may freely discontinue from the genetic aspect of the study at 
any time.
Subject Data Protection
MedImmune will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, or general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a MedImmune physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
Data Management
Any genotype data generated in this study will be stored at a secure system at MedImmune 
and/or designated organisations to analyse the samples.
The results from this genetic research may be reported in a separate report from the CSR or 
published in scientific journals.
MedImmune and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as Hospitals, Academic Organisations, or Health Insurance Companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health-related research purposes. Researchers may see summary 
results but they will not be able to see individual subject data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical Methods and Determination of Sample Size
The number of subjects that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan will be prepared where appropriate.


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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 and microbiome 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 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.
Stool samples retained for further use are registered in the Translational Sciences 
Biorepository during the entire life cycle. Blood samples for future genetic and non-genetic 
testing along with any surplus PK or ADA samples will go to the AstraZeneca Biobank in 
Gothenburg.






SIGNATURE PAGE
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electronically and this page is the manifestation of the electronic signature
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Document Title:
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Document ID:
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SAP_001.pdf: 
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Statistical Analysis Plan
An Exploratory Phase 2, Randomised, Double-blind, Placebo-
controlled, and Open-label Active Comparator Study to Evaluate 
the Effect of MEDI0382 on Hepatic Glycogen Metabolism in 
Overweight and Obese Subjects with Type 2 Diabetes Mellitus
Protocol Number: D5670C00022


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TABLE OF CONTENTS
1
INTRODUCTION ......................................................................................................6
2
STUDY OVERVIEW .................................................................................................6
2.1
Study Objectives...............................................................................................6
2.1.1Primary Study Objective(s) .......................................................................6
2.1.2Secondary Study Objectives ......................................................................6
2.1.3Exploratory Study Objectives....................................................................6
2.2
Study Design.....................................................................................................7
2.3
Treatment Assignment and Blinding .................................................................8
2.4
Sample Size ......................................................................................................9
3
STATISTICAL METHODS........................................................................................9
3.1
General Considerations .....................................................................................9
3.2
Analysis Populations.......................................................................................10
3.3
Study Subjects ................................................................................................11
3.3.1Subject Disposition and Completion Status .............................................11
3.3.2Demographics and Baseline Characteristics.............................................11
3.3.3Study Drug Exposure ..............................................................................11
3.3.4Concomitant Medications........................................................................11
3.4
Efficacy Analyses ...........................................................................................12
3.4.1Primary Efficacy Endpoint(s) and Analyses.............................................12
3.4.1.1
Primary Efficacy Endpoint(s).................................................12
3.4.1.2
Handling of Dropouts and Missing Data.................................12
3.4.1.3
Primary Efficacy Analysis......................................................12
3.4.2Secondary Efficacy Endpoint(s) and Analyses.........................................13
3.4.2.1
Secondary Efficacy Endpoint(s).............................................13
3.4.2.2
Secondary Efficacy Analyses .................................................13
3.4.3Exploratory Efficacy Endpoint(s) and Analyses.......................................14
3.4.3.1
Exploratory Efficacy Endpoint(s)...........................................14
3.4.3.2
Exploratory Efficacy Analyses ...............................................14
3.5
Pharmacodynamic Analyses............................................................................14
3.5.1Exploratory Pharmacodynamic Endpoint(s) and Analyses.......................14
3.5.1.1
Exploratory Pharmacodynamic Endpoint(s) ...........................14
3.5.1.2
Exploratory Pharmacodynamic Analysis ................................15
3.6
Safety Analyses...............................................................................................15
3.6.1Adverse Events and Serious Adverse Events ...........................................15
3.6.2Deaths and Treatment Discontinuations due to Adverse Events...............16
3.6.3Clinical Laboratory Evaluation................................................................16
3.6.4Other Safety Evaluations.........................................................................16


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3.6.4.1
Vital Signs .............................................................................16
3.6.4.2
Electrocardiogram..................................................................16
3.7
Immunogenicity..............................................................................................17
3.8
Pharmacokinetics ............................................................................................17
3.9
Protocol Deviations.........................................................................................18
4
INTERIM ANALYSIS..............................................................................................18
5
REFERENCES .........................................................................................................18
6
VERSION HISTORY ...............................................................................................18
LIST OF TABLES
Table 3.2-1
Analysis Populations ........................................................................11


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List of Abbreviations
Abbreviation or 
Specialized Term
Definition
AE
Adverse event
ANCOVA
Analysis of covariance
ATC
Anatomical Therapeutic Chemical
AUC
Area under the concentration-time curve
BMI
Body mass index
C2
Carbon atom number 2 in glucose molecule (used to assess 2H enrichment)
C6
Carbon atom number 6 in glucose molecule (used to assess 2H enrichment)
CI
Confidence interval
Ctrough
Trough plasma concentration, measured at the end of a dosing interval, taken 
directly before next administration
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
ECG
Electrocardiogram
GLP-1
glucagon-like peptide-1
2H
deuterium
HbA1c
Glycated hemoglobin
IM
Immunogenicity
ITT
Intent-to-treat
IV
intravenous
IWRS
Interactive web response system
MedDRA
Medical dictionary for regulatory activities
MMTT
Mixed-meal tolerance test
MRI
Magnetic resonance imaging
MRS
Magnetic resonance spectroscopy
P
Probability
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PR
ECG PR interval
PT
MedDRA preferred term
QRS
ECG QRS interval
QT
ECG QT interval
QTcF
ECG QT interval corrected for heart rate using Fridericia’s formula
RR
ECG RR interval
SAE
Serious adverse event
SAP
Statistical analysis plan
SPP
Statistical Programming Plan


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Abbreviation or 
Specialized Term
Definition
SC
Subcutaneous
SID
Subject ID
SOC
MedDRA system organ class
T
Time
T2DM
Type 2 Diabetes Mellitus
ULN
upper limit of normal
WHO-DD
WHO Drug Dictionary enhanced






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period where metformin therapy will be suspended at the beginning of the study starting from 
Day -4 (metformin dosing to resume on Day 2) and the end of the study starting from Day 25 
(metformin dosing to resume on Day 30). Across the course of the study (up to 126 days in 
total including screening) subjects will have a total of 6 study visits, 6 nights of inpatient stay 
and will undergo a total of 10 MRS scans alongside additional assessments and blood 
sampling.
Part B:
In Part B a comparison will be made between MEDI0382, 
 
 placebo and liraglutide once daily titrated from 0.6 to 1.8 mg in 7-day intervals. 
The treatment duration will be 35 days in each treatment group, with subjects randomized to 
liraglutide spending 21 days at 1.8 mg, in contrast subjects randomized to MEDI0382 will 
spend 14 days at top dose of 300 μg.
The procedures for subjects who go through to the completion of the visit on Day 8, are 
identical to Part A; aside from the MRS scanning and related activities that will occur at 
baseline prior to treatment, then at T = 0, 5, 14 and 24 hours and at the end of the 35 day 
treatment period as detailed in the schedule of events. The duration of MRS scans will be 
approximately 40 minutes with the exception of the baseline and end of treatment scans used 
for liver fat evaluation which will be prolonged and up to 1 hour 45 minutes in duration. 
2.3
Treatment Assignment and Blinding
An IWRS will be used for randomization to a treatment group and assignment of 
investigational product kit numbers. A subject is considered randomized into the study when 
the IWRS provides the assignment of the subject’s investigational product kit number.
Eligible subjects will be randomized at a 1:1 ratio following screening to receive either 
blinded MEDI0382 SC or placebo SC (Part A) or randomized at a 1:1:1 ratio following 
screening to receive either blinded MEDI0382 SC or placebo SC or open-label liraglutide SC 
(Part B). The IWRS will assign a unique randomization code and treatment group to the 
subject at the time of randomization. Subjects who withdraw from the study may be replaced, 
if deemed necessary by the medical monitor, to ensure that safety data are collected on a 
sufficient number of subjects.
In Part A only, this is a double-blind study in which MEDI0382 and placebo 
 
Neither the subject nor any of 
the investigator or sponsor staff who are involved in the treatment or clinical evaluation of 
subjects will be aware of treatment received. 


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 To maintain the blind in Part A of the study, investigational 
product (MEDI0382 and placebo) prefilled syringes will be handled by an unblinded 
investigational product manager or unblinded study personnel who will not be involved in 
the treatment or clinical evaluation of subjects. An unblinded site monitor will perform 
investigational product accountability, and this will be a different person from the blinded 
site monitor who will oversee other aspects of the study at the clinical site.
. Each subject will 
know the volume of investigational product they have been instructed to select and 
administer, the subject and site staff are blinded with respect to whether they are receiving 
MEDI0382 or placebo. Liraglutide used in Part B will be open-label.
The site will maintain a written plan detailing which staff members are blinded/unblinded 
and the process of investigational product administration used to maintain the blind.
2.4
Sample Size
 
 
 
 
 
 
 
 
 
 
 
 
3
STATISTICAL METHODS
3.1
General Considerations
In the event that there is a delay in data delivery or the full set of results is not expected to be 
available in timely manner (for example; follow-up of positive ADA results at 3 and 6 
CCI


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months after the follow-up visit)  an initial database lock in Part B for the purpose of clinical 
study analysis and reporting will be performed when the last randomized subject completes 
the final visit or is discontinued prior to that visit. Final database lock will occur once all 
results have been received in the database. 
In the event that an initial DBL is required, results received after this point may be reported 
in the clinical study report addendum. 
Data will be presented in data listings sorted by study part, treatment, subject number and 
date collected, where appropriate. Tabular summaries will be presented by study part and 
treatment. Categorical data will be summarized by study part and treatment with the number 
and percentage of subjects within each category. In general, continuous variables will be 
summarized by study part and treatment with descriptive statistics including mean, standard 
deviation, median, minimum, and maximum. For some variables, the geometric mean and 
95% CI may be presented.
All available data will be included in the analyses and missing data will not be imputed 
except as specified in the calculation of the AUC values. Unless specified otherwise, baseline 
values will be defined as the last valid assessment prior to the first administration of study 
medication.
The study objectives will be evaluated with analyses that include data from both Part A and 
Part B, if Part B is conducted. Analyses will also be performed separately for each study part.  
In general, the efficacy analyses will be analyzed with the ITT population and all other 
analyses will be performed with the As-treated population.
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) in a UNIX environment. 
3.2
Analysis Populations
The analysis populations are defined in Table 3.2-1.


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Table 3.2-1
Analysis Populations
Population
Description
Intent-to-treat 
(ITT) population
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 and subjects will be analyzed according to the treatment they 
actually received.
Pharmacokinetic 
population
The PK population includes all subjects who received at least one dose of 
investigational product and had at least one PK blood sample taken that is above 
the lower limit of quantitation.
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 by study part. 
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 study part and 
by treatment. 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, baseline medication use, HbA1c, 
glucose, blood pressure, and pulse rate.
3.3.3
Study Drug Exposure
The number of doses and total dose received will be summarized by study part for each 
investigational product (MEDI0382 or placebo or liraglutide) by descriptive statistics and 
frequencies.
3.3.4
Concomitant Medications
Concomitant medications will be coded using the current WHO Drug Dictionary enhanced
(WHO-DD). The number and percentage of subjects who took concomitant medications for 
the highest anatomical therapeutic chemical (ATC) class and preferred term will be 
summarized by study part and treatment. The summary of concomitant medications will 
include all concomitant medications taken on or after the date of first dose of investigational 


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product or any concomitant medication started prior to first dose of investigational product 
that continued beyond the date of first dose of investigational product.
3.4
Efficacy Analyses
3.4.1
Primary Efficacy Endpoint(s) and Analyses
3.4.1.1
Primary Efficacy Endpoint(s)
Change in hepatic glycogen concentration adjusted for liver volume as measured by MRS at 
T = 4 hours post standardized morning meal from baseline (Day -1) to the end of 28 days of 
treatment (Part A only)
Percentage change in fasting glycogen concentration adjusted for liver volume as measured 
by MRS at T = 24 hours post standardized morning meal from baseline (Day 1) to the end of 
35 days of treatment (Part B only)
3.4.1.2
Handling of Dropouts and Missing Data
Since there is only one post-baseline measurement MRS, subjects who do not have a valid 
baseline evaluation or a valid Day 28 (Part A) and Day 35 (Part B) MRS evaluation at 4 
hours (Part A) and 24 hours (Part B) post standardized morning meal will not contribute to
the analysis.
3.4.1.3
Primary Efficacy Analysis
The primary efficacy analysis will be performed using the ITT population. 
The primary endpoint, change in hepatic glycogen concentration (measured by MRS, 
adjusted for liver volume) at T = 4 hours post standardized morning meal from baseline (Day 
-1) to the end of 28 days of treatment will be analyzed using an analysis of covariance 
(ANCOVA) model with baseline covariate and treatment group. Pairwise comparisons
between MEDI0382 and placebo will be performed within this analysis (Part A only).
The primary endpoint, percentage change in fasting hepatic glycogen concentration (adjusted 
for liver volume) as measured by MRS at T=24 hours post standardized morning meal from 
baseline (Day 1) to the end of 35 days of treatment (Day 36), will be compared between the 
MEDI0382 and placebo groups using an analysis of covariance (ANCOVA) model adjusting 
for baseline value and treatment group (Part B only).


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3.4.2
Secondary Efficacy Endpoint(s) and Analyses
3.4.2.1
Secondary Efficacy Endpoint(s)
•
Percentage change in fasting hepatic glycogen concentration adjusted for liver volume as 
measured by MRS at T = 24 hours post standardized morning meal from baseline (Day -
1) to the end of 28 days of treatment (versus placebo, Part A only) 
•
Percentage change in fasting hepatic glycogen concentration adjusted for liver volume as 
measured by MRS at T = 24 hours post standardized morning meal from baseline (Day 1) 
to the end of 35 days of treatment (versus liraglutide, Part B only)
•
Change in hepatic fat fraction from baseline as measured by magnetic resonance imaging 
(Day -1) to the end of 28 days of treatment (Part A only) 
•
Change in hepatic fat fraction from baseline as measured by magnetic resonance imaging 
(Day 1) to the end of 35 days of treatment (Part B only)
•
Measures of safety and tolerability (vital signs, ECGs, laboratory test results, AEs)
•
Development of ADA and titre (if confirmed positive)
3.4.2.2
Secondary Efficacy Analyses
The secondary efficacy analyses will be performed using the ITT population. 
The percentage change in fasting hepatic glycogen concentration (measured by MRS, 
adjusted for liver volume) at T = 24 hours post standardized morning meal from baseline 
(Day 1) to the end of 35 days of treatment, will be compared between MEDI0382 and 
liraglutide groups only in Part B of the study. This will be done using the ANCOVA model 
adjusting for baseline value and treatment group. A similar analysis will be applied to 
measure change in hepatic fat fraction from baseline (Day -1 or Day 1) to the end of 35 days 
of treatment (Day 35 or 36) versus placebo (Part B only).
The percentage change in fasting glycogen concentration (measured by MRS, adjusted for 
liver volume) at T = 24 hours post standardized morning meal from baseline (Day -1) to the 
end of 28 days of treatment, will be compared between MEDI0382 and placebo groups only 
in Part A of the study. This will be done using the ANCOVA model adjusting for baseline 
value and treatment group. A similar analysis will be applied to measure change in hepatic 
fat fraction from baseline (Day -1) to the end of 28 days of treatment versus placebo (Part A 
only).  






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Statistical Analysis Plan for Protocol D5670C00022
MEDI0382
31May2021; Version 3
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3.6.2
Deaths and Treatment Discontinuations due to Adverse Events
A listing of any deaths will be provided which will include the MedDRA system organ class 
and preferred term. AEs resulting in permanent discontinuation from study drug will be 
summarized by study part and treatment. The summary will include results summarized 
overall and by MedDRA System Organ Class and Preferred Term.
3.6.3
Clinical Laboratory Evaluation
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 study part and treatment group. Other laboratory parameters collected will 
be summarized in a similar manner.  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 study part and treatment at each evaluation time.
3.6.4
Other Safety Evaluations
3.6.4.1
Vital Signs
Vital signs including pulse rate (beats/min), systolic and diastolic blood pressure (mmHg), 
temperature (oC), and respiratory rate (breaths/min), as well as the change from baseline for 
each of those parameters, will be descriptively summarized study part and treatment.
3.6.4.2
Electrocardiogram
Electrocardiogram parameters will be assessed with a single ECG at each evaluation 
(Screening, Day 1, and Day 26) using a digitally recorded standard 12-lead 
electrocardiograph. The ECG parameters: Heart rate, RR, PR, QRS and QT intervals as well 
as derived parameter QT corrected interval QTcF (Fridericia’s formula 

√
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) will be 
summarized.  The results at Day 26 as well as the change from baseline (Day 1) will be 
descriptively summarized by study part and treatment.  For the qualitative variable ECG 
interpretation, the ECG Interpretation results will be summarized with frequencies and 
percentages at each evaluation.


MedImmune
Statistical Analysis Plan for Protocol D5670C00022
MEDI0382
31May2021; Version 3
CONFIDENTIAL AND PROPRIETARY
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SAP template version 3.0
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
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 pharmacokinetic data is described below.  However, the results of these 
analyses will be provided in the pharmacokinetic report that is prepared by the 




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Document Name: d5670c00022-sap-ed-3
Document Title:
Statistical Analysis Plan Edition 3
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