Conditions: Type II Diabetes Mellitus Renal Insufficiency
Keywords: Type 2 Diabetes Mellitus MEDI0382 Renal Impairment Glucose concentration Hemoglobin A1c
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
A study to look at the effect MEDI0382 has on blood sugar in people with type 2 diabetes and kidney problems and also to check that MEDI0382 is well tolerated.

Detailed description:

Arms:
arm 1: Participants will receive subcutaneous (SC) dose of MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days. arm 2: Participants will receive SC dose of placebo matched to MEDI0382 once daily for 32 days.

Interventions: intervention 1: MEDI0382 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive subcutaneous MEDI0382 titrated from 50 μg upto 300 μg (50 μg once daily for 4 days, followed by 100 μg daily for 7 days, 200 μg daily for 7 days, and 300 μg daily for 14 days) for 32 days. intervention 2: Participants will receive SC placebo matched to MEDI0382 once daily for 32 days.

Protocol document:
Prot_000.pdf: 
           NCT03550378


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A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy, Safety, and Pharmacokinetics of 
MEDI0382 in Subjects with Type 2 Diabetes Mellitus and Renal 
Impairment
Sponsor Protocol Number: D5670C00013
Application Number:
EudraCT number 2018-000019-26
Investigational Product:
MEDI0382
Sponsor:
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca, Milstein Building, Granta Park, Cambridge, CB21 
6GH, UK
Medical Monitor:
 MedImmune
Phone: 
; Fax: 
Contract Research Organization: Covance, Inc.
Protocol History, Date:
Original Protocol, 07Feb2018
Protocol Amendment 1, 28Feb2018
Protocol Amendment 2, 06Apr2018
Protocol Amendment 3, 11Oct2018
Protocol Amendment 4, 12Nov2018
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorisation from MedImmune.


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PROTOCOL SYNOPSIS
TITLE
A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of MEDI0382 in Subjects with Type 2 Diabetes Mellitus and Renal Impairment 
HYPOTHESES
Primary Hypothesis:
Administration of MEDI0382 once daily titrated up to a dose level of 
 will result in superior blood 
glucose control versus placebo after 32 days of treatment in subjects with type 2 diabetes mellitus (T2DM) and 
renal impairment.
Secondary Hypotheses:
•
Administration of MEDI0382 once daily titrated up to a dose level of 
 across 32 days will be well 
tolerated in subjects with T2DM and renal impairment
•
Administration of MEDI0382 once daily titrated up to a dose level of 
 will result in superior weight 
loss versus placebo after 32 days of treatment in subjects with T2DM and renal impairment
•
Administration of MEDI0382 once daily titrated up to a dose level of 
 will have a predictable 
pharmacokinetic (PK) profile in subjects with T2DM and renal impairment
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the effect of MEDI0382 titrated up to a dose 
level of 
 on glucose control versus placebo after 
32 days of treatment
•
Percentage change in glucose area under the 
curve (AUC) as measured by a standardised 
mixed-meal tolerance test (MMTT) from 
baseline (Day -5) to the end of 32 days of 
treatment (Day 32)
Secondary
To characterise the safety profile and tolerability of 
MEDI0382 titrated up to a dose level of 
 during 
dosing and follow-up in subjects with T2DM and renal 
impairment 
•
Measures of safety and tolerability (adverse 
events/serious adverse events [AEs/SAEs], vital 
signs, postural blood pressure [BP] changes, 
electrocardiogram [ECG], laboratory test results)
•
Change in mean 24-hour pulse rate, systolic and 
diastolic blood pressure from baseline (Day -5) 
to the end of dosing at each dose level (Days 4, 
11, 18 and 32)
To assess the effects of MEDI0382 titrated up to a 
dose level of 
 on additional measures of 
glycaemic control versus placebo after 32 days of 
treatment 
•
Change in haemoglobin A1c (HbA1c) from 
baseline (Day 1) to the end of 32 days of 
treatment (Day 32)
•
Change in fasting glucose from baseline (Day 1) 
to the end of 32 days of treatment (Day 32)
•
Change in percentage of time spent within a 
target glucose range of 70 mg/dL (3.9 mmol/L) 
to 180 mg/dL (10 mmol/L) over a 7-day period at 
baseline (Days -8 to - 2) to the final week of 
treatment (Days 26-32)
To assess the effects of MEDI0382 titrated up to a 
dose level of 
 on weight versus placebo after 32 
days of treatment
•
Percentage and absolute change in body weight 
from baseline (Day 1) to the end of 32 days of 
treatment (Day 33)


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To characterise the PK profile and immunogenicity of 
MEDI0382
•
PK endpoints: AUC over a dosing duration, 
maximum observed concentration (Cmax), time to 
Cmax (Tmax), trough plasma concentration (Ctrough)
•
Development of anti-drug antibodies (ADA) and 
titre (if confirmed positive)
Exploratory
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY DESIGN  
This is a randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability, efficacy, and PK 
profile of MEDI0382 titrated from 
 up to 
 and administered once daily by subcutaneous (SC) 
injection over 32 days in subjects with T2DM and renal impairment (eGFR ≥ 30 and < 60 mL/min/1.73 m2). 
The study has a 14-day run-in period of diet and exercise and continuous glucose monitoring (CGM), a 32-day 
treatment period, and a 28-day follow-up period. Diet and exercise guidance will be according to local practices. 
It is planned to randomise approximately 40 subjects across multiple study sites. Subjects will be consented, 
screened for suitability, and randomised within 40 days of screening, if eligible. 
Throughout the study, subjects will have the choice to either travel to the clinic for visits or stay overnight 
locally whenever consecutive daily visits are required. Subjects will be expected to fast for at least 8 hours 
overnight prior to Visit 3 (Day -5), Visit 4 (Day 1), Visit 9 (Day 32), and Visit 12 (Day 60).
 
On Visit 2 (Day -14) subjects will attend the clinical unit for a short visit. At this visit they will be given advice 
on diet and exercise (in accordance with local practices) and training in SC injection administration, and fitted 
with a CGM sensor that the subject will be expected to wear continuously for the duration of the study until the 
second follow-up visit (Visit 11). 
 
On Visit 3 (Day -
5), subjects will attend the clinical unit for a long visit and will undergo safety assessments and a mixed-meal 
tolerance test (MMTT). At this time, an ambulatory blood pressure monitoring (ABPM) device will be fitted on 
the contralateral arm to the CGM sensor and will be worn for 24 hours. 
 
Subjects will be randomised on Visit 4 (Day 1) to receive either MEDI0382 or placebo and 
dosing will commence following predose baseline vital signs, blood tests (including HbA1c), an ECG, body 
weight measurement, 
. Subjects will then return for daily dosing or remain 
overnight locally until Day 5, and thereafter will have visits at weekly intervals until a maintenance dose of 
 
 is established. At Visits 6, 7, and 8, ABPM recordings 
will be performed. On the last day of dosing 
(Visit 9; Day 32), subjects will attend for a long day visit and undergo a repeat MMTT, HbA1c, ABPM, 
 
and serial PK sampling alongside safety assessments. On the following day (first follow-up visit, Visit 10; Day 
33) subjects will return to the clinic for a blood draw, urine collection, weight measurement, 
. Two additional follow-up visits (Visit 11; Day 
40±5 and Visit 12; Day 60±5) will be performed after the last dose for safety assessments.
TARGET SUBJECT POPULATION  
Male and female subjects ≥ 18 and < 85 years of age with renal impairment (eGFR ≥ 30 and 
< 60 mL/min/1.73 m2) and T2DM, and who may be on insulin and/or combination oral therapies.
TREATMENT GROUPS AND REGIMENS MEDI0382 or placebo will be administered once daily in the 
morning via SC injection:


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•
MEDI0382 
 once daily for 4 days, followed by 
 daily for 7 days, 
 daily for 7 days, and 
 daily for 14 days (n = 20)
•
Placebo once daily for 32 days (n = 20)
STATISTICAL METHODS 
Sample size: Forty subjects (20 completers in the MEDI0382 group and 20 completers in placebo group) will 
provide > 85% power to detect 18.1% difference between the two treatment groups in percentage change in the 
MMTT glucose AUC from baseline (Day -5) to the end of 32 days of treatment (Day 32), with a two-sided 
significance level of 0.1 and assuming the standard deviation of 20%.
Statistical analyses: The primary efficacy analysis will be performed using the intent-to-treat (ITT) population. 
The primary efficacy endpoint, percentage change in MMTT glucose AUC from baseline (Day -5) to the end of 
32 days of treatment will be analysed using an analysis of covariance (ANCOVA) model. The model will 
include fixed effect of treatment and baseline AUC as a covariate. The difference of the percent change in 
glucose AUC between the two treatment arms will be compared with a two-sided significance level of 0.10.
Secondary efficacy analyses will be performed using the ITT population. All secondary efficacy endpoints will 
be summarised by visit and by treatment group. The change in percentage of time spent within a target glucose 
range of 70 mg/dL (3.9 mmol/L) to 180 mg/dL (10 mmol/L) over a 7-day period at baseline to the final week of 
treatment will be analysed using a Wilcoxon rank-sum test. All other continuous endpoints will be analysed 
using a similar ANCOVA model as that for the primary analysis.
Safety analyses will be performed using the as-treated population.  AEs and SAEs will be coded by the most 
updated version of Medical Dictionary for Regulatory Activities (MedDRA), and the type, incidence, severity, 
and relationship to study investigational product will be summarised by MedDRA System Organ Class and 
Preferred Term and by treatment. AEs leading to discontinuation, AEs leading to death, and deaths will also be 
summarised. Specific AEs will be counted once for each subject for calculating percentages. In addition, if the 
same AE occurs multiple times within a particular subject, the highest severity and level of relationship 
observed will be reported. Subject-level data listings of all AEs will be presented. Other safety data, such as 
vital signs, clinical laboratory data, ECG, and physical examination findings will be descriptively summarised at 
each time point by treatment. Mean ambulatory blood pressure and pulse rate measurements recorded over 24 
hours at different time-points will be analysed using an ANCOVA model, adjusting for treatment and 
measurement at baseline.
Pharmacokinetic analyses: Pharmacokinetic parameters such as maximum concentration (Cmax), time to 
maximum observed concentration (Tmax), and AUCtau, will be estimated from plasma concentration-time data for 
MEDI0382 at the 
 dose level. Descriptive statistics will be generated for PK parameters for the 
MEDI0382 group at 
 and for Ctrough at each dose level.
Immunogenicity analyses: The incidence and impact of ADA to MEDI0382 will be evaluated. The number 
and percentage of subjects with confirmed positive serum antibodies to MEDI0382 will be reported by 
treatment.
Interim analysis: No interim analysis is planned for this study.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS......................................................................................................2
TABLE OF CONTENTS......................................................................................................6
LIST OF ABBREVIATIONS ............................................................................................. 11
1
INTRODUCTION............................................................................................ 13
1.1
Disease Background ......................................................................................... 13
1.2
MEDI0382 Background.................................................................................... 13
1.6
Benefit-risk and Ethical Assessment ................................................................. 15
1.7
Research Hypotheses ........................................................................................ 15
1.7.1
Primary Hypothesis .......................................................................................... 15
1.7.2
Secondary Hypotheses...................................................................................... 15
2
OBJECTIVES AND ENDPOINTS................................................................... 16
2.1
Primary Objective and Associated Endpoint ..................................................... 16
2.2
Secondary Objectives and Associated Endpoints............................................... 16
3
STUDY DESIGN ............................................................................................. 20
3.1
Description of the Study ................................................................................... 20
3.1.1
Overview.......................................................................................................... 20
3.1.2
Treatment Regimen........................................................................................... 21
3.1.3
Dose Escalation ................................................................................................ 22
3.2
Rationale for Dose, Population, and Endpoints ................................................. 26
3.2.1
Dose Rationale.................................................................................................. 26
3.2.2
Rationale for Study Population ......................................................................... 28
3.2.3
Rationale for Endpoints .................................................................................... 28
4
MATERIALS AND METHODS ...................................................................... 30
4.1
Subjects............................................................................................................ 30
4.1.1
Number of Subjects .......................................................................................... 30
4.1.2
Inclusion Criteria .............................................................................................. 30
4.1.3
Exclusion Criteria ............................................................................................. 31
4.1.4
Subject Enrollment and Randomisation............................................................. 33
4.1.5
Withdrawal from the Study............................................................................... 33
4.1.6
Discontinuation of Investigational Product........................................................ 34
4.1.7
Replacement of Subjects................................................................................... 34
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples................... 35
4.2
Schedule of Study Procedures........................................................................... 36
4.2.1
Enrollment/Screening Period ............................................................................ 36


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4.2.2
Randomised Treatment Period .......................................................................... 39
4.2.3
Follow-up Period .............................................................................................. 45
4.3
Description of Study Procedures....................................................................... 46
4.3.1
Efficacy ............................................................................................................ 46
4.3.1.1
Mixed-meal Tolerance Tests............................................................................. 46
4.3.1.2
Blood Tests for Glucose Lowering Efficacy...................................................... 47
4.3.1.3
Weight.............................................................................................................. 47
4.3.2
Medical History, Physical Examination, Electrocardiogram, Weight, and Vital 
Signs................................................................................................................. 47
4.3.2.1
Medical History and Physical Examination....................................................... 47
4.3.2.2
Electrocardiograms........................................................................................... 48
4.3.2.3
Assessment of the Injection Site........................................................................ 48
4.3.2.4
Vital Signs........................................................................................................ 48
4.3.3
Clinical Laboratory Tests.................................................................................. 49
4.3.4
Pharmacokinetic Evaluation and Methods......................................................... 50
4.3.5
Immunogenicity Evaluation and Methods ......................................................... 50
4.3.6
Pharmacodynamic Evaluation and Methods...................................................... 51
4.3.6.1
Training for Application and Wearing of CGM Sensor ..................................... 51
4.3.6.2
Training for Application and Wearing of ABPM Device................................... 51
4.3.10
Estimate of Volume of Blood to Be Collected................................................... 53
4.4
Study Suspension or Termination...................................................................... 53
4.5
Investigational Products.................................................................................... 54
4.5.1
Identity of Investigational Products................................................................... 54
4.5.1.5
Monitoring of Dose Administration .................................................................. 60
4.5.1.6
Reporting Product Complaints .......................................................................... 60
4.5.2
Additional Study Medications........................................................................... 61
4.5.3
Labelling .......................................................................................................... 61
4.5.4
Storage ............................................................................................................. 61
4.5.5
Treatment Compliance...................................................................................... 61
4.5.6
Accountability .................................................................................................. 61
4.6
Treatment Assignment and Blinding ................................................................. 61
4.6.1
Methods for Assigning Treatment Groups......................................................... 61
4.6.2
Methods to Ensure Blinding.............................................................................. 62
4.6.3
Methods for Unblinding.................................................................................... 62
4.6.3.1
Unblinding in the Event of a Medical Emergency ............................................. 62


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4.7
Restrictions During the Study and Concomitant Treatment(s) ........................... 63
4.8
Statistical Evaluation ........................................................................................ 64
4.8.1
General Considerations..................................................................................... 64
4.8.3
Efficacy ............................................................................................................ 65
4.8.3.1
Primary Efficacy Analysis ................................................................................ 65
4.8.3.2
Secondary Efficacy Analyses............................................................................ 65
4.8.4
Safety ............................................................................................................... 65
4.8.4.1
Analysis of Adverse Events .............................................................................. 65
4.8.4.2
Analysis of Clinical Laboratory Parameters ...................................................... 65
4.8.5
Analysis of Immunogenicity/Pharmacokinetics................................................. 66
4.8.5.1
Pharmacokinetic Analyses ................................................................................ 66
4.8.5.2
Immunogenicity Analyses................................................................................. 66
4.8.6
Additional Analyses.......................................................................................... 66
4.8.6.1
Vital Signs Analyses......................................................................................... 66
4.8.6.2
ECG Analyses .................................................................................................. 66
4.8.7
Interim Analysis ............................................................................................... 66
5
ASSESSMENT OF SAFETY ........................................................................... 67
5.1
Definition of Adverse Events............................................................................ 67
5.2
Definition of Serious Adverse Events ............................................................... 67
5.3
Definition of Adverse Events of Special Interest............................................... 68
5.3.1
Hepatic Function Abnormalities........................................................................ 68
5.4
Recording of Adverse Events............................................................................ 68
5.4.1
Time Period for Collection of Adverse Events .................................................. 69
5.4.2
Follow-up of Unresolved Adverse Events......................................................... 69
5.4.3
Deaths .............................................................................................................. 69
5.5
Reporting of Serious Adverse Events................................................................ 69
5.6
Other Events Requiring Immediate Reporting................................................... 70
5.6.1
Overdose .......................................................................................................... 70
5.6.2
Hepatic Function Abnormality.......................................................................... 70
5.6.3
Pregnancy......................................................................................................... 71
5.6.3.1
Maternal Exposure............................................................................................ 71
6
STUDY AND DATA MANAGEMENT........................................................... 72
6.1
Training of Study Site Personnel....................................................................... 72
6.2
Monitoring of the Study.................................................................................... 72
6.2.1
Source Data ...................................................................................................... 73
6.2.2
Study Agreements............................................................................................. 73
6.2.3
Archiving of Study Documents......................................................................... 73
6.3
Study Timetable and End of Study.................................................................... 73
6.4
Data Management............................................................................................. 73


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6.5
Medical Monitor Coverage ............................................................................... 74
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 74
7.1
Subject Data Protection..................................................................................... 74
7.2
Ethics and Regulatory Review .......................................................................... 74
7.3
Informed Consent ............................................................................................. 75
7.4
Changes to the Protocol and Informed Consent Form........................................ 75
7.5
Audits and Inspections...................................................................................... 76
8
REFERENCES................................................................................................. 77
9
CHANGES TO THE PROTOCOL ................................................................... 77
9.1
Protocol Amendment 4, 12Nov2018 ................................................................. 77
9.2
Protocol Amendment 3, 11Oct2018 .................................................................. 78
9.3
Protocol Amendment 2, 06Apr2018.................................................................. 78
9.4
Protocol Amendment 1, 28Feb2018.................................................................. 78
10
APPENDICES.................................................................................................. 80
10.1
Appendix 1 - Signatures.................................................................................... 80
10.2
Appendix 2 – Contraception Guidance.............................................................. 81
10.3
Appendix 3 - Additional Safety Guidance......................................................... 82
10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis .......... 85
10.5
Appendix 5 - Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law.............................................................................. 86
10.5.1
Introduction ...................................................................................................... 86
10.5.2
Definitions........................................................................................................ 86
10.5.3
Follow-up ......................................................................................................... 87
10.5.4
Review and Assessment of Potential Hy’s Law Cases....................................... 88
10.7
Appendix 7 Biological Samples ........................................................................ 92


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LIST OF TABLES
Table 1
Primary Objective and Associated Endpoint ............................................ 16
Table 2
Secondary Objectives and Associated Endpoints...................................... 16
Table 8
Proposed Study Doses and Predicted Safety Margins Based on Rat and 
Cynomolgus Monkey Data ...................................................................... 28
Table 9
Screening and Run-in Procedures ............................................................ 36
Table 10
Treatment Period Study Procedures ......................................................... 40
Table 11
Schedule of Follow-up Procedures........................................................... 45
Table 12
Identification of Investigational Products, 
 Dose and Placebo .. 54
Table 13
Identification of Investigational Products, 
 PFS 
Doses and Placebo................................................................................... 55
Table 14
MEDI0382 
 and Placebo Dose Preparation................................... 56
Table 10-2
Highly Effective Methods of Contraception............................................. 81
LIST OF FIGURES


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ABPM
ambulatory blood pressure monitoring
ACR
albumin creatinine ratio
ADA
anti-drug antibody(ies)
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine transaminase
ANCOVA
analysis of covariance
AST
aspartate transaminase
AUC
area under the curve
AUCMMT.4h
area under the curve for glucose measured over 4 hours by the mixed meal 
tolerance test
AUCtau
area under the curve during the dosing interval
 
BMI
body mass index
BP
blood pressure
CGM
continuous glucose monitoring
CI
confidence interval
Cmax
maximum observed concentration
CRF
case report form
CSR
clinical study report
Ctrough
trough plasma concentration
DILI
drug-induced liver injury
DPPIV
dipeptidyl peptidase-4 
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
HbA1c
haemoglobin A1c
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus


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Abbreviation or 
Specialized Term
Definition
IB 
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFU
instructions for use
IP
investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
IXRS
interactive voice/web response system
LC/MS-MS
liquid chromatography-tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines & Healthcare products Regulatory Agency
MMTT
mixed-meal tolerance test
MTD
maximum tolerated dose
NOAEL
no-observed-adverse-effect level
PFS
prefilled syringe
PK
pharmacokinetic(s)
PT
preferred term
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SGLT2
sodium-glucose co-transporter 2
SID
subject identification
SOC
system organ class
T2DM
type 2 diabetes mellitus
TEAE
treatment emergent adverse event
Tmax
time to maximum concentration
ULN
upper limit of normal
WBC
white blood cell
w/v
weight per volume


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1
INTRODUCTION
1.1
Disease Background
The rising prevalence of type 2 diabetes mellitus (T2DM) and obesity is a cause of substantial 
health and economic burden worldwide. In many cases of T2DM, significant weight loss 
(typically 5% of body weight or more) can promote improvements in glycaemic control, 
cardiovascular risk, and mortality rates, and may even slow or reverse disease progression 
(Petersen et al, 2005). Many existing therapies for T2DM focus upon lowering blood glucose; 
however, there is a major unmet need for treatments that both improve glycaemic control and 
achieve disease-modifying weight loss.
Renal impairment attributed to chronic hyperglycaemia and hypertension is common in 
patients with longstanding T2DM, and is often exacerbated by obesity. Patients with 
significant renal impairment and T2DM therefore stand to benefit from medications that can 
deliver both improvements in glycaemic control and weight loss.
1.2
MEDI0382 Background
MEDI0382 is briefly described below. Refer to the current Investigator’s Brochure (IB) for 
details. 
MEDI0382 is a synthetic peptide with both glucagon-like peptide-1 (GLP-1) and glucagon 
receptor co-agonist activity, which is under development for the treatment of T2DM and 
obesity. GLP-1 receptor agonists are established treatments for T2DM that improve glycaemic 
control, 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
 
 
 
 
 
 
 
 
 
 
Refer to the current MEDI0382 IB for a complete summary of clinical information.
1.5
Rationale for Conducting the Study
 
 
 
 
 
 
 


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1.6
Benefit-risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements.
MEDI0382 is a synthetic peptide with both GLP-1 and glucagon receptor co-agonist activity
that promote glucose lowering and weight loss and is targeted at subjects with T2DM. 
MEDI0382 has the potential to deliver improvements in glycaemic control and lipid 
homeostasis, and is predicted to be a useful therapy for T2DM.
The study design aims to minimise potential risks to subjects participating in this study based 
on the proposed inclusion/exclusion criteria, safety monitoring, and up-titration dosing 
schedule. All subjects will be monitored throughout the study to ensure adequate glycaemic 
control. Subjects will be given appropriate training in subcutaneous (SC) injection 
administration as well as use of any devices. 
Refer to the current IB for information on the potential benefits of MEDI0382 and an 
assessment of the potential and known risks.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
!
Administration of MEDI0382 once daily titrated up to a dose level of 
 will result in 
superior blood glucose control versus placebo after 32 days of treatment in subjects with 
T2DM and renal impairment.
1.7.2
Secondary Hypotheses
!
Administration of MEDI0382 once daily titrated up to a dose level of 
 across 
32 days will be well tolerated in subjects with T2DM and renal impairment
!
Administration of MEDI0382 once daily titrated up to a dose level of 
 will result in 
superior weight loss versus placebo after 32 days of treatment in subjects with T2DM and 
renal impairment
!
Administration of MEDI0382 once daily titrated up to a dose level of 
 will have a 
predictable pharmacokinetic (PK) profile in subjects with T2DM and renal impairment


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2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoint
Table 1
Primary Objective and Associated Endpoint
Type
Objective
Endpoint
Efficacy
To assess the effect of MEDI0382 
titrated up to a dose level of 
 on 
glucose control versus placebo after 
32 days of treatment
•
Percentage change in glucose area 
under the curve (AUC) as measured 
by a standardised mixed-meal 
tolerance test (MMTT) from baseline 
(Day -5) to the end of 32 days of 
treatment (Day 32)
2.2
Secondary Objectives and Associated Endpoints
Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoints
Safety
To characterise the safety profile and 
tolerability of MEDI0382 titrated up to a 
dose level of 
 during dosing and 
follow-up in subjects with T2DM and 
renal impairment
•
Measures of safety and tolerability 
(adverse events/serious adverse 
events [AEs/SAEs], vital signs, 
postural blood pressure [BP] changes, 
electrocardiogram [ECG], laboratory 
test results)
•
Change in mean 24-hour pulse rate, 
systolic and diastolic blood pressure 
from baseline (Day -5) to the end of 
dosing at each dose level (Days 4, 11, 
18, and 32)
Efficacy
To assess the effects of MEDI0382 
titrated up to a dose level of 
 on 
additional measures of glycaemic 
control versus placebo after 32 days of 
treatment
•
Change in haemoglobin A1c 
(HbA1c) from baseline (Day 1) to the 
end of 32 days of treatment (Day 32)
•
Change in fasting glucose from 
baseline (Day 1) to the end of 32 days 
of treatment (Day 32)
•
Change in percentage of time spent 
within a target glucose range of 
70 mg/dL (3.9 mmol/L) to 180 mg/dL 
(10 mmol/L) over a 7-day period at 
baseline (Days -8 to - 2) to the final 
week of treatment (Days 26-32)
Efficacy
To assess the effects of MEDI0382 
titrated up to a dose level of 
 on 
weight versus placebo after 32 days of 
treatment
•
Percentage and absolute change in 
body weight from baseline (Day 1) to 
the end of 32 days of treatment (Day 
33)


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Table 2
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoints
PK/Immunogenicity
To characterise the PK profile and 
immunogenicity of MEDI0382
•
PK endpoints: AUC over a dosing 
duration, maximum observed 
concentration (Cmax), time to Cmax
(Tmax), trough plasma concentration 
(Ctrough) 
•
Development of anti-drug antibodies 
(ADA) and titre (if confirmed 
positive)


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2.3
Exploratory Objectives and Endpoints
Type
Objective
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3
Exploratory Objectives and Endpoints
Type
Objective
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
This is a randomised, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, efficacy, and PK profile of MEDI0382 titrated from 
 up to 
 and 
administered once daily by subcutaneous (SC) injection over 32 days in subjects with T2DM 
and renal impairment (eGFR ≥ 30 and < 60 mL/min/1.73 m2). The study has a 14-day run-in 
period of diet and exercise and continuous glucose monitoring (CGM), a 32-day treatment 
period, and a 28-day follow-up. Diet and exercise guidance will be according to local 
practices. It is planned to randomise approximately 40 subjects across multiple study sites. 
Subjects will be consented, screened for suitability, and randomised within 40 days of 
screening, if eligible. 
Throughout the study, subjects will have the choice to either travel to the clinic for visits or 
stay overnight locally whenever consecutive daily visits are required. Subjects will be 
expected to fast for at least 8 hours overnight prior to Visit 3 (Day -5), Visit 4 (Day 1), Visit 9 
(Day 32), and Visit 12 (Day 60). 
 
 
On Visit 2 (Day -14) subjects will attend the clinical unit for a short visit. At this visit they 
will be given advice on diet and exercise (in accordance with local practices) and training in 
SC injection administration, and fitted with a CGM sensor that the subject will be expected to 
wear continuously for the duration of the study until the second follow-up visit (Visit 11). 
 
. 
On Visit 3 
(Day -5), subjects will attend the clinical unit for a long visit and will undergo safety 
assessments and a mixed-meal tolerance test (MMTT). At this time, an ambulatory blood 
pressure monitoring (ABPM) device will be fitted on the contralateral arm to the CGM sensor 
and will be worn for 24 hours. 
 
 
 Subjects will be randomised on Visit 4 (Day 1) to receive either 
MEDI0382 or placebo and dosing will commence following predose baseline vital signs, 
blood tests (including HbA1c), an ECG, body weight measurement, 
 
. Subjects will then return for daily dosing or remain overnight locally until 
Day 5, and thereafter will have visits at weekly intervals until a maintenance dose of 
 is 
established. At Visits 6, 7, and 8, ABPM recordings 
 
. On the last day of dosing (Visit 9; Day 32), subjects will attend for a long day visit 
and undergo a repeat MMTT, HbA1c, ABPM, 
and serial PK 


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sampling, alongside safety assessments. On the following day (first follow-up visit, Visit 10; 
Day 33) subjects will return to the clinic for a blood draw, urine collection, weight 
measurement, 
. 
Two additional follow-up visits (Visit 11; Day 40±5 and Visit 12; Day 60±5) will be 
performed after the last dose for safety assessments.
3.1.2
Treatment Regimen
MEDI0382 or placebo will be administered once daily in the morning via SC injection:
 


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3.1.4
Management of Study Medication Related Toxicities and Dose 
Modification
Nausea and Vomiting
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).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Management of Hyperglycaemia and Rescue Therapy
In subjects who have sustained hyperglycaemia 
 
 additional open-label rescue therapy should be considered by the investigator and 
should be documented in the relevant section of the CRF. For subjects where hyperglycaemia 


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is suspected, additional venous fasting plasma glucose measurements may be performed if 
necessary to investigate further.
Rescue therapy should be considered by the investigator following discussion with the 
medical monitor if any of the following apply:
!
Fasting plasma glucose >200 mg/dL (11.1 mmol/L) on two occasions less than 8 days 
apart
!
Three capillary plasma glucose levels > 250 mg/dL (13.9 mmol/L) in one week
!
More than 30% of readings in hyperglycaemic range on CGM defined as > 250 mg/dL 
(13.9 mmol/L) in one week
 
 
 
 
  If rescue medication is required, subjects should continue to participate in the study 
and receive their study medication. An interim prescription of the rescue medication will be 
provided by the study site if necessary, but continued prescription of rescue therapy will 
remain the responsibility of the primary care physician or usual diabetes physician. Rescue 
medication will not be provided by the Sponsor for this study.
Investigators should consider discontinuing the investigational product in subjects with 
persistent fasting venous plasma glucose level of > 260 mg/dL (14.4 mmol/L), despite a 
maximum tolerated dose (MTD) of rescue therapy to enable optimization of the subject’s 
glycaemic control. The subject should however remain in the study for all other study 
procedures and continued follow-up until their scheduled end of study date.
 
 


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Management of 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; 
clinically significant hypoglycaemia is defined as a capillary or venous plasma glucose 
reading of < 3.0 mmol/L (54 mg/dL). Spontaneous and clinically significant hypoglycaemia 
has not been experienced in prior studies with MEDI0382 up to a dose of 
 alongside 
metformin treatment.
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 clinically significant hypoglycaemia should be reported by 
investigators as an AE regardless of whether or not the subject is experiencing 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.
For subjects who experience a severe hypoglycaemic episode or a clinically significant 
episode of hypoglycaemia (defined as a capillary or venous plasma glucose reading of 
< 54 mg/dL (3.0 mmol/L) or an interstitial glucose reading < 54 mg/dL (3.0 mmol/L) recorded 
on CGM on two occasions across 15 minutes) a reduction in total daily dose of insulin of 20% 
should be made from the time of awareness of the event. If the subject is not using insulin 
during the study, a 50% dose reduction in oral medication should be made in the following 
order of preference: sulfonylureas, glitinide, pioglitazone, metformin, DPPIV inhibitors. 
Dose reduction should also be considered at the discretion of the investigator and 
following discussion with the medical monitor if > 2% of interstitial glucose readings on 
CGM are < 70 mg/dL (3.9 mmol/L).
Decline in Renal Function
For subjects who have a eGFR of 30-44 mL/min/1.73 m2 (inclusive) at screening and are 
taking an existing dose of metformin that is higher than the recommended dose for that degree 


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of renal impairment, the dose of metformin should be reduced or discontinued at Visit 2 in 
accordance with local guidelines on metformin prescription in renal impairment, or to 500 mg 
once daily if no guidance is in place. Similarly, any subject experiencing a decline in eGFR 
during the study to 30-44 mL/min/1.73 m2 (inclusive) should have their dose of metformin 
reduced or discontinued as described above. 
For subjects who are found to have a decline in renal function to eGFR < 30 mL/min/1.73 m2
during the study, the subject should also be advised to stop metformin therapy and any other 
medications that are contraindicated for this degree of renal impairment. 
For subjects who are eligible to take part in the study and are taking other medications for 
diabetes that are prescribed at a higher dose than recommended for their degree of renal 
insufficiency, dose reduction should be performed at Visit 2 in accordance with local 
treatment guidelines or the drug labelling.
For subjects who are found to have a decline in renal function to eGFR ≤ 25 mL/min/1.73 m2
during the study, the subject should undergo a repeat eGFR level one week later, and if the 
eGFR remains ≤ 25 mL/min/1.73 m2 on a second consecutive test, the investigational product 
(IP) should be discontinued, and the subject should also be advised to stop metformin therapy 
(if they have not already done so) and any other medications that are contraindicated for this 
degree of renal impairment. However, the subject should remain in the study for all other 
study procedures until their scheduled end of study.
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.2.2
Rationale for Study Population
MEDI0382 is a GLP-1 and glucagon receptor co-agonist that promotes glucose lowering and 
weight loss and is targeted at subjects with T2DM. Renal impairment attributed to diabetic 
kidney disease is common in patients with longstanding T2DM. The entry criteria with respect 
to T2DM and eGFR of ≥ 30 and < 60 mL/min/1.73 m2 both maximise recruitment potential 
and provide efficacy, safety, and tolerability data in the intended clinical population who 
concurrently have moderate renal impairment. The eligibility criteria also permit inclusion of 
subjects with an HbA1c of 6.5-10.5% and those who are treated with any combination of oral 
therapy and/or insulin, which reflects the natural history of late stage T2DM and concurrent 
chronic kidney disease (CKD). There is no requirement for a given number of subjects in each 
gender to be enrolled.  It is intended that at least 50% (n=20) of subjects enrolled in the study 
will be taking insulin at a dose of ≥ 20 units/day to enable any effect of MEDI0382 on insulin 
dose adjustment to be observed. In addition, it is intended that approximately 40% (n=16) of 
subjects enrolled in the study will have an eGFR of ≥ 30 and < 45 mL/min/1.73 m2 and at 
least 40% (n=16) of subjects enrolled in the study will have an eGFR of ≥ 45 and 
<  60 mL/min/1.73 m2.  This is to ensure subjects at both ends of the moderate renal 
impairment spectrum are adequately represented.
3.2.3
Rationale for Endpoints
Primary Endpoint
The primary endpoint of glucose AUC as measured by MMTT is required to evaluate the 
efficacy of the 
 dose of MEDI0382 in this population of subjects with T2DM and renal 
impairment.


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Secondary Endpoints
Safety and Tolerability
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional Measures of Glucose Lowering and Weight Loss
To better characterise the glucose-lowering efficacy of MEDI0382 across 32 days of dosing in 
renally impaired subjects, additional markers of glucose control including HbA1c and fasting 
glucose level will be measured, alongside measures of the percentage of time spent within a 
target glucose range measured by CGM.
 
 
Pharmacokinetic Profile and Immunogenicity
Plasma concentrations of MEDI0382 at the 
 dose level will be used to evaluate the PK 
profile (Cmax, time to maximum concentration [Tmax], AUCtau) in this specific population. In 
addition, Ctrough at each dose level will be evaluated to ensure exposure to the drug.
Prior studies of MEDI0382 and metformin co-therapy have shown no signs of a PK 
interaction between MEDI0382 and metformin. Plasma samples predose (Ctrough) will be 
collected and stored for analysis of metformin levels in case that renal function data warrant 
such analyses. 
Anti-drug antibodies (ADA) incidence rate and titre will be tabulated for each treatment to 
monitor immunogenicity. Tiered analyses will be performed to include screening, 
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and analysed for antibody titre and reported, and may be utilised for further characterisation of 
the ADA response.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
It is planned to randomise approximately 40 subjects across multiple study sites.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Age ≥ 18 and < 85 years at screening.
2
Signed and dated written informed consent (with the exception of consent for genetic and 
nongenetic research) prior to performing any protocol-related procedures, including 
screening evaluations.
3
Diagnosed with T2DM with glucose control managed with any insulin*1 and/or oral 
therapy combination where no significant dose changes of oral therapy of more than 50% 
have occurred in the 3 months prior to screening
4
Body mass index (BMI) between 25 and 45 kg/m2 (inclusive) at screening
5
HbA1c range of 6.5 % to 10.5% (inclusive) at screening
6
Renal impairment with eGFR ≥ 30 and < 60 mL/min/1.73 m2 at screening. Approximately 
16 subjects (40%) are required to have a screening eGFR ≥30 and < 45 mL/min/1.73 m2
and at least 16 subjects (40%) are required to have screening eGFR ≥45 and 
< 60 mL/min/1.73 m2. eGFR will be determined by the chronic kidney disease-
epidemiology collaboration (CKD-EPI) equation. In instances where the eGFR estimated 
during the screening period is outside the range expected from the subject’s medical 
history, the subject may be re-tested once.
7
Females of childbearing potential must have a negative pregnancy test at screening and 
randomisation, and must not be lactating. Women of childbearing potential who are 
sexually active with a nonsterilized male partner must be using at least one highly 
effective method of contraception (see Section 10.2 for definition of females of 
childbearing potential and for a description of highly effective methods of contraception) 
from screening and up to 4 weeks after the last dose of investigational product. It is 
strongly recommended for the male partner of a female subject to also use male condom 
plus spermicide throughout this period. Cessation of contraception after this point should 
be discussed with a responsible physician. Periodic abstinence, the rhythm method, and 
the withdrawal method are not acceptable methods of contraception.


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*1 At least 50% of subjects (n=20) enrolled in the study should be taking insulin at a total daily dose of 
≥20 units.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
History or presence of significant medical or psychological conditions, including 
substance dependence/abuse, or significant abnormalities in laboratory parameters or vital 
signs including ECG, which in the opinion of the investigator, would compromise the 
subject’s safety or successful participation in the study. As an example, severe anaemia 
(haemoglobin < 7.0 g/dL) could be exclusionary due to blood sampling required by the 
protocol, at the discretion of investigator.
2
Concurrent participation in another interventional study of any kind and repeat 
randomisation in this study is prohibited
3
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 (if known; whichever is longer) at the time of Visit 2
4
Any subject who has received any of the following medications within the specified 
timeframe prior to the start of the study (Visit 2) (see Section 4.7.2 for further details)
o
Herbal preparations within 1 week prior to the start of dosing (Visit 4) or drugs 
licensed for control of body weight or appetite (eg, orlistat, bupropion-
naltrexone, phentermine-topiramate, phentermine, lorcaserin) within 30 days (or 
5 half-lives of the drug) prior to the start of dosing (Visit 4)
o
Aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily and within 
the last 3 days prior to the start of the run-in period (Visit 2)
o
Paracetamol (acetaminophen) or paracetamol-containing preparations at a total
daily dose of greater than 3000 mg and within the last 3 days prior to the start of 
the run-in period (Visit 2)
o
Ascorbic acid (vitamin C) supplements at a total daily dose of greater than 1000 
mg and within the last 3 days prior to the start of the run-in period (Visit 2)
o
Opiates, domperidone, metoclopramide, or other drugs known to alter gastric 
emptying and within 2 weeks prior to the start of dosing (Visit 4) 
5
Severe allergy/hypersensitivity to any of the proposed study treatments or excipients
6
Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight 
loss), a history of type 1 diabetes mellitus or diabetic ketoacidosis
7
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8
Subjects with suspicion of acute or subacute renal function deterioration (eg, subjects 
with large fluctuations of creatinine values documented within the 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 History of acute or chronic pancreatitis
11 Significant hepatic disease (except for non-alcoholic steatohepatitis or nonalcoholic fatty 
liver disease without portal hypertension or cirrhosis) and/or subjects with any of the 
following results:
o
Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)
o
Alanine transaminase (ALT) ≥ 3 × ULN
o
Total bilirubin ≥ 2 × ULN
12 Poorly controlled hypertension defined as:
o
Systolic BP > 180 mm Hg
o
Diastolic BP ≥ 100 mm Hg
after 10 minutes of seated rest and confirmed by repeated measurement at screening. Subjects 
who fail BP screening criteria may be considered for 24-hour ABPM at the discretion of the 
investigator. Subjects who maintain a mean 24-hour systolic BP ≤ 180 or diastolic BP 
< 100 mm Hg with a preserved nocturnal dip of > 15% will be considered eligible
13 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
14 Severe congestive heart failure (New York Heart Association Class III or IV)
15 Basal calcitonin level > 50 ng/L at screening or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia
16 History of neoplastic disease within 5 years prior to screening, except for adequately 
treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
17 Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody, 
and human immunodeficiency virus (HIV) antibody
18 Nephrotic range proteinuria defined as spot urine ACR > 250 mg/mmol at screening
19 History of substance dependence, alcohol abuse, or excessive alcohol intake (defined as 
an average weekly intake of > 21 alcoholic drinks for men or > 10 alcoholic drinks for 
women) within 3 years prior to screening, and/or a positive screen for drugs of abuse or 
alcohol at screening or on Day -5. Subjects who use tricyclic antidepressants or 


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benzodiazepines for an established clinical indication may be permitted to enter the study 
based upon the judgement of the investigator.
20 Involvement of any AstraZeneca, MedImmune, contract research organization, or study 
site employee or their close relatives
4.1.4
Subject Enrollment and Randomisation
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice/web response system, [IXRS]) and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable. 
Approximately 40% of subjects (n = 16) enrolled in the study will have an eGFR of ≥30 and 
< 45 mL/min/1.73 m2 and at least 40% (n = 16) will have an eGFR of ≥ 45 and 
< 60 mL/min/1.73 m2. In addition, at least 50% of subjects (n=20) enrolled in the study should 
be taking insulin at a total daily dose of ≥ 20 units.
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 inclusion/exclusion criteria (ie, screening failures) should not, 
under any circumstances, be randomised or receive investigational product. There can be no 
exceptions to this rule. Subjects who are enrolled, but subsequently found not to meet all the 
eligibility criteria, should not be randomised or initiated on treatment. If randomisation and 
treatment initiation occur for a subject found not to meet any eligibility criterion, withdrawal 
of the subject from the study will be the decision of the medical monitor.
Subjects may be rescreened once if, in the opinion of the investigator, there is a reason to 
believe they may be eligible.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments) at any time, without prejudice to further treatment. Subjects who withdraw 
consent will be asked about the reason(s) and the presence of any adverse events (AEs) and 
will be encouraged to remain in study for the remainder of the scheduled follow-ups. Adverse 
events will be followed up; diary cards and all study medications should be returned by the 
subject. If a subject withdraws from further participation in the study, then no further study 
visits or data collection should take place.


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4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:
1
Withdrawal of consent from further treatment with investigational product 
2
Lost to follow-up
3
An AE that, in the opinion of the investigator or the sponsor, warrants discontinuation of 
further dosing; specific examples include:
!
Dose-limiting symptoms with respect to GI tolerability and in particular if a subject 
requires intravenous fluids to treat volume depletion secondary to nausea and vomiting, 
even after measures are taken to reduce the risk of vomiting, after discussion with the 
medical monitor
!
eGFR ≤ 25 mL/min/1.73 m2 on two consecutive blood tests
!
Acute kidney injury (AKI) in a subject as defined by:
o
An increase in serum creatinine by 0.3 mg/dL (26.5 μmol/L) within 48 hours in 
at least 2 readings
o
An increase in serum creatinine to 1.5 times baseline in at least 2 readings, which 
is known or presumed to have occurred within the prior 7 days
!
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 with persistent fasting glucose level of > 260 mg/dL (14.4 mmol/L) despite a 
MTD of rescue therapy to enable optimisation of the subject’s glycaemic control
!
Any subject where Hy’s Law criteria on liver function tests is met: AST or ALT ≥ 3 × 
ULN together with Total bilirubin ≥ 2 × ULN
!
Any subject who develops a life-threatening arrhythmia including sustained ventricular 
tachycardia, ventricular fibrillation or new ECG changes of second or third-degree heart 
block
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 interventional clinical 
study.
4.1.7
Replacement of Subjects
Subjects who withdraw from the study will be replaced where possible. A maximum number 
of three subjects may be replaced during the study.


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4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.2
Schedule of Study Procedures
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, blood draws should occur last. The timing of the first two assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time.
4.2.1
Enrollment/Screening Period
Table 9 shows all procedures to be conducted at the screening visit and run-in procedures. 
Table 9
Screening and Run-in Procedures
Study Period
Screening
Run-in
Visit Number
V1
V2
V3 a
Remote 
contact
Procedure / Study Day 
D-40 to D-15
D-14
D-5
D-1
Written informed consent/ 
assignment of SID number
X
 
 
 
 
 
 
 
 
Outpatient visit to clinic c
X
X
X 
Medical history
X
Physical examination (full)
X
Weight, height and BMI 
calculation
X
ECG
X
Vital signs d, e
X
Xe
Collect blood for
Serum chemistry (including 
eGFR calculation) 
X
LFTs, Cr, and eGFR 
calculation
X
Haematology (FBC)
X
X
HbA1c
X
Calcitonin
X
HIV-1 and -2 antibodies; 
hepatitis B and C serology
X


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Table 9
Screening and Run-in Procedures
Study Period
Screening
Run-in
Visit Number
V1
V2
V3 a
Remote 
contact
Procedure / Study Day 
D-40 to D-15
D-14
D-5
D-1
MMTT (collect samples for 
glucose at all time points) f
X
Fasting blood sample for 
active GLP-1
X
Collect urine for
Urinalysis (dipstick)
X
X
Urine albumin/creatinine 
ratio g                                    
X
X
X
Pregnancy test (women of 
childbearing potential only) h
X
X
Drug and alcohol screen
X
X
 
CGM device demonstration
X
X
CGM sensor application
X
CGM i
ABPM j
X
Diet and exercise advice
X
 
 
SC injection self-
administration training l
X
X
X
Concomitant medications
X
X m
X
Verify eligibility criteria
X
X
X
Assessment of AEs / SAEs
X
X
X
X
Glucose meter and diary 
provision n
X
 


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AEs = adverse events; ABPM = ambulatory blood pressure monitoring; BMI = body mass index; BP = blood 
pressure; CGM = continuous glucose monitoring; CR = creatinine; D = Day; ECG = electrocardiogram; eGFR = 
estimated glomerular filtration rate; FBC = full blood count; GLP-1 = glucagon-like peptide-1; HbA1c = 
glycated haemoglobin; HIV = human immunodeficiency virus; IFU = instructions for use; LFT = liver function 
tests (albumin; alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase [ALP], and total 
bilirubin); MMTT = mixed meal tolerance test; PK = pharmacokinetic; SAE = serious adverse events; SC = 
subcutaneous; SID = subject identification; V = visit
a
Subjects are required to fast for at least 8 hours overnight prior to the visit. Subjects are permitted to drink 
water during this period of fasting. For days where subjects are required to fast the investigator/study team 
may need to consider dose
 
 
 
 
c
The diet of subjects should not be restricted in any way during the study (unless fasting or a standardised 
liquid meal is specified).
d
Blood pressure should be measured at heart level and opposite to the arm where the CGM device is applied, 
with the subject supine and rested for 10 minutes prior to the measurement. * Day-5: vital signs to be taken 
prior to fitting the ABPM device
e
Vital Signs Schedule (blood pressures, pulse rate, respiratory rate, and temperature): on days where ABPM 
is due to be checked a set of vital signs should be performed prior to application of the ABPM cuff. Blood 
pressure should be measured at heart level and opposite to the arm where the CGM device is applied, with 
the subject supine and rested for 10 minutes prior to the measurement. For time points where ECG 
recording precedes vital sign measurement, the 10-minute rest in the supine position prior to the ECG 
suffices for the rest prior to vital sign measurement.
f
Following a minimum 8-hour fast overnight, a blood sample for glucose will be taken immediately (within 
15 minutes) prior to the subject drinking one entire can of Ensure Plus as a standardised meal (ie, ‘0 
minutes’).  Blood samples for glucose will additionally be drawn at 15, 30, 45, 60, 90, 120, 180 and 240 
minutes (± 5 minutes) after consumption of the standardised meal. 
g
Urine sample for urine albumin/creatinine ratio at Visit 1 screening may be taken at any time and does not 
need to be a first void specimen. At Visit 2 (Day-14) and Visit 3 (Day -5) urine sample for urine albumin / 
creatinine ratio should be taken as an early morning specimen during the first void of the day.
h
Pregnancy tests do not need to be conducted in women who are surgically sterile (ie, bilateral tubal ligation, 
bilateral oophorectomy, or complete hysterectomy) or are post-menopausal (defined as at least 1 year since 
last menses and/or having an elevated follicle stimulating hormone laboratory value which is in the post-
menopausal range in previous laboratory test results).
i
CGM device should be worn continuously throughout the study until V11 and the sensor should be applied 
to the arm, taking into account subject preference and which side the ABPM device will be used. The 
sensor applied to the skin is single use and may not be re-attached once removed.
j
Subjects will be fitted with the ABPM device whilst at the clinical unit, which may involve practice 
inflations. The ABPM device should be applied on the arm contralateral to the arm where the CGM device 
is applied. The subject will then wear the monitor / cuff for approximately 24 hours and will remove at the 
end of the 24-hour period whilst at home and will return the monitor at their next visit.
k
 
 
 
l
Subject’s ability to self-administer investigational product will be verified using normal saline subcutaneous 
injections as required by the subjects until they feel confident in self-injection. Training will be given to 
familiarise subject with Instructions for Use (IFU) booklet and to assess suitability for self-injection using 
the prefilled syringe (PFS).
m


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n
A glucose meter, test strips and diary should be provided to the subject.  The subject should be trained in its 
use and advised to test their capillary plasma glucose at any time the subject feels unwell or has symptoms 
of hypoglycaemia (hunger, dizziness, shaking, sweating or irritability).
o
 
4.2.2
Randomised Treatment Period
Table 10 shows all procedures to be conducted during the treatment period. 


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Table 10
Treatment Period Study Procedures
Visit Number
V4 a
V5
V6
V7
V8
V9 a
Procedure / Study Day
D1
D2, D3, D4
D5
D12
D19
D32
Daily visits for dosing b
X
Outpatient visit to clinic c
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
Physical examination 
(abbreviated)
X
X
X
X
X
Vital signs d
X
X
X
X
X
ABPM e
X
X
X
X
ECG f
X
X
X
X
X
Body weight g
X
X
X
X
X
 
Randomisation 
X
IP administration i  (SC)
X
X
X
X
X
X
Dispense IP
X
X
X
X
X
.X
Up-titration j
X 
X
X
Collect blood for
Haematology panel (predose 
as applicable) 
X
X
X
X
X
Serum chemistry (including 
eGFR calculation; predose as 
applicable)
X
X
X
X
X


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Table 10
Treatment Period Study Procedures
Visit Number
V4 a
V5
V6
V7
V8
V9 a
Procedure / Study Day
D1
D2, D3, D4
D5
D12
D19
D32
Lipase and amylase
X
X
X
X
X
Calcitonin
X
X
Lactate
X
X
Fasting lipid profile 
X
X
Fasting glucose
X
X
HbA1c
X
X
PK for MEDI0382 k
X
X
X
X
X
Samples for potential future 
metformin PK analysis (predose)l
X
X
X
X
X
ADA m
X
X
X
 
 
 
 
MMTT (collect samples for 
glucose only at all time points) o
X
Collect urine for
Pregnancy test (women of 
childbearing potential only)p
X
Urinalysis (dipstick; predose 
as applicable)
X
X
X
X
X
Urine albumin/creatinine 
ratio q
X
X
X
X
X


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Table 10
Treatment Period Study Procedures
Visit Number
V4 a
V5
V6
V7
V8
V9 a
Procedure / Study Day
D1
D2, D3, D4
D5
D12
D19
D32
 
CGM r
CGM sensor application/change s
X
X
X
X
Check CGM readings 
 
 
X
X
X
X
Glucose meter and diary 
provision t
Assessments of AEs / SAEs
X
X
X
X
X
X
ABPM = ambulatory blood pressure monitoring; ADA = anti-drug antibody; AE = adverse event; BP = blood pressure; CGM = continuous glucose monitoring; 
D = Day; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate;; HbA1c = glycated haemoglobin; IP = investigational product; MMTT = mixed 
meal tolerance test; PFS = prefilled syringe; PK = pharmacokinetic; SAE = serious adverse event; SC = subcutaneous; ULN = upper limit of normal; V = visit
a
Subjects are required to fast for at least 8 hours overnight prior to the visit. Subjects are permitted to drink water during this period of fasting. For days 
where subjects are required to fast the investigator/study team may need to consider dose 
 
 
.
b
Subjects are required to receive their doses at the clinic on Days 1 – 4, as preparation of the 
 dose necessitates dilution and must be performed by site 
staff. Subjects are also required to dose at the clinic on study day visits when predose assessments are required.  Subjects may travel to the site for daily 
visits during this time, or alternatively should be given the option to stay overnight locally if this is more convenient.
c
The diet of subjects should not be restricted in any way during the study (unless fasting or a standardised liquid meal is specified).
d
Vital Signs Schedule (blood pressures (postural at Day 1 predose and Day 32), heart rate, respiratory rate, and temperature): on days where ABPM is due to 
be checked a predose set of vital signs should be performed prior to application of the ABPM cuff. Blood pressure should be measured whilst supine at 
heart level in the nondominant arm where possible, opposite to the arm where the CGM device is applied, with the subject supine and rested for 10 minutes 
prior to the measurement. For time points where ECG recording precedes vital sign measurement, the 10-minute rest in the supine position prior to the ECG 
suffices for the rest prior to vital sign measurement.
•
Day 1; vital signs to be taken; predose (-15 min), 15, 30, and 60 minutes (± 5 min) and 2 hours (± 10 min) postdose


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!
Day 1 predose and Day 32; postural blood pressure supine and then standing should be performed
•
Days 5, 12, 19, 32; vital signs to be taken prior to fitting ABPM device
e
Subjects will be fitted with the ABPM device while at the clinical unit, which may involve practice inflations. The ABPM device should be applied on the 
opposite arm to the arm where the CGM device is applied. The subject will then wear the monitor/cuff for approximately 24 hours and will remove at the 
end of the 24-hour period whilst at home and will return the ABPM device at their next visit.
f
A digital ECG recording should be performed predose and 2 hours post-dose after the subject has rested for 10 minutes in the supine position on Days 1 and 
32. No specific time point is required for other visits.
g
Body weight should be measured in the morning prior to breakfast (predose on Day 1); refer to Section 4.3.1.3 for details.
h
 
 
i
Dosing will occur daily from Day 1 to Day 32 inclusive.  Subjects are required to be dosed at the clinic for the 
 dose and on study day visits when 
predose procedures are required (Days 5, 12, 19, and 32). See Section 4.3 for further information. Ideally subjects should self-administer doses under 
supervision and study site staff should ensure that the subject self-administers the first dose of IP delivered via PFS on Day 5 to ensure that they are 
confident in self-injecting via PFS at home.
j
Up-titration steps will be performed on Day 5 (dose will increase from 
), Day 12 (dose will increase from 
) and Day 19 
(dose will increase from 
)
k
PK Sampling Schedule for MEDI0382:
•
Day 1: Predose 
•
Day 5: Predose
•
Day 12: Predose
•
Day 19: Predose 
•
Day 32: Predose and at 0.5, 1, and 2 hours (± 15 min); 4, 6 and 8, (± 30 min) postdose
•
Day 33: 24 hours (± 15 min) postdose
l
Samples will be collected for potential future metformin PK analysis only in subjects who are taking metformin (metformin PK samples are to be taken 
prior to metformin dose administration and therefore subjects should be advised to delay their morning metformin dose until after this blood test on these 
study visits.)
m
ADA sampling schedule: Day 1 predose; Day 12 predose; Day 32 predose
n
During the informed consent process subjects will be asked to provide consent for the main study
 
 Only sample(s) for which the subject has consented will be taken.


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o
MMTT schedule: Following a minimum 8-hour fast overnight and where relevant, 2.5 hours after taking the IP, a blood sample for glucose will be taken 
immediately prior (within 15 minutes) to the subject drinking one entire can of Ensure Plus as a standardised meal (ie, “0 minutes”). Blood samples for 
glucose will additionally be drawn at 15, 30, 45, 60, 90, 120, 180, and 240 minutes (± 5 min) after consumption of the standardised meal. 
 
 
 
p
A urine pregnancy test should be conducted on any female subject of childbearing potential as detailed in the schedule. Pregnancy tests do not need to be 
conducted in women who are surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or are postmenopausal 
(defined as at least 1 year since last menses and/or having an elevated follicle stimulating hormone laboratory value which is in the postmenopausal range in 
previous laboratory test results).
q
Urine sample for urine albumin / creatinine ratio should be taken as an early morning specimen during the first void of the day and predose where relevant.
r
CGM device should be worn continuously throughout the study until the second follow-up visit (V11) and the sensor should be applied to the arm, taking 
into account subject preference and which side the ABPM device will be used on. The sensor applied to the skin is single-use and may not be re-attached 
once removed.
s
CGM sensor application should occur at least 2 hours predose+/- 15 minutes on Day 1; thereafter, existing CGM sensors should be removed and a new 
sensor applied at 0800 hours ± 120 minutes on Day 12 and at any time on Day 19. On Day 32, a new sensor will be applied and worn until the second 
follow-up visit (V11). Whenever a new CGM sensor is applied, at least 1 hour afterwards, the site staff should ensure the sensor is activated.
t
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 plasma 
glucose at any time the subject feels unwell or has symptoms of hypoglycaemia (hunger, dizziness, shaking, sweating, or irritability).


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4.2.3
Follow-up Period
Table 11 shows all procedures to be conducted during the follow-up period. 
Table 11
Schedule of Follow-up Procedures
Study Period
Follow-up Period
Visit Number
V10
V11
V12 (EoS) a
Procedure / Study Day
D33
D40 ± 5
D60 ± 5
Outpatient visit to the clinic
X
X
X
Physical examination (abbreviated)
X
X
Weight 
X b
X
X
ECG
X
X
Vital signs
X
X
Collect blood for
Serum chemistry (including eGFR calculation)
X
X
X
Fasting glucose
X
Calcitonin c
X b
Haematology
X
X
ADAd
X c
HbA1c
X
PK for MEDI0382e
X
Collect urine for
Urinalysis (dipstick)
X
X
Urine albumin / creatinine ratio f
X
X
X
Pregnancy test (women of childbearing potential 
only)g
X
X
Check CGM readings 
 
X
X
Removal of CGM sensor
X
Glucose meter and diary provision
X
X
Assessment of AEs / SAEs
X
X
X
Concomitant medications
X
X
AE = adverse event; ADA = anti-drug antibody; BMI = body mass index; CGM = continuous glucose 
monitoring; ECG = electrocardiogram; eGFR = estimated creatinine clearance; EoS = End of study; HbA1c = 
glycated haemoglobin; SAE = serious adverse event.
a
Subjects are required to fast for at least 8 hours overnight prior to the visit.
 
 


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b
D33 body weight should be measured in the morning prior to breakfast. Refer to Section 4.3.1.3 for details.
c
Calcitonin need only be re-measured in subjects who had a level > upper limit of normal (ULN) on Day 32
d
If this sample is ADA positive, the subject will be asked to return to provide another sample at 
approximately 3 months after the end-of-study visit (post-study sample). If this sample is ADA positive, 
additional visit(s) every 3 months should continue until a sample tests negative for ADA.
e
PK Sampling Schedule for MEDI0382: 
•
Day 1: Predose 
•
Day 5: Predose
•
Day 12: Predose
•
Day 19: Predose 
•
Day 32: Predose and at 0.5, 1, and 2 hours (± 15 min); 4, 6 and 8 (± 30 min) postdose
•
Day 33: 24 hours (± 15 min) postdose
f
Urine sample for urine albumin / creatinine ratio should be taken as an early morning specimen during the 
first void of the day.
g
A urine pregnancy test should be conducted on any female subject of childbearing potential as detailed in 
the schedule. Pregnancy tests do not need to be conducted in women who are surgically sterile (ie, bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or are postmenopausal (defined as at least 
1 year since last menses and/or having an elevated follicle stimulating hormone laboratory value which is in 
the postmenopausal range in previous laboratory test results).
4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
Mixed-meal Tolerance Tests
A standardised MMTT will be used to assess change in glucose AUC measured from baseline 
(Day -5) to the end of 32 days of treatment. A detailed MMTT schedule is provided in the 
footnotes to Table 9 and Table 10. 
Following a minimum 8-hour fast the subject will undergo an MMTT which will involve the 
consumption of a standardised liquid meal (Ensure Plus, a nutritional supplement containing 
the components of fat, carbohydrate, and protein, which make up a standard MMTT) within 
15 minutes, and timed serial blood samples will be obtained for measurement of glucose 
through 240 minutes after consumption of the standardised meal (with no additional food 
intake during this time). Blood will be drawn within 15 minutes before consuming the 
standardised liquid meal (ie, “0 minutes”), and at 15, 30, 45, 60, 90, 120, 180, and 
240 minutes (± 5 minutes) after consumption. Blood sampling should occur as close as 
possible to the specified times for the MMTT. Sampling ± 5 minutes of the specified time will 
not be considered a protocol deviation but the exact time of sampling should be recorded. At 
Day 32 the serial blood sampling will begin 2.5 hours after Investigational Product 
administration.
Subjects who use a quick acting or pre-mixed form of insulin with breakfast should receive 
their usual/current dose of breakfast-time insulin with the Ensure Plus milkshake ie, dose 
reduction of insulin is not required. Subjects who carbohydrate count or vary insulin dose in 
relation to meal type are to be advised that the Ensure Plus milkshake contains approximately 


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44.4 g of carbohydrate, 10.8 g of fat and 13.8 g of protein and to adjust their insulin dose on 
this basis. 
 
 
 
 
 
4.3.1.2
Blood Tests for Glucose Lowering Efficacy
Blood samples will be collected to evaluate blood glucose (fasting) and HbA1c levels (see 
Table 9, Table 10, and Table 11 for evaluation times).
4.3.1.3
Weight
Weight will be measured at the time points specified in the schedules of procedures, after the 
subject has toileted and removed bulky clothing, including shoes. Whenever possible, the 
same calibrated scale should be used for each measurement for any given subject.
4.3.2
Medical History, Physical Examination, Electrocardiogram, Weight, 
and Vital Signs
4.3.2.1
Medical History and Physical Examination
Complete medical history will include past and current medical conditions, including 
cardiovascular, respiratory, GI, renal, hepatic, neurological, endocrine, lymphatic, 
hematologic, immunologic, dermatological, psychiatric, and genitourinary disorders, drug and 
surgical history, or any other diseases or disorders.
Physical examinations will be performed by a physician or qualified designee and will include 
examination of the following body systems: immunologic/allergy; head, ears, eyes, nose, 
throat; respiratory; cardiovascular; GI; musculoskeletal; neurological (structured neurological 
examination to encompass mental status; cranial nerves; nystagmus; motor system – muscle 
strength; sensory system – sensation; bowel and bladder function; deep tendon reflexes; gait; 
station; coordination; fundoscopy; and cerebellar function); psychiatric (to the extent of 
determining whether or not the subject is willing and able to cooperate with the required study 
procedures in the investigator’s judgement); dermatological; haematologic/lymphatic; and 
endocrine.
Any focal deficit identified at baseline should be documented in the eCRF.
The full physical examination including structured neurological examination is required at 
screening. Targeted/abbreviated examinations (evaluation of selective body systems at the 


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judgment of the physician or qualified designee based on subject presentation) are sufficient 
for the remaining time points.
Clinically significant abnormal findings will be recorded. Physical examinations will be 
performed at the time points specified in the schedules of procedures. Height will be measured 
at screening.
4.3.2.2
Electrocardiograms
At the visits specified in Table 9, Table 10, and Table 11, 12-lead digital ECGs will be 
obtained after the subject has rested for 10 minutes in the supine position. Only a single ECG 
of 10 seconds’ duration will be required at the specified time points. 
The same centrally provided recorder will be used for each evaluation for each subject. Date 
and time settings should be checked at the start of each study day to ensure that they are set to 
the correct time.
Skin preparation should be thorough and electrode positions should be according to standard 
12-lead ECG placement. 
Electrocardiograms will be digitally recorded but must be printed on paper. In this study 
lead II will be analysed and reported as primary. Lead V2 or V5 will be analysed, for all visits, 
as backup for the individual where analysis in lead II is not deemed possible for predose or 
significant parts of whole visits or whole visits. The following variables should be captured: 
heart rate, RR, PR, QRS, axis, ST-T morphology, 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.
4.3.2.3
Assessment of the Injection Site
Site staff will check the investigational product 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. 
4.3.2.4
Vital Signs
Vital sign measurements (BP, pulse, body temperature and respiratory rate) will be obtained 
after the subject has rested in the 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). Route of body temperature measurement will be 
according to local protocols. Where indicated on Visit 4 (Day 1) predose and Visit 9 (Day 32) 
postural BP assessed supine and then standing should be measured.


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4.3.3
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study. 
Clinical laboratory safety tests will be performed in a licensed central clinical laboratory. 
Urine pregnancy tests may be performed at the site using a licensed test (urine human 
chorionic gonadotropin [hCG]; 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 (see Table 9, Table 10, Table 11 for 
the schedule of tests): 
Serum Chemistry
Sodium
Bicarbonate
Potassium
Aspartate transaminase (AST)
Chloride
Phosphorus
Glucose
Blood urea nitrogen (BUN) or serum urea
Creatinine
Alkaline phosphatase (ALP)
Albumin
Alanine transaminase (ALT)
Calcium
Total bilirubin 
Magnesium
Hematology
Hematocrit
Platelet count
Hemoglobin
Mean corpuscular hemoglobin concentration
Red blood cells (RBC)
Mean corpuscular volume
White blood cells (WBC) count with differential
Urinalysis
pH
Specific gravity
Bilirubin
Color
Glucose
Appearance
Ketones
WBC Casts
Blood
RBC Casts
Protein
Note: Urinalysis for protein, glucose, ketones, and blood may be performed at the site using a licensed test 
(dipstick).
Pregnancy Test (females of childbearing potential only)
!
Urine human chorionic gonadotropin (hCG) 


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Other Tests
!
Urine albumin / creatinine ratio
!
Urine drug screen (screening and Day -5 only)
!
Alcohol screening test (screening and Day -5 only)
!
Pancreatic amylase, lipase
!
Calcitonin
!
Lactate
!
HIV-1 and -2 antibodies (screening only)
!
Hepatitis B and C serology (screening only)
!
Fasting lipid profile
4.3.4
Pharmacokinetic Evaluation and Methods
Blood will be collected to evaluate PK of MEDI0382 in plasma (see Table 10 and Table 11
for collection time points and timing with regard to dosing). The PK of MEDI0382 in plasma 
will be measured utilizing a validated liquid chromatography-tandem mass spectrometry 
(LC/MS-MS) method. 
For those subjects who are taking metformin, blood samples will be collected and stored for 
measurement of metformin PK if the resulting analyses are deemed to be useful to further 
evaluate safety of MEDI0382 (see Table 10 for collection time points). Blood samples will be 
stored for up to 6 months after clinical study report finalisation. Evaluations will be performed 
using a validated LC/MS-MS assay.
Residual MEDI0382 PK samples will be retained for up to 5 years after clinical study report 
(CSR) finalisation.
4.3.5
Immunogenicity Evaluation and Methods
Blood samples will be collected to evaluate serum ADA responses to MEDI0382 (see 
Table 10 and Table 11 for collection time points). A screening assay will be used to determine 
ADA-positive samples. This will be in the form of a traditional ligand-binding “bridging” 
assay using electrochemiluminescence. Any positive samples will be tested in a confirmatory 
assay whereby the specificity of the ADA response will be confirmed as either positive or 
negative with respect to MEDI0382. Cross-reactivity of ADA-positive samples to GLP-1 and 
glucagon may also be assessed. Titer evaluation will be performed on samples that are 
confirmed positive for ADA. 
At the end of study visit (Visit 12), if a subject’s sample is confirmed ADA positive, the 
subject will be asked to return to provide another sample in 3 months to evaluate whether or 
not ADAs persist. If the sample taken in 3 months is ADA positive, the subject will be asked 


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to return to provide a sample in another 3 months (ie, 6 months after the end of study visit). If 
the sample is ADA positive at 6 months, the subject will be monitored until ADA levels have 
returned to baseline. 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.
4.3.6
Pharmacodynamic Evaluation and Methods
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3.6.2
Training for Application and Wearing of ABPM Device
Subjects will be given training at their local study site about how to set up and apply the 
ABPM device. In brief, an appropriate size cuff encircling 80% to 100% of the arm will be 
selected and the device will be fitted to the subject (on the contralateral side to the CGM 
device), with the bladder placed over the artery and an initial test reading performed. The 


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subjects will be advised that for the first reading the device will inflate to a pressure of 
180 mm Hg, and thereafter the device will adapt to inflate to a pressure just above the last 
recorded BP. The subject will be advised to undergo normal daily activities while wearing the 
cuff, and he/she will be advised to avoid any strenuous form of activity, bathing, or showering 
while wearing the cuff. The subject will be advised to remain still during a measurement with 
the arm relaxed at heart level. The subject will also be given advice on how to wear the device 
during the day and at night while sleeping, and what to expect in terms of frequency of 
readings during the day (every 15 minutes) and overnight (every 30 minutes). During ABPM, 
systolic BP, diastolic BP, heart rate pressure, heart rate, and mean arterial pressure readings 
will be recorded over a period of 24 hours.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.3.10
Estimate of Volume of Blood to Be Collected
The estimated volume of blood to be collected from each subject over the entire course of the 
study is approximately 200.5 mL if the subject is taking metformin or approximately 180.5
mL if the subject is not taking metformin. An additional approximately 18.5 mL will be 
collected if a subject consents to optional genetic research and a further approximately 27 mL 
if a subject consents to optional future nongenetic research, yielding a maximum total volume 
collected of approximately 246 mL. If repeats of any blood tests are required, the volume of 
blood collection will increase accordingly.
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or permanently terminate this study at 
any time. The reasons for temporarily suspending or permanently terminating the study may 
include but are not limited to the following: 


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1
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects
2
Subject enrollment is unsatisfactory
3
Non-compliance that might significantly jeopardize the validity or integrity of the study 
4
Sponsor decision to terminate development of the investigational product for this 
indication
5
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 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) promptly 
and provide the reason(s) for the suspension/termination. If the study is suspended for safety 
reasons and it is deemed appropriate by the sponsor to resume the study, approval from the 
relevant regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to 
resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Products
MedImmune will provide the investigators with investigational product, diluent, and placebo 
(Table 12 and Table 13) using designated distribution centres. 
 
 
 
 
 
 
 


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4.5.1.1
In-clinic Vial Dosing, 
 MEDI0382: IP Handling, Inspection, and Dose 
Preparation
Investigational Product Handling
Investigational product kits should be stored at 2°C to 8°C in the original container. 
Investigational products do not contain preservatives, are supplied for single-dose use only, 
and any unused portion must be discarded. 
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. MEDI0382 is supplied as a sterile 
liquid solution 
. The MEDI0382 or Placebo solution in vials 
should not be cloudy, discoloured, or contain any visible particles. If there are any defects 
noted with the investigational product, the investigator and site monitor should be notified 
immediately. Refer to the Product Complaint section (Section 4.5.1.6) for further instructions.
Dose Preparation: 
 Dose and Placebo
The final delivery volume and concentration for the 
 dose level are described in 
Table 14. The volume to be delivered will be withdrawn using a 
 syringe with a 
27 gauge needle. Dilution and preparation of doses for administration is to be performed 
aseptically. Total in-use storage time from needle puncture of the investigational product vial 
to start of administration should not exceed 4 hours. If storage time exceeds these limits, a 
new dose must be prepared from a new vial.
 
 
 
 
 
 
 
  


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4.5.1.5
Monitoring of Dose Administration
In prior experience with MEDI0382, there has been 1 injection-site reaction and no 
anaphylactic reactions. During visits to the clinical unit, the site of administration will be 
checked for signs of injection-site reaction as required
As with any exogenous peptide or biologic product, allergic reactions to dose administration 
are possible. Therefore, appropriate drugs and medical equipment to treat acute anaphylactic 
reactions must be immediately available at the study sites where the first 5 doses will be 
administered, and study personnel must be trained to recognize and treat anaphylaxis.
4.5.1.6
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labelled conditions unless otherwise instructed.
In the case of discovery of a defect in a PFS at home, subjects should be instructed not to 
dispose of the defective device, but to store it safely and separately at 2-8°C. Arrangements 
will be made for the defective item to be returned to the clinic for further investigation as 
required.
MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone:
+1-301-398-2105
+1-877-MEDI-411 (+1-877-633-4411)
Fax:
+1-301-398-8800
Mail:
MedImmune
Attn: Product Complaint Department


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One MedImmune Way
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
Additional medications that may be used during the study, and management of their dose and 
potential toxicities, is discussed in Section 3.1.4.
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
Investigational product is administered at the study site by study site personnel for the first 
four doses, who will monitor compliance. Thereafter, study site personnel should monitor 
compliance through verbal report and drug accountability at each study visit.  
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to MedImmune. All unused 
investigational product will be returned to a MedImmune-authorized depot or disposed of 
upon authorization by MedImmune or designee.
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 blinded 
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 blinded investigational product kit numbers for the subject.
Subjects will be randomised using a 1:1 ratio to receive either MEDI0382 or placebo. 
Sufficient subjects will be invited to participate in the study such that in total approximately 
40 subjects will be randomised and 20 will complete dosing in the active arm and 20 will 
complete dosing in the placebo arm.
 


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The first dose of investigational product (MEDI0382 or placebo) must be administered the 
same day the investigational product is assigned, within 4 hours after the investigational 
product is assigned. If there is a delay in the administration of investigational product such 
that it will not be administered within the specified timeframe, the study monitor must be 
notified immediately.
4.6.2
Methods to Ensure Blinding
This is a double-blind study in which MEDI0382 and placebo PFS titration volumes are not 
identical/indistinguishable in appearance. 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, investigational product (MEDI0382 and placebo) PFS will be handled by an unblinded 
investigational product manager or unblinded study personnel that will not be involved in the 
treatment or clinical evaluation of subjects. An unblinded qualified designee may administer 
investigational product to subjects during in-clinic visits. 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 (see 
Section 6.2). 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.
In the event that treatment allocation for a subject becomes known to the investigator or other 
study staff involved in the management of study subjects, the sponsor must be notified 
immediately. 
4.6.3
Methods for Unblinding 
4.6.3.1
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product assignment are contained in the IXRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
investigational product administered to the subject. If the management of a medical 
emergency would be the same whether or not MEDI0382 was received by the subject, the 
treatment assignment should not be unblinded. 


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MedImmune retains the right to unblind the treatment assignment 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 to the blinded site staff or blinded 
MedImmune/contract research organization (CRO) trial team, 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 concomitant medication 
taken from the time of screening until the end of the study (final study visit). Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.7.2. Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, anti-
emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines.
4.7.2
Prohibited Concomitant Medications
Other than the medications described above, use of herbal supplements is not permitted. 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
 
:
!
Concurrent or previous use of a GLP-1 analogue containing preparation within the last 30 
days or 5 half-lives of the drug, if known, whichever is longest, at the time of Visit 2
!
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 dosing (Visit 4)
!
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 dosing 
(Visit 4)
!
Concurrent use of opiates, domperidone, metoclopramide, or other drugs known to alter 
gastric emptying and within 2 weeks prior to the start of dosing (Visit 4) 


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!
Concurrent use of aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily 
and within the last 3 days prior to the start of the run-in period (Visit 2)
!
Concurrent use of paracetamol (acetaminophen) at a total daily dose greater than 
3000 mg and within the last 3 days prior to the start of the run-in period (Visit 2)
!
Concurrent use of ascorbic acid (vitamin C) at a total daily dose of > 1000 mg and within 
the last 3 days prior to the start of the run-in period (Visit 2)
4.8
Statistical Evaluation
4.8.1
General Considerations
Tabular summaries will be presented by treatment group. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics. Additional details of statistical analyses will be 
described in the statistical analysis plan. Analyses of secondary and exploratory efficacy 
variables will be performed without any adjustment for multiplicity.
Analysis Populations
Intent to Treat: The intent-to-treat (ITT) population is defined as all subjects that are 
randomised and receive any amount of investigational product, analysed according to 
randomised treatment assignment. All efficacy analyses will be performed on the ITT 
population unless otherwise specified.
As-Treated Population: The as-treated population is defined as all subjects who received at 
least 1 dose of investigational product and will be analysed according to the treatment actually 
received. All safety analyses will be performed on the as-treated population.
PK Population: The PK population includes all subjects who received at least 1 dose of 
investigational product and had at least one PK sample taken with a value above the lower 
limit of quantitation.
Immunogenicity Population: The Immunogenicity population includes all subjects in the as-
treated population who have at least one serum immunogenicity result.
4.8.2
Sample Size
Forty subjects (20 completers in the MEDI0382 group and 20 completers in placebo group) 
will provide > 85% power to detect 18.1% difference between the two treatment groups in 
percentage change in the MMTT glucose AUC from baseline (Day -5) to the end of 32 days of 
treatment (Day 32), with a two-sided significance level of 0.1 and assuming the standard 
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4.8.3
Efficacy
4.8.3.1
Primary Efficacy Analysis
The primary efficacy analysis will be performed using the ITT population. The primary 
efficacy endpoint, percentage change in MMTT glucose AUC from baseline (Day -5) to the 
end of 32 days of treatment will be analysed using an analysis of covariance (ANCOVA) 
model. The model will include fixed effect of treatment and baseline AUC as a covariate. The 
difference of the percent change in glucose AUC between the two treatment arms will be 
compared with a two-sided significance level of 0.10.
4.8.3.2
Secondary Efficacy Analyses
Secondary efficacy analyses will be performed using the ITT population. All secondary 
efficacy endpoints will be summarised by visit and by treatment group. The change in 
percentage of time spent within a target glucose range of 70 mg/dL (3.9 mmol/L) to 
180 mg/dL (10 mmol/L) over a 7-day period at baseline to the final week of treatment will be 
analysed using a Wilcoxon rank-sum test. All other continuous endpoints will be analysed 
using a similar ANCOVA model as that for the primary analysis.
 
 
4.8.4
Safety
4.8.4.1
Analysis of Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) by system organ class (SOC) and preferred term (PT). Specific AEs will be 
counted once for each subject for calculating rates, but will be presented in total in subject 
listings. In addition, if the same AE occurs multiple times within a particular subject, the 
highest severity and level of causality will be reported. If any associations of interest between 
AEs and baseline characteristics are observed, additional stratified results may be presented. 
All treatment-emergent AEs will be summarized overall and by MedDRA SOC and PT, by 
severity and 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
Laboratory parameters will be assessed at baseline as well as throughout the study. 
Frequencies of abnormal laboratory measurements will be presented for each laboratory 
parameter. Also, laboratory parameters will be assessed by presenting tables containing 
information related to laboratory shifts from baseline relative to the normal range, as well as 
descriptively over time.


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4.8.5
Analysis of Immunogenicity/Pharmacokinetics
4.8.5.1
Pharmacokinetic Analyses
Pharmacokinetic parameters such as maximum concentration (Cmax), time to maximum 
observed concentration (Tmax), and AUCtau, will be estimated from plasma concentration-time 
data for MEDI0382 at the 
 dose level if data permit. Descriptive statistics will be 
generated for PK parameters for the MEDI0382 group at 
 and for Ctrough at each dose 
level. Subjects who have at least one measurable concentration time point of investigational 
product will be used for this analysis.
4.8.5.2
Immunogenicity Analyses
The incidence and impact of ADA to MEDI0382 will be evaluated. The number and 
percentage of subjects with confirmed positive serum antibodies to MEDI0382 will be 
reported by dose level. 
4.8.6
Additional Analyses
4.8.6.1
Vital Signs Analyses
The change in the 24-hour average systolic BP, diastolic BP, and pulse rate from the ABPM 
will be summarized for each post-baseline evaluation. Vital signs (blood pressure, pulse rate, 
temperature and respiration rate) will be summarized at each visit.
4.8.6.2
ECG Analyses
Frequencies of abnormal ECGs and descriptive statistics of changes in ECG variables heart 
rate and RR, PR, QRS, QT, and QTc intervals will be summarized.
4.8.7
Interim Analysis
No interim analysis is planned for this study.


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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 unfavourable 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, 
haematuria) 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 hospitalization or prolongation of existing hospitalization 
!
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 jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the investigational product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or nonserious. 
The rapid reporting of AESIs allows ongoing surveillance of these events to characterise and 
understand them in association with the use of this investigational product.
All AESIs should be recorded in the eCRF within 24 hours. In addition, AESIs that are also 
SAEs should be reported to MedImmune Patient Safety within 24 hours. Instructions to the 
site on how to record (in the eCRF) and report AESI are provided in Section 5.4 and 
Section 5.5 respectively. The AESIs for this study are defined below.
Hepatic function abnormality meeting the definition of Hy’s Law is considered an AESI. See 
Section 5.6.2 for the definition and reporting of AESIs of hepatic function abnormality. 
5.3.1
Hepatic Function Abnormalities
Refer to Section 5.6.2 and Section 10.5 for the definition and follow-up for liver 
abnormalities. There are no other AESIs in this study.
5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the investigator for severity, relationship 
to the investigational product, possible etiologies, and whether the event meets criteria of an 
SAE and therefore requires immediate notification to the sponsor (see Section 5.5). See 
Section 5.2 for the definition of SAEs and Section 10.3 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 on the SAE Report Form.


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5.4.1
Time Period for Collection of Adverse Events
AEs will be collected from time of signature of informed consent, throughout the treatment 
period, and including the follow-up period (Day 60±5).
All SAEs will be recorded from the time of informed consent.
For nontreatment-emergent AEs (ie, AEs that occur during the period from the time informed 
consent is signed but prior to the subject receiving investigational product), only AEs 
associated with protocol-related procedures should be reported. After the start of treatment, all 
treatment-emergent AEs (TEAEs; Section 5.1) should be reported.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 
eCRF. MedImmune retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
5.4.3
Deaths
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:
•
All deaths (including those that are clearly the result of disease progression) should be 
reported and documented in the eCRF and reported as an SAE within 24 hours. The report 
should contain a comment regarding the co-involvement of disease progression, if 
appropriate, and should assign main and contributory causes of death.
•
Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) may be helpful in the assessment of the cause of death, and if performed a copy 
of the post-mortem results should be forwarded to the sponsor representative(s) within the 
usual timeframes (refer to Section 5.5 for additional information).
5.5
Reporting of Serious Adverse Events
All SAEs must be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs 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 
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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. 
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the IB, unless otherwise specified in this protocol.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose 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 5.5. 
For other overdoses, reporting must occur within 30 days.
5.6.2
Hepatic Function Abnormality
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need 
to be reported as SAEs. Please refer to Section 10.5 for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law. 


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5.6.3
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.6.3.1
Maternal Exposure
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 5.5) 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.


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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, MedImmune representatives will have regular contacts with the study site.  
Both a blinded and unblinded site monitor will be assigned to each site.  The blinded site 
monitor will oversee study conduct, 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 
!
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 that any 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.
!
Review of temperature logs for refrigerators and freezers to store investigational product 
or biological specimens
The unblinded site monitor will oversee management of the investigational product, including 
ensuring that study drug accountability checks are being performed.
The MedImmune representatives will be available between visits if the investigator(s) or other 
staff at the study sites needs information and advice about the study conduct.


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6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this 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 will 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 their last protocol-specified visit/assessment (including telephone contact)or 
assessed for the primary endpoint of the study, regardless of the number of doses of 
investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.5 and Section 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. 
6.4
Data Management 
Data management will be performed by MedImmune Data Management staff or other party
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.


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6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the Principal Investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system.
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 IRB/IEC responsible for each site must review and approve the final study protocol, 
including the final version of the Informed Consent Form and any other written information 
and/or materials to be provided to the subjects. The IRB/IEC must also approve all advertising 
used to recruit subjects for the study. The investigator is responsible for submitting these 
documents to the applicable IRB/IEC, and distributing them to the study site staff.
The opinion of the IRB/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.
MedImmune should approve any substantive modifications to the Informed Consent Form that 
are needed to meet local requirements.
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Before the study is initiated, MedImmune will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. MedImmune 
will provide safety updates/reports according to local requirements, including suspected 
unexpected serious adverse reactions where relevant, to regulatory authorities, IRB/IEC, and 
principal investigators.
Each Principal Investigator is responsible for providing the IRB/IEC reports of any serious 
and unexpected adverse drug reactions from any other study conducted with the 
investigational product. MedImmune will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. MedImmune will develop a core 
informed consent form for use by all investigators in the clinical study. MedImmune must 
approve any modifications to the informed consent form 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 Informed Consent Form(s) is/are stored in the Investigator’s 
Study File
!
Ensure a copy of the signed Informed Consent Form(s) is/are 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 informed consent form that is approved by an IRB/IEC
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune.
Substantial changes must be documented in a study protocol amendment. MedImmune will 
distribute amended versions of the protocol to the principal investigator(s). Before 
implementation, amended protocols must be approved by relevant IRB/IEC (see Section 7.2) 


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and according to local requirements, the national regulatory authority approval. The IRB/IEC 
must also approve revisions to the informed consent form, advertising, and any other written 
information and/or materials resulting from the change to the protocol.
If local regulations require, any unsubstantial changes will be communicated to or approved 
by each IRB/IEC.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/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, Good Clinical Practice 
(GCP), guidelines of the International Council for Harmonisation (ICH), and any applicable 
regulatory requirements. The investigator will contact MedImmune immediately if contacted 
by a regulatory agency about an inspection at the site.


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8
REFERENCES
Bagger JI, Holst JJ, Hartmann B, Andersen B, Knop FK, Vilsbøll T. Effect of oxyntomodulin, 
glucagon, GLP-1, and combined glucagon +GLP-1 infusion on food intake, appetite, and 
resting energy expenditure. J Clin Endocrinol Metab. 2015;100(12):4541-52.
Center for Drug Evaluation and Research (CDER). Byetta Pharmacology Review. 2005.
Habegger KM, Stemmer K, Cheng C, Müller TD, Heppner KM, Ottaway N, et al. Fibroblast 
growth factor 21 mediates specific glucagon actions. Diabetes. 2013;62(5):1453-63.
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.
Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of 
nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate 
weight reduction in patients with type 2 diabetes. Diabetes. 2005;54(3):603-8.
Victoza (liraglutide) 6 mg/mL for injection in pre-filled pen (Summary of Product
Characteristics [SPC]). Last updated 2016 December 07; Novo Nordisk Limited, West 
Sussex, United Kingdom. Available from: URL: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/001026/WC500050017.pdf
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 
randomised controlled trial. Int J Obes. 2006;30(12):1729-36.
9
CHANGES TO THE PROTOCOL
9.1
Protocol Amendment 4, 12Nov2018
Key Details of Amendment
Reason for Amendment
Amendment 4 / 12Nov2018
Section 3.2.2 Rationale for Study Population, Section 
4.1.2 Inclusion Criteria, and Section 4.1.4 Subject 
Enrollment and Randomisation
“At least” has been changed to “Approximately” to 
provide additional flexibility to recruitment in view 
of lower than expected numbers of  eligible subjects 
in the eGFR 30 to 45 mL/min/1.73 m2category. 


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9.2
Protocol Amendment 3, 11Oct2018
Key changes to the protocol are summarized in the table below.
Key Details of Amendment
Reason for Amendment
Amendment 3 / 11Oct2018
Protocol Synopsis, and Section 3.1.1 Overview, 
Section 4.6.3.2 Unblinding for Interim Analysis 
Purposes, and Section 4.8.7 Interim Analysis
The planned interim analysis has been cancelled as 
there is no longer a time pressure to have these data 
for Phase 3 planning.  
There are no emerging safety signals from the 
ongoing study.
9.3
Protocol Amendment 2, 06Apr2018
Text revisions resulting from this amendment have been made in response to 
recommendations made by the Medicines & Healthcare products Regulatory Agency 
(MHRA) and are incorporated in the body of Protocol Amendment 2. Key changes to the 
protocol are summarized in the table below.
Key Details of Amendment
Reason for Amendment
Amendment 2 / 06Apr2018
Section 4.1.6 Discontinuation of Investigational 
Product
Updated in line with recommendations from MHRA: 
Clarified dose-limiting symptoms in the first bullet of 
criterion #3.
Bullet removed regarding subjects who did not meet 
inclusion, or met exclusion criteria.
Added bullet regarding subjects who meet Hy’s Law.
Added bullet regarding ECG abnormalities.
Section 4.2.2 Randomised Treatment Period, Table 
10 (footnote f)
Updated to add a 2-hour post-dose ECG on Days 1 
and 32.
Section 4.2.2 Randomised Treatment Period, Table 
10 
Addition of amylase and lipase sampling at Days 5, 
12 and 19.
Section 5.4.3 Deaths
Updated to detail that all deaths (including those that 
are clearly the result of disease progression) will be 
reported as an SAE.
9.4
Protocol Amendment 1, 28Feb2018
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. Key changes to the protocol are summarized in the table below.


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Key Details of Amendment
Reason for Amendment
Amendment 1 / 28Feb2018
 
Section 4.1.3 Exclusion Criteria
Exclusion criterion #8: typographic error adjustment
Section 4.2.2 Randomised Treatment Period
Addition of weight to schedule of assessments on 
Day 32
Section 4.3.2.2 Electrocardiograms
Amended to clarify that review of ECG is from lead II 
on V2
 
Section 4.7.2 Prohibited Concomitant Medication
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 Visit 2” (previously Visit 1)
Text modified to align with updated Company 
template and practice 


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10
APPENDICES
10.1
Appendix 1 - Signatures
Sponsor Signature(s)
A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, 
Safety, and Pharmacokinetics of MEDI0382 in Subjects with Type 2 Diabetes Mellitus and 
Renal Impairment
I agree to the terms of this protocol.
Signature and date: 
Electronic signature attached
, 
 Vice President, Clinical Development
Clinical Therapeutic Area Head
One MedImmune Way, Gaithersburg MD, 20878, USA
Telephone number: 


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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 sterilization includes bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) defined as 12 months with no menses without an alternative medical cause 
and/or have a follicle-stimulating hormone [FSH] levels in the safety laboratory’s normal 
range for postmenopausal phase on prior laboratory testing
A highly effective method of contraception is defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly. The acceptable methods of 
contraception are described in Table 10-2. 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 10-2
Highly Effective Methods of Contraception 
Barrier Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing system (UIS) a
•
Bilateral tubal occlusion
•
Vasectomized partner b
•
Sexual abstinence c
Combined (estrogen and progestogen containing 
hormonal contraception) d
∀
Injectable
∀
Transdermal (patch)
Progestogen-only hormonal contraception associated 
with inhibition of ovulation d
∀
Injectable
∀
Implantable
∀
Intravaginal
a
This is also considered a hormonal method.
b
With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate).
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject.
d
Oral forms of contraception are not acceptable given that vomiting may arise as a potential side-effect of 
MEDI0382


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10.3
Appendix 3 - Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
Examples of such events are:
!
Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization
!
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.


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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 
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. The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the investigational product.
!
Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product?
!
Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or products of the same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties? 
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect investigational product?


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!
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, or other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? MedImmune would not normally recommend or 
support a re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship?
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the investigational product?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-emergent 
SAEs. A protocol-related SAE may occur as a result of a procedure or intervention required 
during the study (eg, blood collection, washout of an existing medication). The following 
guidelines should be used by investigators to assess the relationship of SAEs to the protocol:
Protocol related:
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record.
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).


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10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases 
and Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Diseases (NIAID) 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, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
(b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
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 to identify and appropriately report cases 
of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries. 
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. Hy’s Law 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 potential Hy’s Law/Hy’s Law 
cases and for reporting AEs and SAEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
10.5.2
Definitions
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 
(ALP).
Hy’s Law
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the investigational product, can be found to explain the combination of increases; eg, elevated 
ALP indicating cholestasis, viral hepatitis, or another drug.  
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.


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Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any subject who meets any of the following identification criteria 
in isolation or in combination:
!
ALT ≥ 3 × ULN
!
AST ≥ 3 × ULN
!
TBL ≥ 2 × ULN
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the sponsor study representative
!
Determine whether the subject meets PHL criteria by reviewing laboratory reports from 
all previous visits
!
Promptly enter the laboratory data into the laboratory eCRF
10.5.3
Follow-up
Potential Hy’s Law Criteria 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 study protocol.
Potential Hy’s Law Criteria Met
If the subject does meet potential Hy’s Law criteria the investigator will notify the sponsor 
study representative who will then inform the study team. The Study Physician contacts the 
investigator, to provide guidance, discuss and agree an approach for the study subjects’ 
follow-up and the continuous review of data. Subsequent to this contact the investigator will:
!
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated
!
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the medical monitor. This includes deciding which the tests available in the Hy’s 
Law lab kit should be used.
!
Complete the Liver CRF Modules as information becomes available
!
If at any time (in consultation with the medical monitor) the potential Hy’s Law case 
meets serious criteria, report it as an SAE using standard reporting procedures


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10.5.4
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.
No later than 3 weeks after the biochemistry abnormality was initially detected, the medical 
monitor will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting potential Hy’s Law criteria other than DILI 
caused by the investigational product. The medical monitor and Global Safety Physician will 
also be involved in this review together with other subject matter experts as appropriate.
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the sponsor’s standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:
!
Report an SAE (report term ‘Hy’s Law’) according to 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 3 weeks 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:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above
!
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are met. Update the SAE report according to the outcome of 
the review


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FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090.pdf
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 7 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 
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/gene expression results to subjects, any 
insurance company, any employer, their family members, or general physician unless required 
to do so by law.


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Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a MedImmune 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/gene expression 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.
10.7
Appendix 7 Biological Samples
Storage, Re-use and Destruction of Biological Samples
Biological samples will be stored for a maximum of 15 years from the date of the Last 
Subject’s Last Visit, after which they will be destroyed. 
The results of biomarker research will be reported either in the CSR itself or as an addendum, 
or separately in a scientific report or publication. The results of this biomarker research may 


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be pooled with biomarker data from other studies with the study drug to generate hypotheses 
to be tested in future research. ADA samples will be stored for up to 2 years after marketing 
approval.
Labelling and Shipment of Biological Samples
The principal investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria).
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with MedImmune and appropriate 
labelling, shipment and containment provisions are approved.
Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The principal investigator at each study site keeps full traceability of collected biological 
samples from the subjects while in storage at the study site until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival. The sample receiver keeps full 
traceability of the samples while in storage and during use until used or disposed of or until 
further shipment and keeps documentation of receipt of arrival.
MedImmune keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the Translational Sciences Biorepository 
during the entire life cycle.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: D5670C00013-amendment-4
Document Title:
D5670C00013-amendment-4
Document ID:
Doc ID-003943310
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
12-Nov-2018 22:22 UTC
Management Approval
12-Nov-2018 10:25 UTC
Content Approval
12-Nov-2018 19:27 UTC
Content Approval
12-Nov-2018 12:19 UTC
Author Approval
12-Nov-2018 16:04 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
Statistical Analysis Plan


TABLE OF CONTENTS
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 


List of Abbreviations