Clinical trial NCT03745937
Conditions: Type 2 Diabetes Mellitus
Keywords: MEDI0382, diabetes, obesity, overweight, type 2 diabetes mellitus
Sponsor: MedImmune LLC
Start date: 2019-01-07; Completion date: 2019-05-28
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2a, randomized, blinded, placebo-controlled study in up to 20 overweight or obese participants with type 2 diabetes mellitus. The participants will participate in the study for approximately 18 weeks, including screening, run-in and treatment periods and a safety follow-up.

Detailed description:

Arms: arm 1: Participants will receive subcutaneous (SC) dose of MEDI0382 uptitrated weekly once daily up to 8 weeks during the up-titration period and thereafter once daily in 3-week treatment extension period (TEP). arm 2: Participants will receive SC dose of placebo matched to MEDI0382 once daily up to 8 weeks during the uptitration period and thereafter once daily through 3 week TEP. arm 3: Participants will receive SC dose of MEDI0382 uptitrated weekly once daily up to 8 weeks during the up-titration period and thereafter once daily in 3-week TEP. arm 4: Participants will receive SC dose of placebo matched to MEDI0382 once daily up to 8 weeks during the up-titration period and thereafter once daily through 3 week TEP.
Interventions: intervention 1: MEDI0382 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous dose of MEDI0382 will be up-titrated weekly once daily up to 8 weeks during the uptitration period and thereafter once daily in 3-week TEP. intervention 2: Subcutaneous dose of placebo matched to MEDI0382 will be administered once daily up to 8 weeks during the up-titration period and thereafter once daily through 3 week TEP.

Protocol documents:
Prot_000.pdf: 
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A Phase 2a Randomized, Blinded, Placebo-controlled Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy 
of MEDI0382 in Overweight/Obese Subjects with Type 2 Diabetes 
Mellitus
Sponsor Protocol Number: D5670C00030
Application Number:
EudraCT number: 2018-003128-35
Investigational Product:
MEDI0382
Sponsor:
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca, Milstein Building, Granta Park, Cambridge, CB21 
6GH, UK 
Medical Monitor:
 
Contract Research Organization: Covance 
Protocol History, Date: Original Protocol, 10Sep2018
Protocol Amendment 1, 31Oct2018 
Protocol Amendment 2, 17Dec2018
Protocol Amendment 3, 16Apr2019
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from MedImmune.


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PROTOCOL SYNOPSIS
TITLE
A Phase 2a Randomized, Blinded, Placebo-controlled Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of MEDI0382 in Overweight/Obese Subjects with Type 2 Diabetes Mellitus
HYPOTHESES  
Primary Hypothesis: Daily subcutaneous (SC) administration of ascending doses of MEDI0382, titrated 
weekly to the highest clinically tolerated dose (HCTD), will result in an acceptable safety/tolerability profile in 
overweight/obese subjects with type 2 diabetes mellitus (T2DM). 
Secondary Hypothesis:
•
Once daily SC administration of MEDI0382, titrated weekly to the HCTD, will have a predictable 
pharmacokinetic (PK) and immunogenic profile in overweight/obese subjects with T2DM. 
•
Administration of MEDI0382 titrated weekly to the HCTD, will result in clinically relevant improvement 
in blood glucose control in overweight/obese subjects with T2DM. 
•
Administration of MEDI0382 titrated weekly to the HCTD, will result in clinically relevant body weight 
loss versus placebo in overweight/obese subjects with T2DM.
OBJECTIVES AND ENDPOINTS  
Primary Objective(s) and Associated Endpoints
Objective
Endpoint
Assess the safety and tolerability of 
MEDI0382 titrated up to the highest 
clinically tolerated dose (HCTD)
•
Incidence of treatment-emergent adverse events (TEAEs) 
and treatment-emergent serious adverse events (TESAEs) 
through the end of the up-titration period (up to 8 weeks) 
and through the end of the follow-up period
•
Clinically important changes in 12-lead electrocardiogram 
(ECG), vital signs (including heart rate and blood pressure), 
physical examination, and clinical laboratory evaluations 
through the end of up-titration period (up to 8 weeks) and 
through the end of the follow-up period
Secondary Objective(s) and Associated Endpoints
Objective
Endpoint
To characterize the PK profile of 
MEDI0382 titrated up to the HCTD
•
Area under the concentration-time curve (AUC) over a dosing 
duration (AUCtau), maximum observed concentration (Cmax), 
time to Cmax ((Tmax), trough plasma concentration (Ctrough), and 
accumulation ratio (Cmin [R0])
To characterize the immunogenicity of 
MEDI0382 titrated up to the HCTD
•
Anti-drug antibodies (ADAs) to MEDI0382 at baseline 
through end of study


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•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To assess the effects of MEDI0382, 
titrated up to the HCTD, on additional 
measures of glucose control
•
Change in fasting plasma glucose from Day -1 versus each 
week of the up-titration period, the end of the up-titration 
period, and the end of the treatment extension period
•
Change in HbA1c from Day -1 to the end of the treatment 
extension period
To assess the effects of MEDI0382, 
titrated up to the HCTD, on body weight
•
Percentage and absolute change in body weight from baseline 
to the end of the up-titration period and the end of the 
treatment extension
•
Percentage and absolute change in body weight from baseline 
to the end of each week of the up-titration period 
•
Proportion of subjects achieving > 5% body weight loss from 
baseline to the end of the treatment extension period.
 
 
 
 
 
 
 
 
 
 


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STUDY DESIGN  
This is a randomized, blinded, placebo-controlled study designed to evaluate the safety, tolerability, PK and 
efficacy of ascending doses of MEDI0382 in overweight or obese subjects with T2DM. This study will enroll 
subjects aged 18 to 74 years with a body mass index (BMI) ≥ 27 and ≤ 35 kg/m2. Subjects will have a diagnosis 
of T2DM and inadequate blood glucose control as defined by an HbA1c of 6.5% to 8.5%, and will be on 
metformin monotherapy. Subjects prescribed oral dual therapy with a dipeptidyl peptidase-4 inhibitor, 
sulphonylurea, glitinide, or a sodium-glucose co-transporter 2 inhibitor in addition to metformin at screening 
may be eligible to enter the study in Cohort 2 only following a 4-week washout period.
Twenty subjects will be enrolled to 2 cohorts: Cohort 1 (n = 8) and Cohort 2 (n = 12). For each cohort, subjects 
will be randomly assigned in a 3:1 ratio to receive MEDI0382 at doses titrated to a 
 
or placebo. The study has a run-in period of 10 days and an up to 8-week up-titration 
treatment period (for the primary analysis) followed by a 3-week treatment extension period at the HCTD 
followed by a 28-day follow up period. 
In Cohort 1, MEDI0382 or matched placebo will be administered daily starting at 
 
 
 
 
 
 
 
 
 
 
Subjects will be asked to provide informed consent before undergoing screening assessments to determine their 
eligibility to participate in the study. Consent may be collected at a visit prior to performing the assessments 
themselves. Screening will take place within 14 days of subjects starting a 10-day run-in period. The screening 
period may be extended to up to 42 days for those subjects who are undergoing wash-out from a second 
anti-hyperglycemic agent. During the run-in period, subjects will refrain from taking prohibited medications but 
will continue to take their prescribed stable dose of metformin as they will for the duration of their participation 
in the study. 
 may 
receive further training in self-injection technique if required, as determined at the screening visit. An 
ambulatory blood pressure monitoring (ABPM) device will be fitted and worn for 24 hours.
Following the run-in period, subjects will be admitted to the clinical unit on Day -2 and will undergo initial 
safety assessments and blood tests. At this time, an ABPM device will be fitted and worn for 24 hours; 
 
. Subjects will be weighed on the 
morning of Day -1, and further blood tests and a series of ECGs will be conducted. Subjects will eat a 
standardized, breakfast, lunch, and evening meal at given times without consuming any other food until the 
following day. Eligibility criteria will also be reverified prior to dosing. Subjects will be randomized at any time 
from Day -1 to prior to receiving a MEDI0382 or placebo dose on Day 1. 
Each dosing period consists of 7 days of dosing and will begin on Day 1. On Day 1, dosing will begin after 
predose safety assessments including vital signs, blood tests, and an ECG. 
 will 
require a dilution by site staff prior to administration, subjects will have the option to remain as inpatients or 
alternatively attend the clinical unit daily for dosing and other assessments as applicable during the first two 
weeks. During this time, subjects will undergo supervision to self-administer the investigational product. If the 
subject returns on a daily basis, the visits should be at approximately the same time each day. Investigational 


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product should be administered within 24 to 28 hours post the last dose. On the morning of Days 7 and 14, 
subjects not still residing in the clinical unit will be admitted to undergo blood samples for PK, and fitting of the 
ABPM device that is worn for 24 hours. On Days 8 and 15, safety assessments will be performed and an 
up-titration step made as per the randomization. Subjects who elect to remain as inpatients will be discharged 
home following completion of the Day 15 visit. Subjects will attend the clinical unit thereafter as indicated in 
the schedule of events. 
On Day 35 subjects will be admitted to the clinic, for PK and safety assessments prior to up-titration 
 
the following day, then remaining in-house for approximately 24 hours for safety and efficacy assessments. This 
inpatient period will be repeated on Days 42 and 49 and will include up-titration to 
; 
subject to the findings of the DEC who will review 72 hours safety data at each of these dose levels. Subjects 
will return to the clinic following an overnight fast as an outpatient to undergo PK sampling and fitting of the 
ABPM device on Day 56, subject to continued dose escalation and will be discharged on the first day of the 
treatment extension period.
After the initial titration period to determine the HCTD, subjects will continue at the HCTD for a further 
3 weeks, returning to the clinical unit at Days 7 (for an outpatient visit) and Days 20-21 (for an inpatient visit) of 
the treatment extension for safety and efficacy assessments and resupply of investigational product as required. 
A follow up visit will be performed for final safety assessments 28 days after the last dose of investigational 
product or as convenient in the event of discontinuation.
Subjects in Cohort 2 will follow the up-titration schedule defined by Cohort 1, with the 3-week treatment 
extension period being conducted at the HCTD; thus, the duration of Cohort 2 subjects’ participation in the 
study will be determined by the results obtained from Cohort 1. Dosing in Cohort 2 will occur ≥ 7 days after 
initiation of Cohort 1.
TARGET SUBJECT POPULATION  
Overweight or obese subjects with T2DM, aged ≥ 18 ≤ 74 years with a BMI ≥ 27 and ≤ 35 kg/m2. Subjects will 
have a diagnosis of T2DM and inadequate blood glucose control as defined by an HbA1c of 6.5% to 8.5%, and 
will be on metformin monotherapy.
TREATMENT GROUPS AND REGIMENS
MEDI0382 will be administered for up to 8 weeks during the up-titration period to determine the HCTD as 
follows: 
•
 
 
 
 
 
 
 
 
 
 
 
 


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STATISTICAL METHODS 
Sample size:  The total study sample size is 20 subjects, who will be randomized by 2 cohorts: 8 subjects in 
Cohort 1 and 12 subjects in Cohort 2. For each cohort, subjects will be randomized in a 3:1 ratio to the 
MEDI0382 arm or the placebo arm. The sample size for this study was empirically determined to obtain 
adequate safety and tolerability evaluation. 
 
 
Statistical analyses:
Two analyses are planned for this study as follows:
•
A primary analysis after the up-titration period for Cohort 2, and
•
A final analysis after the safety follow-up period for Cohort 2.
Analyses will be conducted for each cohort and for two cohorts combined. Formal statistical modeling analysis 
for certain efficacy endpoints will only be conducted for two-cohort combined analyses.
Pharmacokinetic analysis and immunogenicity: 
PK parameters such as MEDI0382 Cmax, Tmax, and area under the concentration-time curve during the dosing 
interval (AUC0-tau) will be evaluated from 
 
Descriptive statistics including mean, standard deviations, median, minimum, and 
maximum will be generated for all PK parameters for MEDI0382 at each dose level separately, and for the 
Ctroughs. Samples confirmed positive for ADA will be tested and analyzed for antibody titer and reported. ADA 
incidence rate and titer will be tabulated for each treatment.
 


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................. 12
1
INTRODUCTION............................................................................................ 14
1.1
Disease Background ......................................................................................... 14
1.2
MEDI0382 Background.................................................................................... 14
1.3
Summary of Nonclinical Experience................................................................. 14
1.4
Summary of Clinical Experience....................................................................... 15
1.5
Rationale for Conducting the Study .................................................................. 15
1.6
Benefit-Risk and Ethical Assessment................................................................ 16
1.7
Research Hypotheses ........................................................................................ 17
1.7.1
Primary Hypothesis .......................................................................................... 17
1.7.2
Secondary Hypotheses...................................................................................... 17
2
OBJECTIVES AND ENDPOINTS................................................................... 18
2.1
Primary Objective(s) and Associated Endpoints................................................ 18
2.1.1
Secondary Objectives and Associated Endpoints............................................... 18
2.1.2
Exploratory Objectives and Associated Endpoints ............................................ 20
3
STUDY DESIGN ............................................................................................. 20
3.1
Description of the Study ................................................................................... 20
3.1.1.1
Overview.......................................................................................................... 20
3.1.2
Treatment Regimen........................................................................................... 23
3.1.3
Dose Escalation ................................................................................................ 24
3.1.3.1
Dose Escalation Committee .............................................................................. 24
3.1.3.2
Dose Escalation Stopping Criteria..................................................................... 25
3.1.4
Management of Study Medication Related Toxicities ....................................... 25
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 Endpoint(s).................................................................................. 28
3.2.3.1
Primary Endpoint.............................................................................................. 28
3.2.3.2
Secondary Endpoints ........................................................................................ 29
3.2.3.3
Exploratory Endpoints ...................................................................................... 29
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 Randomization ............................................................ 33
4.1.5
Withdrawal from the Study............................................................................... 33
4.1.6
Discontinuation of Investigational Product........................................................ 34
4.1.7
Replacement of Subjects................................................................................... 35


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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
4.2.2
Randomized/Up-titration Treatment Period....................................................... 38
4.2.3
Treatment Extension at HCTD and Follow-up Period ....................................... 43
4.3
Description of Study Procedures....................................................................... 46
4.3.1
Efficacy ............................................................................................................ 46
4.3.1.1
Glucose measurements...................................................................................... 46
4.3.1.2
Standardized Meals........................................................................................... 47
4.3.1.3
Body Weight..................................................................................................... 47
4.3.2
Safety ............................................................................................................... 48
4.3.2.1
Medical History and Physical Examination....................................................... 48
4.3.2.2
Body Mass Index.............................................................................................. 48
4.3.2.3
Electrocardiograms........................................................................................... 48
4.3.2.4
Vital signs......................................................................................................... 49
4.3.3
Clinical Laboratory Tests.................................................................................. 50
4.3.3.1
Serum Chemistry.............................................................................................. 50
4.3.3.2
Hematology...................................................................................................... 50
4.3.3.3
Coagulation Panel (Screening Only) ................................................................. 51
4.3.3.4
Urinalysis ......................................................................................................... 51
4.3.3.5
Drug/Alcohol Screen ........................................................................................ 51
4.3.3.6
Other Tests ....................................................................................................... 51
4.3.4
Pharmacokinetic Evaluation and Methods......................................................... 51
4.3.5
Immunogenicity Evaluation and Methods ......................................................... 52
4.3.6
Genetic Evaluations and Methods ..................................................................... 52
4.3.7
Storage, Re-use and Destruction of Biological Samples .................................... 52
4.3.8
Estimate of Volume of Blood to Be Collected................................................... 52
4.4
Study or Study Component Suspension or Termination..................................... 53
4.5
Investigational Products.................................................................................... 53
4.5.1
Identity of Investigational Product(s) ................................................................ 53
4.5.1.1
Investigational Product Handling and Inspection............................................... 54
4.5.1.2
Dose Preparation............................................................................................... 55
4.5.1.3
Treatment Administration................................................................................. 56
4.5.1.4
Monitoring of Dose Administration .................................................................. 57
4.5.1.5
Reporting Product Complaints .......................................................................... 57
4.5.2
Additional Study Medications........................................................................... 58
4.5.3
Labeling ........................................................................................................... 58
4.5.4
Storage ............................................................................................................. 58
4.5.5
Treatment Compliance...................................................................................... 58
4.5.6
Accountability .................................................................................................. 58
4.5.6.1
In-clinic Accountability .................................................................................... 58
4.5.6.2
Accountability for Doses Administered by the Subject during the At-home 
Self-administration Period ................................................................................ 59
4.6
Treatment Assignment and Blinding ................................................................. 59
4.6.1
Methods for Assigning Treatment Groups......................................................... 59


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4.6.2
Methods to Ensure Blinding.............................................................................. 59
4.6.3
Methods for Unblinding.................................................................................... 59
4.6.3.1
Unblinding in the Event of a Medical Emergency ............................................. 59
4.6.3.2
Unblinding for Planned Analysis Purposes........................................................ 60
4.7
Restrictions During the Study and Concomitant Treatment(s) ........................... 60
4.7.1
Permitted Concomitant Medications ................................................................. 60
4.7.2
Prohibited Concomitant Medications ................................................................ 60
4.8
Statistical Evaluation ........................................................................................ 61
4.8.1
General Considerations..................................................................................... 61
4.8.2
Sample Size...................................................................................................... 62
4.8.3
Efficacy ............................................................................................................ 62
4.8.3.1
Primary Efficacy Analysis ................................................................................ 62
4.8.3.2
Secondary Efficacy Analyses............................................................................ 62
4.8.3.3
Exploratory Analyses........................................................................................ 62
4.8.4
Safety ............................................................................................................... 62
4.8.4.1
Analysis of Adverse Events .............................................................................. 62
4.8.4.2
Analysis of Clinical Laboratory Parameters ...................................................... 63
4.8.5
Analysis of MEDI0382 Immunogenicity/Pharmacokinetics .............................. 63
4.8.6
Analysis of Metformin Exposure ...................................................................... 64
5
ASSESSMENT OF SAFETY ........................................................................... 64
5.1
Definition of Adverse Events............................................................................ 64
5.2
Definition of Serious Adverse Events ............................................................... 64
5.3
Definition of Adverse Events of Special Interest............................................... 65
5.4
Recording of Adverse Events............................................................................ 65
5.4.1
Time Period for Collection of Adverse Events .................................................. 65
5.4.2
Follow-up of Unresolved Adverse Events......................................................... 65
5.4.3
Adverse Events Based on Signs and Symptoms ................................................ 66
5.4.4
Adverse Events Based on Examination and Tests.............................................. 66
5.4.5
Hy’s Law.......................................................................................................... 66
5.5
Reporting of Serious Adverse Events................................................................ 66
5.6
Other Events Requiring Immediate Reporting................................................... 67
5.6.1
Overdose .......................................................................................................... 67
5.6.2
Pregnancy......................................................................................................... 68
5.6.2.1
Maternal Exposure............................................................................................ 68
5.6.3
Medication Error............................................................................................... 68
6
STUDY AND DATA MANAGEMENT........................................................... 70
6.1
Training of Study Site Personnel....................................................................... 70
6.2
Monitoring of the Study.................................................................................... 70
6.2.1
Source Data ...................................................................................................... 70
6.2.2
Study Agreements............................................................................................. 70
6.2.3
Archiving of Study Documents......................................................................... 71
6.3
Study Timetable and End of Study.................................................................... 71
6.4
Data Management............................................................................................. 71


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6.5
Medical Monitor Coverage ............................................................................... 71
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 72
7.1
Subject Data Protection..................................................................................... 72
7.2
Ethics and Regulatory Review .......................................................................... 72
7.3
Informed Consent ............................................................................................. 73
7.4
Changes to the Protocol and Informed Consent Form........................................ 73
7.5
Audits and Inspections...................................................................................... 73
8
REFERENCES................................................................................................. 75
9
CHANGES TO THE PROTOCOL ................................................................... 76
9.1
Protocol Amendment 3, 12Apr2019.................................................................. 76
9.2
Protocol Amendment 2, 17Dec2018.................................................................. 76
9.3
Protocol Amendment 1, 31October2018 ........................................................... 77
LIST OF TABLES
Table 1
Primary Objective(s) and Associated Endpoints....................................... 18
Table 2
Secondary Objective(s) and Associated Endpoints................................... 18
Table 3
Exploratory Objective(s) and Endpoints................................................... 20
Table 4
Proposed Study Doses and Predicted Safety Margins Based on Safety 
Data from the Cynomolgus Monkey ........................................................ 28
Table 5
Schedule of Screening and Run-in Procedures ......................................... 37
Table 6
Schedule of Treatment/Up-titration Period Study Procedures................... 39
Table 7
Schedule of Procedures for Treatment Extension at HCTD and Follow-
up Periods................................................................................................ 43
Table 8
Identification of Investigational Products................................................. 54
Table 9
MEDI0382 and Placebo Dose Preparation ............................................... 56
Table 10
Highly Effective Methods of Contraception............................................. 78


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LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 23
LIST OF APPENDICES
Appendix A
Contraception Guidance........................................................................... 78
Appendix B
Additional Safety Guidance ..................................................................... 79
Appendix C
National Institute of Allergy and Infectious Disease and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis.............. 82
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 83
Appendix E
Genetic Research..................................................................................... 88


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ABPM
ambulatory blood pressure monitoring
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine transaminase
AST
aspartate transaminase
AUC
area under the concentration-time curve
AV
atrioventricular
BMI
body mass index
BP
blood pressure
CI
confidence interval
Cmax
maximum observed concentration
Ctrough
trough plasma concentration
CSR
Clinical Study Report
DEC
dose escalation committee
DILI
drug-induced liver injury
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
E-R
exposure-response
GCP
Good Clinical Practice
GI
gastrointestinal
GFR
glomerular filtration rate
GLP-1
glucagon-like peptide 1
HbA1c
hemoglobin A1c
hCG
human chorionic gonadotropin
HCTD
highest clinically tolerated dose
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council on Harmonisation


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Abbreviation or 
Specialized Term
Definition
IEC
Independent Ethics Committee
LC-MS/MS
liquid chromatography-tandem mass spectrometry
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MMTT
mixed meal tolerance test
NASH
non-alcoholic steatohepatitis
NOAEL
no-observed-adverse-effect-level
PK
pharmacokinetic(s)
PT
preferred term
SAE
serious adverse event
SC
subcutaneous
SID
subject identification
SOC
system organ class
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TEAE
treatment-emergent adverse event
Tmax
time to maximum observed concentration
ULN
upper limit of normal
w/v
weight/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 glycemic control, 
cardiovascular risk, and mortality rates, and may even slow or reverse disease progression 
(Shulman, 2005). Many existing therapies for T2DM focus upon lowering blood glucose; 
however, there is a major unmet need for treatments that both improve glycemic control and 
achieve disease-modifying weight loss.
1.2
MEDI0382 Background
MEDI0382 is briefly described below. Refer to the current Investigator’s Brochure (IB) for 
details. 
MEDI0382, a synthetic oxyntomodulin-like peptide with targeted glucagon-like peptide 1 
(GLP-1) and glucagon receptor activity, is under development for the treatment of T2DM, 
obesity, and non-alcoholic steatohepatitis (NASH). GLP-1 receptor agonists are established 
treatments for T2DM that improve glycemic 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 (Habegger et al, 2013; Lynch et al, 
2014). 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). Co-infusion of GLP-1 and glucagon has synergistic 
effects on reducing food intake and promoting weight loss in human subjects (Cegla et al, 
2014). MEDI0382 has previously delivered significant metabolic benefit to overweight and 
obese patients with T2DM over a relatively short period of dosing in a Phase 1/2 clinical study 
(D5670C00002) (Ambery et al, 2018).
1.3
Summary of Nonclinical Experience
Consistent with GLP-1 receptor monoagonists, MEDI0382 exposure in both rats and 
cynomolgus monkeys resulted in the anticipated pharmacologic effects on body weight 
(reduced gain or loss), food consumption (sporadic reductions), water consumption (low 
throughout dosing periods), gastric emptying (delayed in rats), liver (changes indicative of an 
effect on energy homeostasis in both species), pancreas (hypercellularity of the pancreatic 
islets and acinar degranulation), adrenal glands (increased prominence of the zona 
glomerulosa), and lungs (increased macrophage in rats only). 
 
 


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Refer to the current MEDI0382 IB for a complete summary of nonclinical information.
1.4
Summary of Clinical Experience
In a randomized Phase 1/2 study of MEDI0382 in overweight/obese subjects with T2DM 
(D5670C00002), treatment with MEDI0382 at doses ≤ 200 μg for 41 days, including two 
4-day titration steps at 100 μg (starting dose) and 150 μg, was associated with a reduction in a 
mixed meal tolerance test (MMTT) glucose area under the concentration-time curve (AUC) 
from time zero to 4 hours (AUC0-4h) of 32.78% (90% confidence interval [CI] 36.98, 28.57) 
versus 10.16% (90% CI 14.10, 6.21) in placebo (p < 0.001). A reduction in body weight of 
4.12% (90% CI 4.48, 3.36) in MEDI0382-treated subjects versus 1.78% (90% CI 2.52, 1.03) 
in placebo (p < 0.001) was also observed at this dose level. The majority of subjects 
experienced at least 1 treatment-emergent adverse event (TEAE), and the most frequent 
TEAEs were gastrointestinal (GI)-related. The most frequently reported TEAEs (> 30%) in 
subjects receiving MEDI0382 were nausea (52%), vomiting (32%), and headache (36%). The 
majority of TEAEs were mild or moderate in severity.
Additional cohorts in the same study were treated with MEDI0382 at ≤ 300 μg for 7 days 
following either three (Cohort 5) or two (Cohort 6) 5-day titration steps from a starting dose of 
100 μg. A reduction in MMTT glucose AUC of 41.7% and 36.7% was observed following 
treatment with MEDI0382 in Cohorts 5 and 6, respectively, whereas treatment with placebo 
yielded a decrease of 14.5% and 8.0%, respectively (p ≤ 0.0001 for each). A decrease in body 
weight versus placebo was observed in Cohorts 5 and 6 with a least squares mean change 
from baseline of -3.4 kg (90% CI -4.4, -2.4) and -2.1 kg (90% CI -3.3, -0.9), respectively in 
MEDI0382-treated subjects versus -0.68 kg (90% CI -2.2, 0.9) and -0.86 (90% CI -2.7, 1.0), 
respectively, in placebo. The titration regimens of both cohort 5 and 6 were tolerated with 
82% and 83% of subjects, respectively, reporting at least 1 treatment-related adverse event 
(AE); none of the treatment-related AEs were ≥ grade 3 or serious. In Cohort 5, 72.7% of 
subjects treated with MEDI0382 reported GI-related AEs, with 27.3% reporting at least 1 
event of nausea and 27.3% at least 1 event of vomiting. In Cohort 6, 75% of subjects treated 
with MEDI0382 reported GI-related AEs, with 41.7% reporting at least 1 event of nausea and 
8.3% at least 1 event of vomiting.
Refer to the current MEDI0382 IB for a complete summary of clinical information.
1.5
Rationale for Conducting the Study
Ongoing clinical Phase 2a and 2b studies (D5670C00011 and D5670C00004) are 
investigating MEDI0382 doses at ≤ 300 μg for up to 24 months in subjects with T2DM. This 
study will evaluate the safety and tolerability of higher doses of MEDI0382 
 than 
previously studied, and the impact of starting at a lower dose 
 resulting in a slower 
titration regimen, on the tolerability profile. 


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Current experience with marketed GLP-1 receptor agonists (eg, liraglutide) (Habegger et al,
2013; Henderson et al, 2016) suggests that exposure to higher doses may be associated with 
greater extent and durability of weight loss (Astrup et al, 2009; Davies et al, 2015). This may 
be particularly true of GLP1/glucagon dual receptor agonists where the glucagon agonist 
component is likely to drive incremental weight loss over time (Habegger et al, 2013; 
Henderson et al, 2016). Thus, it is anticipated that higher doses of MEDI0382 will achieve 
greater weight loss over a given period with the potential to impact insulin resistance and 
further improve glucose control. This study will explore the safety and tolerability of higher 
doses of MEDI0382 (
 to determine the highest clinically tolerated 
dose (HCTD), which can then be studied in future long-term efficacy studies as a potential 
maintenance dose.
It is also known from currently available GLP-1 monoagonists that a controlled up-titration 
regime is associated with improved tolerability. This study will therefore also explore the 
effect of starting at a lower starting dose 
 of MEDI0382 than has previously been 
studied, on tolerability, particularly in relation to GI side effects. This will allow the 
identification of the optimal titration regime for further exploration in future studies.
1.6
Benefit-Risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonization 
(ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements.
MEDI0382 is a GLP-1 receptor and glucagon receptor co-agonist that promotes glucose 
lowering and weight loss and is targeted at subjects with T2DM. MEDI0382 has the potential 
to deliver improvements in glycemic control and body weight, and is anticipated to be a useful 
therapy for T2DM. However, it should be noted that given the short treatment duration in this 
study little direct benefit to the subject’s underlying T2DM should be expected.
Potential risks for MEDI0382 are based on available published data for GLP-1 receptor 
monoagonists and glucagon receptor monoagonists, as well as clinical and nonclinical data for 
MEDI0382. Identified risks for MEDI0382 are nausea and vomiting. According to the current 
IB, potential risks for MEDI0382 include tachycardia, alterations in blood pressure (BP), 
QT-interval prolongation, anaphylactic-type reactions, injection site reactions, skin rash, 
pancreatitis, pancreatic carcinoma, and thyroid cancer. The study design aims to minimize 
potential risks to subjects participating in this study based on the proposed inclusion/exclusion 
criteria, safety monitoring, and up-titration dosing schedule. Additionally, all subjects will be 
monitored throughout the study to ensure adequate glycemic control. 
Since nausea and vomiting events have been observed in other clinical studies with 
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study protocol includes strategies to manage GI AEs if they arise. These include reduction of 
meal sizes, maintaining adequate hydration, and treating the subjects with antiemetics if 
required. To further mitigate the GI AEs, subjects enrolled in this study will initiate treatment 
with MEDI0382 at a dose level of 
 thus introducing two additional titration steps not 
previously used.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The investigator will provide a summary of available, relevant, clinical safety data to the 
medical monitor/sponsor, which will form part of the package of information the Dose 
Escalation Committee (DEC) will review to make escalation decisions. More information on 
the DEC can be found in the DEC charter. 
Refer to the current IB for further information on the potential benefits of MEDI0382 and an 
assessment of the potential and known risks.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
Daily SC administration of ascending doses MEDI0382, titrated weekly to the HCTD will 
result in an acceptable safety/tolerability profile in overweight/obese subjects with T2DM. 
1.7.2
Secondary Hypotheses

Once daily SC administration of MEDI0382, titrated weekly to the HCTD, will have a 
predictable pharmacokinetic (PK) and immunogenic profile in overweight/obese subjects 
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
Once daily SC administration of MEDI0382 titrated weekly to the HCTD, will result in 
clinically relevant improvement in blood glucose control versus placebo in 
overweight/obese subjects with T2DM. 

Once daily administration of MEDI0382 titrated weekly to the HCTD, will result in 
clinically relevant body weight loss versus placebo in overweight/obese subjects with 
T2DM. 
2
OBJECTIVES AND ENDPOINTS 
2.1
Primary Objective(s) and Associated Endpoints
Table 1
Primary Objective(s) and Associated Endpoints
Type
Objective
Endpoint
Safety
Assess the safety and 
tolerability of MEDI0382 
titrated up to the highest 
clinically tolerated dose 
(HCTD)
•
Incidence of treatment-emergent adverse events and 
treatment-emergent serious adverse events through 
the end of the up-titration period (up to 8 weeks) and 
through the end of the follow-up period
•
Clinically important changes in 12-lead 
electrocardiogram, vital signs (including heart rate 
and blood pressure), physical examination, and 
clinical laboratory evaluations through the end of 
up-titration period (up to 8 weeks) and through the 
end of the follow-up period
2.1.1
Secondary Objectives and Associated Endpoints
Table 2
Secondary Objective(s) and Associated Endpoints
Type
Objective
Endpoint
PK
To characterize the 
pharmacokinetic (PK) profile of 
MEDI0382 titrated up to the 
highest clinically tolerated dose 
(HCTD)
•
AUC over a dosing duration (AUCtau), maximum 
observed concentration (Cmax), time to Cmax 
(Tmax), trough plasma concentration (Ctrough), and 
accumulation ratio (Cmin [R0])
Immunogenicity
To characterize the 
immunogenicity of MEDI0382 
titrated up to the HCTD
•
Anti-drug antibodies (ADAs) to MEDI0382 at 
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Table 2
Secondary Objective(s) and Associated Endpoints
Type
Objective
Endpoint
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy
To assess the effects of 
MEDI0382, titrated up to the 
HCTD, on additional measures of 
glucose control
•
Change in plasma fasting glucose from Day -1 
versus each week of the up-titration period, the 
end of the up-titration period, and the end of the 
treatment extension period
•
Change in HbA1c from Day -1 to the end of the 
treatment extension period
Efficacy
To assess the effects of 
MEDI0382, titrated up to the 
HCTD, on body weight
•
Percentage and absolute change in body weight 
from baseline to the end of the up-titration period 
and the end of the treatment extension
•
Percentage and absolute change in body weight 
from baseline to the end of each week of the up-
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Table 2
Secondary Objective(s) and Associated Endpoints
Type
Objective
Endpoint
•
Proportion of subjects achieving > 5% body 
weight loss from baseline to the end of the 
treatment extension period.
 
 
 
 
 
 
 
 
 
 
 
 
3
STUDY DESIGN
3.1
Description of the Study
3.1.1.1
Overview
This is a randomized, blinded, placebo-controlled study designed to evaluate the safety, 
tolerability, PK and efficacy of ascending doses of MEDI0382 in overweight or obese subjects 
with T2DM. This study will enroll subjects aged ≥ 18 and ≤ 74 years with a body mass index 
(BMI) ≥27 and ≤ 35 kg/m2. Subjects will have a diagnosis of T2DM and inadequate blood 
glucose control as defined by a hemoglobin A1c (HbA1c) of 6.5% to 8.5%, and will be on 
metformin monotherapy. Subjects prescribed oral dual therapy with a dipeptidyl peptidase-4 
inhibitor, sulphonylurea, glitinide, or a sodium-glucose co-transporter 2 inhibitor in addition 
to metformin at screening may be eligible to enter the study in Cohort 2 only following a 
4-week washout period.
 
 
 
 
 
 


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Subjects will be asked to provide informed consent before undergoing screening assessments 
to determine their eligibility to participate in the study. Screening will take place within 
14 days of subjects starting a 10-day run-in period. The screening period may be extended to 
up to 42 days for those subjects who are undergoing wash-out from a second 
anti-hyperglycemic agent. During the run-in period, subjects will refrain from taking 
prohibited medications but will continue to take their prescribed stable dose of metformin as 
they will for the duration of their participation in the study. 
 
, and 
may receive further training in self injection technique if required, as determined at the 
screening visit. An ambulatory blood pressure monitoring (ABPM) device will be fitted and 
worn for 24 hours. 
Following the run-in period, subjects will be admitted to the clinical unit on Day -2 and will 
undergo initial safety assessments and blood tests. At this time, an ABPM device will be fitted 
and worn for 24 hours; 
 Subjects 
will be expected to wear a sensor continuously until the end of the study, which will require 
periodic replacement. Following an overnight fast, subjects will be weighed on the morning of 
Day -1, and further blood tests and a series of electrocardiograms (ECGs) will be conducted. 
Subjects will eat a standardized, breakfast, lunch, and evening meal at given times without 
consuming any other food until the following day. Eligibility criteria will also be reverified 
prior to dosing. Subjects will be randomized at any time from Day -1 to prior to receiving a 
MEDI0382 or placebo dose on Day 1.
 
 
 
 
 
 


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After the initial titration period to determine the HCTD, subjects will continue at the HCTD 
for a further 3 weeks, returning to the clinical unit at Day 7 (for an outpatient visit) and Days 
20-21 (for an inpatient visit) of the treatment extension for safety and efficacy assessments 
and resupply of investigational product as required. A follow-up visit will be performed for 
final safety assessments 28 days after the last dose of investigational product or as convenient 
in the event of discontinuation.
Subjects in Cohort 2 will follow the up-titration schedule defined by Cohort 1, with the 
3-week treatment extension period being conducted at the HCTD; thus, the duration of 
Cohort 2 subjects’ participation in the study will be determined by the results obtained from 
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3.1.2
Treatment Regimen
Following randomization, eligible subjects will receive either MEDI0382 or placebo (3:1 
ratio) once daily in the morning via SC injection.
MEDI0382 will be administered for up to 8 weeks during the up-titration period to determine 
the HCTD as follows: 
 
 
 
 
 
 


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3.1.3
Dose Escalation
 
 
 If progression to the next dose level is not endorsed by the 
DEC, the prior dose level will be declared as the HCTD. Subjects will be down titrated to the 
HCTD on the next feasible dosing day and complete the 7-day dosing period at that level. The 
3-week treatment extension will be triggered from the end of that 7-day dosing period.
More detailed information on dose escalation can be found in the DEC charter. 
3.1.3.1
Dose Escalation Committee
A DEC will be formed for safety data review and monitoring. The DEC will also make 
decisions on progression to treatment at a higher dose or on meeting dose escalation stopping 
criteria as outlined in the DEC Charter. 
Relevant available safety data will be reviewed at the DEC meeting for subjects at the current 
dose period as well as the cumulative safety data (including data that are not yet source 
document verified such as laboratory values, AEs, ECG, and vital signs) to date, to make an 
informed decision on whether to dose escalate or not.  
After reviewing the data from a given dose period, the DEC will make one of the following 
decisions:

Escalate to the next dose level

Stop dose escalation and proceed to 3-week treatment extension at the HCTD.


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
Request for review and decision by the MedImmune Safety Review Board on how to 
proceed, or whether to suspend or stop the study.
The rules for dose escalation are discussed in Section 3.1.3.2.
3.1.3.2
Dose Escalation Stopping Criteria 
Dose escalation will be stopped if the DEC determines that any of the following criteria are 
met.

More than 50% of subjects treated with MEDI0382 in a specific dose period experience 
grade 2 or higher AEs assessed as related to MEDI0382 and require discontinuation of 
MEDI0382

One serious adverse event (SAE) occurs in a MEDI0382 subject that is assessed as related 
to MEDI0382

Two or more subjects receiving MEDI0382 experiences any of the following:

An average absolute (regardless of baseline value) cardiac QTc interval corrected for 
heart rate by the formula of Fridericia (QTcF) > 500 msec, or an increase of QTcF 
> 60 msec above the baseline value, confirmed (persistent for ≥ 5 minutes) on a 
repeat 12-lead ECG 

Tachycardia, defined as resting supine heart rate > 125 beats per minute persisting for 
at least 10 minutes (measured at 5 timepoints in the 10-minute period)

Symptomatic bradycardia, defined as resting supine heart rate < 40 beats per minute 
while awake, persisting for at least 10 minutes; or asymptomatic bradycardia defined 
as resting supine heart rate < 30 beats per minute while awake persisting for at least 
10 minutes (measured at 5 timepoints in the 10-minute period)

Hypertension, defined as an increase from baseline in resting supine systolic blood 
pressure (BP) > 40 mmHg or above 180 mmHg and persisting for at least 10 minutes, 
or an increase from baseline in resting supine diastolic BP > 20 mmHg or above 
100 mmHg and persisting for at least 10 minutes

The above cardiac criteria do not apply if provoked by complicated venepuncture or other 
vagal provocation
If any of these criteria are met, then the DEC will either:

Recommend that the study proceed to 3-week treatment extension at the HCTD, or

Request for review and decision by the MedImmune Safety Review Board on how to 
proceed or whether to suspend or stop the study
3.1.4
Management of Study Medication Related Toxicities 
GI Tolerability
In this study, dose escalation may be limited by GI tolerability, specifically with respect to 
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Prior to receiving investigational product, subjects will be advised that transient nausea and 
vomiting are possible and will receive counseling about meal size and eating habits.
Specifically, subjects will be advised to avoid administering the medication close to a large or 
high-fat meal; to consume small, frequent meals 4 to 5 times a day that are low in fat and 
insoluble fibers; and to stop eating when they are feeling full. Subjects will also be advised to 
avoid carbonated beverages, alcohol, and smoking to help prevent the occurrence of nausea 
and vomiting. This advice should be reiterated should symptoms of nausea and vomiting 
occur once investigational product dosing has initiated. If symptoms do not improve despite a 
change of dietary habits, metformin may be withheld for 3 days, or alternatively, subjects 
should be offered antiemetic therapy in accordance with institutional and local practice 
guidelines. A centrally acting antiemetic such as a 5HT-3 antagonist (eg, ondansetron) or 
cyclizine is the preferred treatment in the first instance, rather than a prokinetic agent such as 
domperidone or metoclopramide.
Hyperglycemia
In the unlikely event of suspected persistent hyperglycemia in a subject based on either 
symptoms of hyperglycemia (eg, thirst, polyuria, blurred vision), capillary blood glucose 
readings (eg, 3 readings > 260 mg/dL [14.4 mmol/L] within one week), the investigator 
should perform additional fasting blood glucose levels as necessary to further investigate, and 
subjects should be asked to monitor capillary plasma glucose levels up to 5 times per day. If 
2 or more laboratory plasma fasting glucose levels of > 260 mg/dL [14.4 mmol/L] taken at 
least 3 days apart are detected, the subject should be discontinued from the study 
(Section 4.1.6), and rescue therapy should be considered in line with current local guidelines. 
Hypoglycemia
Any blood glucose level 54 mg/dL (< 3.0 mmol/L) with or without symptoms is considered as 
clinically significant hypoglycemia and should be reported by the Investigator as an AE. 
Spontaneous and clinically significant hypoglycemia has not been observed in prior studies 
with MEDI0382 up to a dose of 300 µg alongside metformin treatment.  All subjects will be 
provided with a glucometer and will be advised to check their capillary blood glucose level if 
they have symptoms of hypoglycemia (hunger, dizziness, shaking, sweating, or irritability) or 
feel unwell. Any such subjects should be managed using local protocols for treatment and 
follow-up of any hypoglycemic episode. Pharmacological treatments administered for 
hypoglycemia, eg, dextrose/glucose tablets, glucose infusion, glucagon injection etc, should 
be recorded in the electronic case report form (eCRF) as concomitant medications.
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
Based on PK/pharmacodynamic (PD) modeling conducted using available clinical literature 
data on GLP-1 and glucagon receptor modulators, the clinically efficacious dose of 


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MEDI0382 was predicted to be in the range of 300 to 2000 µg/day; however, clinical data 
from Study D5670C00001 identified dose-limiting tolerability issues (multiple episodes of 
vomiting) at the 300 µg dose administered as a single dose without initial up-titration. The 
principle of dose up-titration to achieve greater tolerability at higher than initial doses was 
well established with daily GLP-1 agents (Victoza, 2016). Studies of other GLP-1 receptor 
agonists suggest that the maximal dose response with respect to weight loss may be seen at 
higher doses in comparison to those at which maximal reduction in blood glucose is achieved 
(Davies et al, 2015; Nauck and Marre, 2009). This is particularly true of GLP-1/glucagon dual 
agonists where the glucagon agonist component is likely to drive incremental weight loss over 
time, and confer accompanying improvements in glycemic control (Henderson et al, 2016).
This study is designed to explore both the appropriate dose titration schedule for repeated 
doses of MEDI0382 and the highest clinically tolerated repeat-dose in subjects with T2DM. 
Therefore, the proposed dose range allows characterization of the safety/tolerability profile of 
MEDI0382 at a relevant pharmacological range and facilitates design of future studies.
The no-observed-adverse-effect-level (NOAEL) of 90 µg/kg/day was based on findings in the 
9-month, daily repeat dose SC toxicology study in the cynomolgus monkey. These were 
considered to be consistent with pharmacology-mediated induction of weight loss/lower 
weight gain, reversible changes in the pancreas (acinar degranulation and hypercellularity of 
the pancreatic islets), and changes in energy utilization and associated metabolic stress (minor 
changes in blood chemistry parameters, lower thymus weights). Treatment was also associated 
with changes in the skin (dermal irritation, acanthosis and hyperkeratosis) in 3 of 4 female 
cynomolgus monkeys dosed.
While the NOAEL determined in the rat 6-month, daily repeat dose SC toxicology study (ie, 
7.5 µg/kg/day) was lower than that in the cynomolgus monkey, this was driven primarily by 
the findings in the thyroid gland (C-cell hyperplasia, adenoma, and carcinoma) that were 
considered, in this species, to be adverse. This is a known class effect with GLP-1 receptor 
agonists that is considered rodent specific and of unknown relevance to humans (Center for 
Drug Evaluation and Research, 2005). Therefore cynomolgus monkey, and the toxicity profile 
of MEDI0382 generated in that species, are considered to be the most appropriate non-clinical 
species to use for clinical risk assessment and the setting of safety margins.
 
 
 
 
 


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Rationale for Study Population
MEDI0382 is a synthetic oxyntomodulin-like peptide with targeted GLP-1 and glucagon 
receptor activity, which relies upon glucose-dependent insulin release (the incretin effect) for 
glucose lowering efficacy, and is therefore targeted at subjects with T2DM.  
Adult subjects with T2DM who are overweight or obese are likely to benefit most from losing 
weight. While subjects with a BMI > 40 kg/m2, or > 35 kg/m2 with 1 or more obesity-related 
comorbidity may be offered bariatric surgery, those with a BMI in the range of 27-35 kg/m2
rely upon conservative or medical management for weight reduction. The entry criteria with 
respect to T2DM and BMI of 27-35 kg/m2 creates a more homogeneous population than has 
been studied previously, limiting the potential effect of exposure on tolerability, while 
generating safety, and tolerability data in the likely intended clinical population.
3.2.3
Rationale for Endpoint(s)
3.2.3.1
Primary Endpoint
In a previous study (D5670C00002), repeat doses of MEDI0382 ≤ 
 have been shown to 
have an acceptable tolerability and safety profile. However, this study is the first to explore 
higher doses of MEDI0382 
 in the T2DM population. Therefore, it is appropriate 
that safety and tolerability represent the primary endpoint. Safety and tolerability will be 
measured with safety laboratory tests, physical examination, ABPM recording of heart rate 
and BP, ECG and other vital signs, and recording of AEs.


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3.2.3.2
Secondary Endpoints 
Pharmacokinetic and Immunogenicity Profile
Plasma concentrations of MEDI0382 will be used to evaluate the PK profile (Cmax, time to 
maximum observed concentration [Tmax], AUCtau). In addition, trough plasma concentrations
(Ctrough) will be evaluated to establish accumulation ratio and explore PK linearity.
Anti-drug antibody (ADA) incidence rate and titer will be tabulated for each treatment to 
monitor immunogenicity. Samples confirmed positive for ADA will be tested and analyzed 
for antibody titer and reported.
 
 
 
 
 
 
 
 
 
 
 
Body Weight
Prior experience with MEDI0382 has demonstrated a weight-lowering effect at doses 
≤300 µg (Ambery et al, 2018). Therefore, percentage and absolute change in weight and the 
proportion of subjects achieving clinically significant weight loss (> 5% of body weight) will 
be recorded to document the effect of MEDI0382 on body weight at higher doses than 
previously studied 
 
 
 
 
 
 
 


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4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Up to 20 subjects will be randomized in 2 cohorts: 8 subjects in Cohort 1 and 12 subjects in 
Cohort 2.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Subjects aged 18 to 74 years (inclusive) at screening
2
Provision of signed and dated written informed consent (with the exception of consent for 
genetic and non-genetic research) prior to any study specific procedures 
3
BMI between 27 and 35 kg/m2 (inclusive) at screening
4
HbA1c range of 6.5% to 8.5% (inclusive) at screening (Note: Subjects may be re-tested 
for the HbA1c entry criterion only once.)
5
Willing and able to self-inject investigational product for the duration of the study
6
Diagnosed with T2DM with glucose control managed with metformin monotherapy 
where no significant dose change (increase or decrease ≥ 500 mg/day) has occurred in the 
three months prior to screening. For inclusion into Cohort 2 only, subjects prescribed oral 
dual therapy with a dipeptidyl peptidase-4 inhibitor, sulphonylurea, glitinide, or a 
sodium-glucose co-transporter 2 inhibitor in addition to metformin at screening may be 
eligible to enter the study following a 4-week washout period. Following wash-out, the 
subject must re-attend for fasting plasma glucose and HbA1c measurement to confirm 
eligibility prior to run-in. At this visit, an HbA1c of between 6.5% to 8.5%, inclusive and
fasting plasma glucose level < 225 mg/dL (< 13.0 mmol/L) is acceptable. If the subject 
fails to meet these criteria, one repeat measurement is allowed on a different day prior to 
Day -10. 
7
Female subjects must have a negative pregnancy test at screening and randomization, and 
must not be lactating. 
8
Female subjects of childbearing potential who are sexually active with a male partner 
must be using at least one highly effective method of contraception (see Appendix A for 
definition of females of childbearing potential and for a description of highly effective 
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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.
4.1.3
Exclusion Criteria
1
History of, or any existing condition that, in the opinion of the investigator, would 
interfere with evaluation of the investigational product, put the subject at risk, influence 
the subject’s ability to participate or affect the interpretation of the results of the study 
and/or any subject unable or unwilling to follow study procedures during the run-in 
period
2
Any subject who has received another investigational product as part of a clinical study or 
a GLP-1 analogue containing preparation within the last 30 days or 5 half-lives of the 
drug (whichever is longer) at the time of screening
3
Concurrent participation in another study of any kind and repeat randomization in this 
study is prohibited
4
Any subject who has received any of the following medications within the specified 
timeframe prior to the start of the study (see Section 4.7.2 for further details)

Herbal preparations within one week prior to the start of dosing 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 

Opiates, domperidone, metoclopramide, or other drugs known to alter gastric 
emptying and within 2 weeks prior to the start of dosing 

Antimicrobials within the quinolone (eg, ciprofloxacin), macrolide (eg, 
clarithromycin) or azole class (eg, ketoconazole) within 2 weeks prior to the start of 
dosing

Any change in antihypertensive medication within 3 months prior to screening

Aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily

Paracetamol (acetaminophen) or paracetamol-containing preparations at a total daily 
dose of greater than 3000 mg

Ascorbic acid (vitamin C) supplements at a total daily dose of greater than 1000 mg
5
Severe allergy/hypersensitivity to any of the proposed study treatments, standardized 
meals, 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, or if the subject has 
been treated with daily SC insulin within 90 days prior to screening
7
Acute pancreatitis, pancreatic amylase, and/or pancreatic lipase > 3 × ULN; history of 
chronic pancreatitis; or serum triglyceride levels > 11 mmol/L (1000 mg/dL) at screening
8
Significant inflammatory bowel disease, gastroparesis or other severe disease or surgery 
affecting the upper GI tract (including weight-reducing surgery and procedures), which 


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may affect gastric emptying or could affect the interpretation of safety and tolerability 
data
9
Significant hepatic disease (except for NASH or non-alcoholic fatty liver disease without 
portal hypertension or cirrhosis) and/or subjects with any of the following results at 
screening:

Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)

Alanine transaminase (ALT) ≥ 3 × ULN

Total bilirubin (TBL) ≥ 2 × ULN
10 Impaired renal function defined as estimated glomerular filtration rate (GFR) 
< 60 mL/minute/1.73m2 at screening (GFR estimated according to Modification of Diet in 
Renal Disease (MDRD) using MDRD Study Equation IDMS-traceable [SI units]).
11 Poorly controlled hypertension defined as:

Systolic BP > 160 mmHg

Diastolic BP or ≥ 90 mmHg
After 10 minutes of supine rest and confirmed by repeated measurement at screening. 
Subjects who fail BP screening criteria may be considered for 24-hour ABPM at the 
discretion of the investigator. Subjects who maintain a mean 24-hour BP 
< 160/100 mmHg with a preserved nocturnal dip of > 15% will be considered eligible.
12 Any clinically important abnormalities in rhythm, conduction, or morphology of the 
resting 12-lead ECG or any abnormalities that may interfere with the interpretation of 
serial ECG changes, including corrected QT (QTc) interval changes at screening, as 
judged by the investigator
13 Prolonged QT intervals corrected for heart rate using Fridericia’s formula (QTcF) 
> 450 ms, or family history of long QT-segment at screening
14 PR (PQ) interval prolongation (> 220 msec), intermittent second (Wenckebach block 
while asleep is not exclusive), or third-degree atrioventricular (AV) block, or AV 
dissociation 
15 Persistent or intermittent complete bundle branch block. Subjects with QRS > 110 msec 
but < 115 msec are acceptable if there is no evidence of ventricular hypertrophy or 
pre-excitation
16 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
17 Severe congestive heart failure (New York Heart Association Class III or IV)
18 Basal calcitonin level > 50 ng/L at screening or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia 
19 Hemoglobinopathy, hemolytic anemia or chronic anemia (hemoglobin, <11.5 g/dL 
[115 g/L]) for males, < 10.5 g/dL (105 g/L) for females) at screening or any other 
condition known to interfere with the interpretation of HbA1c measurement
20 History of neoplastic disease within 5 years prior to screening, except for adequately 
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21 Any positive results for serum hepatitis B surface antigen, hepatitis C antibody, and 
human immunodeficiency virus (HIV) antibody
22 History of substance dependence, alcohol abuse, or excessive alcohol intake (defined as 
an average daily intake of > 24 g for men or > 12 g women) within 3 years prior to 
screening and/or a positive screen for drugs of abuse or alcohol at screening or on 
admission to the study unit. Subjects who use benzodiazepines for chronic anxiety or 
sleep disorders may be permitted to enter the study.
23 Symptoms of depression or any other psychiatric disorder requiring treatment with 
medication (eg, anti-depressants, anti-psychotics) at screening. However, subjects who 
use benzodiazepines for chronic anxiety or sleep disorders may be permitted to enter the 
study.
24 History of severe allergy/hypersensitivity, including to any component of the 
investigational product formulation or other biological agent, or ongoing clinically 
important allergy/hypersensitivity as judged by the investigator
25 Blood/plasma donation within 1 month of screening
26 Involvement of any AstraZeneca, MedImmune, the contract research organization, or the 
virtual study site employee or their close relatives 
Subjects may be rescreened once if in the opinion of the investigator there is a reason to 
believe they may be eligible.
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a MedImmune subject identification (SID) 
number will be assigned by the investigational site comprised of the 7-digit site number plus a 
progressive 4-digit number before screening evaluations may begin to assess study eligibility 
(inclusion/exclusion) criteria. The MedImmune SID number will be used to identify the 
subject during the screening process and throughout study participation, if applicable.
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized), including the reason(s) for screening failure. Subjects who meet 
study eligibility criteria and are randomized will be assigned a unique randomization code and 
a treatment arm.
If a subject who does not meet all the inclusion/exclusion criteria is randomized and treated in 
error, the investigator should inform the medical monitor immediately.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and protocol-defined 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 AEs. If the 


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subject is willing, the subject will be seen and assessed by the investigator (early 
discontinuation visit). AEs will be followed up, 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.
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
4
Pregnancy in a female subject (see Section 5.6.2 for additional details regarding 
pregnancy)
5
Signs or symptoms of severe hepatic impairment including abnormal laboratory values 
according to below:
(a) ALT and/or AST are > 3 × ULN and TBL > 2 × ULN
(b) ALT and/or AST are > 5 × ULN for ≥ 14 consecutive days, at any time after initial 
confirmatory results
(c) ALT and/or AST are > 8 × ULN
6
Average absolute (regardless of baseline value) cardiac QTc interval corrected for heart 
rate by QTcF > 500 msec, or an increase of QTcF > 60 msec above the baseline value, 
confirmed (persistent for ≥ 5 minutes) on a repeat 12-lead ECG
7
Any one of the following: 
(a) Tachycardia, defined as resting supine pulse rate > 125 beats per minute persisting 
for at least 10 minutes 
(b) Symptomatic bradycardia, defined as resting supine pulse rate < 40 beats per 
minute while awake, persisting for at least 10 minutes
(c) Asymptomatic bradycardia, defined as resting supine pulse rate < 30 beats per 
minute while awake persisting for at least 10 minutes
(d) Hypertension, defined as an increase from baseline in resting supine systolic 
> 40 mmHg or above 180 mmHg and persisting for at least 10 minutes and/or 
increase from baseline in resting supine diastolic BP > 20 mmHg or above 
100 mmHg and persisting for at least 10 minutes
8
Persistent hyperglycemia detected as 2 or more laboratory plasma fasting glucose levels 
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Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including the 28-day post-last-dose safety 
follow-up visit and continued follow-up of any AEs unless consent is withdrawn from further 
study participation, the subject is lost to follow-up, the subject starts alternative treatment, or 
the subject is enrolled in another clinical study.
4.1.7
Replacement of Subjects
Subjects will not be replaced.
For Cohort 1, up to 3 additional subjects may be screened and enter the run-in period to ensure 
that a sufficient number of subjects are randomized. If these subjects are not required for 
Cohort 1, they are available to be randomized into Cohort 2.
If the screening visit for these subjects is outside the allowed time window, they will undergo 
a second screening and run in period in order to be eligible for Cohort 2. When these subjects 
are randomized, the data from the second screening/run in (if needed) will be used for 
reporting.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
If a subject withdraws consent to the use of mandatory biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
MedImmune is not obliged to destroy the results of this research. As collection of the 
biological samples is an integral part of the study, then the subject is withdrawn from further 
study participation.
The principal investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to MedImmune.

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented.

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site.

Ensures that the subject and MedImmune are informed about the sample disposal.
MedImmune ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.


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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, the blood draws should occur last. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time.
4.2.1
Enrollment/Screening Period
Table 5 shows all procedures to be conducted at the screening visit. Assessments should, 
where practically possible, be performed in the order shown in the table.


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Table 5
Schedule of Screening and Run-in Procedures
Study Period
Screening a
Run-in
Visit Number
V1
V2
Procedure / Study Day 
Day -25 to -12
Day -11 to -3 l
Written informed consent/assignment of 
SID number #
X
Optional informed consent for sample for 
future genetic research
X
Optional informed consent for sample for 
future non-genetic research
X
Medical history, including smoking and 
alcohol history
X
Physical examination (full) b
X
Verify eligibility criteria
X
Weight c, height, and BMI calculation
X
Demographics
X
12-lead ECG d
X
Vital signs (BP, pulse, body temperature, 
RR) e
X
Collect blood for:
Serum chemistry
X
Coagulation panel
X
Hematology
X
HbA1c f
X
Plasma glucose g
X
Calcitonin
X
HIV-1 and -2 antibodies; hepatitis B 
and C serology
X
Triglycerides
X
Pancreatic amylase, lipase
X
Serum b-HCG (pregnancy test, females 
only)
X
FSH (postmenopausal females only) m
X
Collect urine for:
Urinalysis
X
Urine drug and alcohol screen h
X


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Table 5
Schedule of Screening and Run-in Procedures
Study Period
Screening a
Run-in
Visit Number
V1
V2
Procedure / Study Day 
Day -25 to -12
Day -11 to -3 l
SC injection training/demonstration j
X
X
ABPM k
X
Glucometer and diary dispensed 
X
ABPM = ambulatory blood pressure monitoring; BMI = body mass index; BP = blood pressure; 
 
ECG = electrocardiogram; FSH = follicle-stimulating hormone; HbA1c = 
hemoglobin A1c; HIV = human immunodeficiency virus; SC = subcutaneous; SID = subject identification; V = 
visit
a
Screening period may be extended to Day -42 in Cohort 2 if washout of oral anti-diabetic therapy (other 
than metformin) is required 
b
Only the screening physical examination will be a full examination. For all time points thereafter, only a 
targeted physical examination is required.
c
Body weight should be measured in the morning while the subject is fasted and prior to breakfast, after the 
subject has toileted and removed bulky clothing, including shoes. Calibrated scales should be used.
d
A single digital ECG recording should be performed after the subject has rested for 10 minutes.
e
BP and heart rate should be measured once at heart level in the non-dominant arm where possible, with the 
subject supine for 10 minutes prior to the measurement (rest period for ECG will suffice).
f
HbA1C to be re-checked prior to the start of the run-in period only for those subjects washing out from a 
second anti-hyperglycemic agent
g
Fasting plasma glucose to be checked prior to the start of the run-in period for those subjects washing out 
from a second anti-hyperglycemic agent
h
An alcohol breath test is an acceptable alternative to an alcohol urine test.
i
Subjects should be shown the device and given an explanation as to how it is worn.
j
Subject’s ability to administer a SC injection will be verified by undergoing a single SC injection using 
normal saline provided by the site. Willingness to perform this for the duration of the study should be 
discussed with the subject. Further training may be given during the run-in period as required.
k
Subjects will be fitted with the ABPM device while at the clinical unit, which may involve practice 
inflations. The subject will then wear the monitor/cuff for approximately 24 hours (including overnight at 
home) and will remove the device at home at the end of the 24-hour period. 
l
 
m
FSH should only be checked in female subjects who are post-menopausal and have no previous 
confirmatory laboratory FSH result available. 
# Collection of Informed consent may occur prior to the other screening assessments, on a separate visit if 
required
 


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4.2.3
Treatment Extension at HCTD and Follow-up Period
Table 7 shows all procedures to be conducted during the treatment extension and follow-up 
period.
Table 7
Schedule of Procedures for Treatment Extension at HCTD and 
Follow-up Periods 
Study Period
Treatment Extension at HCTD
Follow-up
Timepoint
Day 1 
of TE
Day 7 
of TE
Day 20 
of TE
Day 21 
of TE
Day 1 
post 
last 
dose
Day 2 
post 
last 
dose
Day 3 
post 
last 
dose
28 days post last 
dose/EDV (± 3 
days)
Procedure/Visit 
Number
V11
V12
V13
V14
V15
V16
Outpatient clinic 
visit
X
X a
X a
X a
X
Inpatient clinic 
visit 
X
X
X
Day of 
discharge from 
clinical unit on 
completion of 
assessments
X
X
Fasting for 
minimum of 10 
hours prior to 
the morning of 
the study day
X
Standardized 
meal day b
X
Targeted 
physical 
examination
X
X
Vital signs (BP, 
pulse, body 
temperature) c
X
X
X
X
ABPM d
X
ECG e
X
X
X
X
X
X
X
Body weight f
X
X
X
Investigational 
product 
administration
Subject will self-administer 
investigational product daily via SC 
injection
Blood tests


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Table 7
Schedule of Procedures for Treatment Extension at HCTD and 
Follow-up Periods 
Study Period
Treatment Extension at HCTD
Follow-up
Timepoint
Day 1 
of TE
Day 7 
of TE
Day 20 
of TE
Day 21 
of TE
Day 1 
post 
last 
dose
Day 2 
post 
last 
dose
Day 3 
post 
last 
dose
28 days post last 
dose/EDV (± 3 
days)
Procedure/Visit 
Number
V11
V12
V13
V14
V15
V16
Hematology 
panel
X
X
Serum 
Chemistry 
panel
X
X
Fasting 
plasma 
glucose
X
Fasting lipase 
and amylase
X
Calcitonin
X
Fasting lipid 
panel
X
X
HbA1c
X
X
PK for 
MEDI0382g
X
X
X
X
X
X
PK for 
metformin h
X
X
X
X
X
X
ADA
X
X
Blood sample 
for optional 
future non-
genetic 
research
X
Urine 
collection for:
Urinalysis
(dipstick; 
predose as 
applicable)
X
X
X
Pregnancy test 
(if applicable)
X
X


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Table 7
Schedule of Procedures for Treatment Extension at HCTD and 
Follow-up Periods 
Study Period
Treatment Extension at HCTD
Follow-up
Timepoint
Day 1 
of TE
Day 7 
of TE
Day 20 
of TE
Day 21 
of TE
Day 1 
post 
last 
dose
Day 2 
post 
last 
dose
Day 3 
post 
last 
dose
28 days post last 
dose/EDV (± 3 
days)
Procedure/Visit 
Number
V11
V12
V13
V14
V15
V16
 
 
AEs/SAEs
Throughout study
Concomitant 
medications
Throughout study
ADA = anti-drug antibody; AE = adverse event; ABPM = ambulatory blood pressure monitoring; BP = blood 
pressure; 
 ECG = electrocardiogram; EDV = early discontinuation 
visit; HbA1c = hemoglobin A1c; PK = pharmacokinetics; SAE = serious adverse event; SC = subcutaneous; 
TE = treatment extension
a
Subjects may choose to remain in the clinical unit as an inpatient if it is more convenient.
b
Subjects will eat a standardized breakfast, lunch and evening meal at approximately 9 am, 1 pm and, 
6 pm. No further food should be consumed until any fasted assessments have been carried out the 
following morning. Water is permitted ad libitum.
c
Vital Signs Schedule (BP, pulse, and temperature): on days where ABPM is due to be checked a predose 
set of vital signs should be performed prior to application of the ABPM cuff. Blood pressure should be 
measured once at heart level in the nondominant arm where possible, 
 
 with the subject supine 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. Vital signs should be measured predose 
(where applicable) on a given day.
d
ABPM device will be worn for 24 hours while in the clinical unit
e
A triplicate ECG recording will be collected on Days 1 and 7 of TE, predose; Day 21 of TE; predose, 1, 2 
(± 15 minutes); 4, 6, 8, and 12 and 24, 48, and 72 (± 30 minutes) hours postdose. The ECG triplicate 
recording should be done prior to the PK samples being taken.
f
Body weight should be measured in the morning while the subject is fasted and prior to breakfast, after 
the subject has toileted and removed bulky clothing including shoes. Calibrated scales should be used.
g
PK Sampling Schedule for MEDI0382: Days 1 and 7 of TE, predose; Day 21 of TE; predose, 1, 2 
(± 15 minutes); 4, 6, 8, and 12 and 24, 48, and 72 (± 30 minutes) hours postdose.
h
PK Sampling Schedule for Metformin: Days 1 and 7 of TE, predose; Day 21 of TE; predose, 1, 2 
(± 15 minutes); 4, 6, 8, and 12 hours post dose. Further predose samples should be taken on Days 1, 2 
and 3 post last MEDI0382 dose. On days where metformin PK samples are collected, the dose, time and 
date of the last metformin dose should be recorded relative to the samples taken
i
 


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4.3
Description of Study Procedures
4.3.1
Efficacy
The following efficacy assessments will be performed and/or measured at the time points 
specified in the schedules of study procedures (Table 5, Table 6, and Table 7).
4.3.1.1
Glucose measurements 
All subjects will be provided with a glucometer and a diary during the run-in period, and site 
staff will explain how the glucometer works and allow the subject to demonstrate proper use 
under supervision before being discharged from the clinic.
Subjects will be advised to use the glucometer to check their capillary blood glucose level as 
per their usual schedule and if they have symptoms of hypoglycemia (hunger, dizziness, 
shaking, sweating, or irritability) or feel unwell and will be expected to record the level and 
symptoms in their diary.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.3.1.2
Standardized Meals
On standardized meal days, subjects should only consume what is provided to them to eat by 
staff. Subjects will receive the same nutritionally balanced breakfast, lunch, and evening meal
at approximately 9 am, 1 pm, and 6 pm respectively, ensuring there is at least 4 hours between 
the start of each meal on any given day. The clinical site may determine appropriate meals to 
serve, however subjects must be served the same meals on each day the assessment is 
specified. Water may be given ad libitum but subjects should refrain from any other beverages 
until 7 am the following morning when the fast may be broken. Subjects will be required to 
fast for at least 10 hours prior to breakfast on the standardized meal day.
4.3.1.3
Body Weight
Body weight will be measured according to the schedule presented in Table 5, Table 6, and 
Table 7. Body weight should be measured in the morning while the subject is fasted and prior 
to breakfast. 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 after screening, at the site the same (properly calibrated) scale should be 
used for each measurement for any given subject. The subject’s body weight will be recorded 
in kg to 1 decimal place at minimum. 


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4.3.2
Safety
4.3.2.1
Medical History and Physical Examination
Complete medical history will include history (including smoking and alcohol history) and 
current medical conditions, past or present cardiovascular disorders, respiratory, GI, renal, 
hepatic, neurologic, endocrine, lymphatic, hematologic, immunologic, dermatologic, 
psychiatric, genitourinary, drug and surgical history, or any other diseases or disorders.
Physical examinations will be performed by a physician or qualified designee and full 
examinations include the following body systems: immunologic/allergy; head, ears, eyes, 
nose, and throat; respiratory; cardiovascular; GI; musculoskeletal; neurological psychiatric (to 
the extent of determining whether or not the subject is willing and able to cooperate with the 
required study procedures in the investigator’s judgment); dermatologic; 
hematologic/lymphatic; and, endocrine. In addition, the injection site will be assessed.
Clinically significant abnormal findings will be recorded. A complete physical examination 
will be performed according to the schedule presented in Table 5, Table 6, and Table 7. 
Targeted examinations (evaluation of selective body systems at the judgment of the physician 
or qualified designee based on subject presentation) are sufficient for the remaining time 
points. 
4.3.2.2
Body Mass Index
BMI will be calculated as BMI = weight / (height)2], where weight is measured in kg, and 
height in meters. The height measurement recorded at screening will be used for each BMI 
calculation for a given subject.
BMI will be measured according to the schedules presented in Table 5, Table 6, and Table 7.
4.3.2.3
Electrocardiograms
Subjects should rest in the supine position at least 10 minutes before ECG recordings are 
conducted. ECGs may be repeated per site’s local procedure. Further ECGs will be performed 
in accordance with the schedule provided in Table 5 and Table 7 (screening and treatment 
extension).
The ECGs will be interpreted by a qualified physician (the investigator or qualified designee) 
at the clinical study site. The investigator should date and sign the ECG tracing and record the 
clinical significance of any abnormal result on the tracing. ECG data and evaluation will be 
recorded in the eCRF. 
Paper copies of ECGs will be stored at the study center and digital copies transmitted to a 
central archive. Digital copies may be interpreted where required by other qualified physicians 
outside the study site. 


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The following variables will be reported: RR, PR, QRS, QT, and QTcF intervals. 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.
Telemetry
Telemetry will be used to continuously monitor heart rate and rhythm activity as a real-time 
safety measure. Telemetry will be monitored as tolerated (ie, balanced in consideration of 
potential skin abrasion AEs). Telemetry measurements using 3 leads will be performed for a 
minimum of 8-hours post dosing during inpatients visits and on Day -1 as specified in the 
schedule of events. Any significant abnormality in telemetry before dosing should be 
documented in the eCRF as part of the subject’s medical history, and abnormalities after 
dosing should be reported as AEs. Significant abnormalities include atrial or VT lasting for 
more than 3 beats, or symptomatic heart block (ie, pulse < 40 bpm accompanied by 
symptomatic hypotension for at least 10 minutes). Any clinically significant change noted on 
telemetry will be followed up by performing and printing a 12-lead ECG.
4.3.2.4
Vital signs
Vital sign measurements (BP, heart rate, respiration rate, and body temperature) are to be 
obtained in accordance with the schedule provided in Table 5, Table 6, and Table 7. Vital 
signs are to be taken prior to investigational product administration, and, if possible, before 
drawing blood. 
On days where ABPM is due to be checked, a predose set of vital signs should be performed 
prior to application of the ABPM cuff. Blood pressure should be measured once with the arm 
at heart level and measurements performed using an adequate arm cuff size. The nondominant 
arm should be used where possible, 
 
with the subject supine 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. The pulse rate should be 
measured for 30 seconds to determine the rate. If a specific post dose reading falls on a given 
day, only those reading need be taken.
Further vital signs measurements will be recorded in accordance with the schedule provided in 
Table 5 and Table 7 (screening and treatment extension).
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 BP cuff will be selected and the device will be 
fitted to the nondominant arm of the subject, with the bladder placed over the artery and an 
initial test reading performed. The subjects will be advised that for the first reading the device 
will inflate to a pressure of 180 mmHg, and thereafter the device will adapt to inflate to a 


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pressure just above the last recorded BP. The subject will be advised to undergo normal daily 
activities while wearing the cuff, and he/she will be advised to avoid any strenuous form of 
activity, bathing, or showering while wearing the cuff. The subject will be advised to remain 
still during a measurement with the arm relaxed at heart level. The subject will also be given 
advice on how to wear the device during the day and at night while sleeping, and what to 
expect in terms of frequency of readings during the day (every 15 minutes) and overnight 
(every 30 minutes). During ABPM, systolic BP, diastolic BP, heart rate pressure, heart rate, 
and mean arterial pressure readings will be recorded over a period of 24 hours.
4.3.3
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study. 
Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed local clinical laboratory. Urine tests may be performed at the site using a licensed test 
(dipstick). Abnormal clinically significant 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 5, Table 6, and Table 7
for the schedule of tests. 
4.3.3.1
Serum Chemistry
•
blood urea nitrogen
•
calcium
•
creatinine
•
glucose (fasting where required)
•
total protein
•
sodium
•
albumin
•
potassium
•
TBL 
•
chloride
•
alkaline phosphatase 
•
bicarbonate
•
ALT 
•
phosphorus
•
AST 
•
gamma glutamyl transferase
Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed concurrently.
4.3.3.2
Hematology
•
red blood cell count
•
platelet count
•
hemoglobin
•
mean cell volume 
•
hematocrit
•
mean corpuscular hemoglobin concentration 
•
absolute white blood cell count
•
mean corpuscular hemoglobin
•
white blood cell count with percent differential


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4.3.3.3
Coagulation Panel (Screening Only)
•
prothrombin time
•
thrombin time
•
activated partial thromboplastin time
•
international normalized ratio
4.3.3.4
Urinalysis 
•
pH
•
ketones
•
specific gravity
•
protein
•
glucose
•
microscopic analysis (if positive for blood, 
nitrates, or protein) by local laboratory
•
blood (urine hemoglobin/erythrocytes/blood)
•
bilirubin
•
color
•
leukocytes
•
appearance
•
urobilinogen
Urinalysis for pH, specific gravity, protein, glucose, ketones, bilirubin, blood, leukocytes, urobilinogen and 
nitrate may be performed at the site using a licensed test (dipstick).
4.3.3.5
Drug/Alcohol Screen

Site standard urine drug screen will be used. 

Breathalyzer or urine alcohol screening is acceptable.
4.3.3.6
Other Tests 

Urine human chorionic gonadotropin (hCG) (All Females)

Follicle-stimulating hormone (postmenopausal women only)

Serum beta-hCG (at screening only) (All Females)

Serum HIV-1

Serum HIV-2 antibodies

Serum hepatitis B surface antigen

Serum hepatitis C antibody

Calcitonin

Pancreatic amylase, lipase

Fasting lipid panel (Total cholesterol, high-density lipoprotein, low-density lipoprotein, 
triglycerides)

HbA1c
4.3.4
Pharmacokinetic Evaluation and Methods
Blood will be collected predose and at specific post dose times to evaluate PK of MEDI0382 
in plasma (see Table 6 and Table 7 for collection time points). The PK of MEDI0382 in 
plasma will be measured utilizing a validated liquid
 
 


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Blood will be collected predose and at specific post dose times to evaluate PK of metformin in 
plasma (see Table 6 and Table 7 for collection time points). The PK of metformin in plasma 
will be measured utilizing a validated LC-MS/MS method. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
4.3.5
Immunogenicity Evaluation and Methods
Blood samples will be collected to evaluate ADA responses to MEDI0382 (see Table 6 and 
Table 7 for collection time points). Evaluations will be performed using validated 
immunoassays. Tiered analyses will be performed to include screening, confirmatory, and titer 
assay components, and the positive-negative cut points will be statistically determined from 
drug-naive validation samples. Cross-reactivity to GLP-1 and glucagon may be assessed on 
samples confirmed positive for MEDI0382 specific ADA. Samples may be utilized for further 
characterization of the ADA response, including possible assessment of neutralizing antibody.
Instructions for immunogenicity (ADA) sample collection, processing, storage, and shipment 
can be found in the Laboratory Manual. Serum samples for analysis of ADA will be collected 
according to the schedule presented in Table 6 and Table 7. 
At the end of study visit, if a subject’s sample is 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 to return to provide a 
sample in another 3 months (ie, 6 months after the end of study visit). If the sample is ADA 
positive at 6 months, the investigator and the medical monitor will discuss what further action 
will be taken.
4.3.6
Genetic Evaluations and Methods
The subject’s consent to participate in the genetic research components of the study is 
optional. See Appendix E for further information.
4.3.7
Storage, Re-use and Destruction of Biological Samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed. 
4.3.8
Estimate of Volume of Blood to Be Collected
The estimated volume of blood to be collected from each subject over the entire course of 
their participation in the study is approximately 589 mL. 


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4.4
Study or Study Component Suspension or Termination
MedImmune reserves the right to temporarily suspend or permanently terminate this study or 
component of the study at any time. The reasons for temporarily suspending or permanently 
terminating the study may include but are not limited to the following: 
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 based on a planned futility analysis
If MedImmune determines that temporary suspension or permanent termination of the study 
or component 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 or component of the study is suspended or terminated for safety reasons, 
MedImmune will promptly inform all investigators, heads of the medical institutions (where 
applicable), and/or institutions conducting the study. MedImmune will also promptly inform 
the relevant regulatory authorities of the suspension/termination along with the reasons for 
such action. Where required by applicable regulations, the investigator or head of the medical 
institution must inform the Independent Ethics Committee (IEC) promptly and provide the 
reason(s) for the suspension/termination. If the study or component of the study is suspended 
for safety reasons and it is deemed appropriate by MedImmune to resume the study or 
component of the study, approval from the relevant regulatory authorities (and IECs when 
applicable) will be obtained prior to resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
The sponsor will provide the investigator(s) with investigational product (Table 8) using 
designated distribution centers. 


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4.5.1.1
Investigational Product Handling and Inspection
Investigational Product Inspection
Each vial selected for dose preparation should be inspected prior to use. The MEDI0382 or 
placebo solution in vials should not be cloudy, discolored, 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 4.5.1.5) for 
further instructions.
In-clinic Investigational Product Handling
Investigational product should be stored at 2°C to 8°C in the original container, and should be 
protected from heat and light.
Investigational products are supplied in single-use vials and do not contain preservatives, so 
after dose preparation any unused portion must be discarded. Preparation of syringes for dose 
administration is to be performed using aseptic techniques. Total in-use storage time from 
needle puncture of the investigational product vial to start of administration should not exceed 
4 hours at room temperature. If storage time exceeds these limits, a new dose must be 
prepared from new vials.


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At-home Investigational Product Handling
The entire carton of investigational product should be stored in the refrigerator. Subjects 
should be asked to ensure they have a normal domestic refrigerator at home, which should be 
between 2°C and 8°C. Investigational product should be protected from heat and light.
Subjects should be instructed not to store the investigational product directly adjacent to the 
refrigerator cooling element. Investigational product should not be used if it has been frozen. 
The subject should be instructed to remove from the refrigerator only the 1-vial kit required 
for their daily dose. All other kits are to be kept in the original carton in the refrigerator until 
required. Prior to administration, the single vial of investigational product to be used for 
injection should be removed from the refrigerator and kept at room temperature for 
approximately 15 minutes for temperature equilibration. The subject is not to administer 
investigational product if the time outside of the refrigerator exceeds 4 hours; if storage time 
exceeds this limit, a new dose must be prepared from a new vial. 
Vials are single-use only, and the subject should be instructed not to re-use the vial after 
administration of a single dose. After administration, the used vial, syringe and needle should 
be directly discarded into the provided sharps bin.
4.5.1.2
Dose Preparation 
 
 
 
 
 
 Only the 
supplied diluent may be used for this dilution step. 
If diluent is required, investigational product should be removed from the refrigerator and kept 
at room temperature for at least 30 minutes and a maximum of 4 hours for temperature 
equilibration. If no dilution is required, 15 minutes is recommended for temperature 
equilibration.
To make a 10-fold dilution of MEDI0382 or placebo, it is recommended to withdraw 0.1 mL 
of the supplied investigational product using a 1 mL syringe and 27G needle, and add it into a 
sterile empty vial. Using a new 1 mL syringe and 27G needle, add 0.9 mL of diluent into the 
same vial. The needle specified for dilution may be substituted for either a 20 or 30G needle 


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as feasibility dictates. The vial should be mixed by swirling gently to make a homogenous 
final admixture. Do not shake. The diluted dose should be administered using a 1.0 mL 
syringe (Table 9). Dilution and preparation of doses for administration is to be performed 
using aseptic techniques.
Doses of 100 μg or greater do not require a dilution step and should be administered directly 
using a 0.3 mL insulin syringe.
4.5.1.3
Treatment Administration
In-clinic Treatment Administration
The first day of dosing is considered Day 1. On the day of each dose, investigational product 
will be administered according to the schedule of procedures, as soon as practical upon 
waking each morning prior to breakfast, ideally at the same time each day. Investigational 
product will be administered by the subject under supervision as an SC injection in the lower 


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abdomen using 
 
At-home Treatment Administration
 
 as soon as practical upon waking each morning prior to 
breakfast, ideally at the same time each day. Subjects should be instructed to rotate the 
injection site around the abdomen.
After administration, the used vial, needle and syringe should all be directly discarded in the 
provided sharps bin. Further details are provided in the home dosing instructions.
If a dose of investigational product is missed, subjects should contact the site for further 
instructions.
Subjects must return any unused investigational product, and the sharps bin, at their next visit 
to the clinical site. All items can be returned at room temperature.
4.5.1.4
Monitoring of Dose Administration
Monitoring of In-clinic Dose Administration
As with any exogenous peptide delivered SC, allergic reactions to dose administration are 
possible. Therefore, appropriate drugs and medical equipment to treat acute anaphylactic 
reactions must be immediately available, and study personnel must be trained to recognize and 
treat anaphylaxis and in basic life support techniques and acute care for life-threatening 
emergencies. During the post-dosing period, vital signs will be periodically assessed (see 
Section 4.3.2.4). Injection sites should be routinely examined at each study site visit. If any 
injection-site reaction meets the criteria for an AE (see Section 5), the event is to be reported 
on the AE eCRF, with the reaction described as specifically as possible.
Recording of Missed Doses During At-home Dose Administration
Subjects will be instructed on how and what to record daily for missed doses in the Daily 
Diary.
4.5.1.5
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.


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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
One MedImmune Way,
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. 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. Investigational product should be stored at 2°C to 8°C (36°F to 46°F) in the 
original container while in the clinic. Separate instructions for at-home dosing and storage will 
be provided.
4.5.5
Treatment Compliance
Investigational product will be administered by subjects while being observed by study site 
personnel, who will monitor compliance during the inpatient period. Compliance during the 
at-home dosing period will be monitored via returned vials.
4.5.6
Accountability
4.5.6.1
In-clinic 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.


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4.5.6.2
Accountability for Doses Administered by the Subject during the At-home 
Self-administration Period
Subjects will be instructed to return any unused vials, and the sharps bin, to the site when they 
return for their next clinic visits.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
Subjects will be randomized using a 3:1 ratio to receive either MEDI0382 or placebo. A 
manual randomization schedule will be used assign a unique randomization code and 
investigational product kit(s) for the subject at each randomization. 
Investigational product (MEDI0382 or placebo) must be administered within 24 hours after 
the treatment group 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 medical 
monitor must be notified immediately.
4.6.2
Methods to Ensure Blinding
This is a blinded study in which the subjects and investigator are blinded to investigational 
product, and MedImmune staff involved in the study are unblinded. Investigational product 
and placebo are indistinguishable in appearance, identically labelled, and supplied as fully 
blinded kits.
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 using emergency unblinding envelopes which will be held 
securely at the study site. In general, unblinding should only occur if management of the 
medical emergency would be different based on the subject having received investigational 
product. In most cases, the management of a medical emergency would be the same whether 
or not investigational product was received by the subject. If this was the case, the 
investigational product allocation should not be unblinded.
MedImmune retains the right to unblind the treatment allocation for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities. 
If a subject’s investigational product allocation is unblinded to the blinded staff, the subject 
should be discontinued from investigational product.


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4.6.3.2
Unblinding for Planned Analysis Purposes 
Planned analyses are described in Section 4.8.1. Since MedImmune staff are unblinded to 
investigational product treatment per the study design, no additional procedures related to 
unblinding are required for analysis purposes.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the 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 
(except those listed in section 4.7.2), anti-emetics, anti-diarrheal, and analgesics, and other 
care as deemed appropriate, and in accordance with their institutional guidelines.
Concomitant medications being taken for stable concurrent conditions not felt to impact study 
integrity may be acceptable upon approval of the investigator and sponsor (or designee).  A 
stable regimen of antihypertensive agents for a minimum of 3 months prior to screening is 
permitted. Similarly, a stable treatment regimen of thyroid replacement therapy for a 
minimum of 2 months prior to screening is permitted.
4.7.2
Prohibited Concomitant Medications
Other than the medications described above, use of the following medications, including over 
the counter medications, herbal supplements, vitamins etc. at the times specified in the list 
below is not permitted, generally speaking from the time specified in the entry criteria until 
after the 28-day post-last-dose safety follow-up visit
Subjects should not be initiated on any new medications to control blood glucose levels during 
the dosing and follow up period unless it is deemed necessary by the Investigator for safety 
and following discussion with the Medical Monitor.

Concurrent or previous use of a GLP-1 analogue containing preparation within the last 
30 days or 5 half-lives of the drug, whichever is longest, prior to the start of screening 
(Visit 1)

Concurrent or prior use of any herbal preparations or dietary supplements marketed for 
control of body weight or appetite within 1 week prior to the start of screening


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
Concurrent or previous use of drugs approved for weight loss (eg, orlistat, 
bupropion-naltrexone, phentermine-topiramate, phentermine, lorcaserin) within the last 
30 days or 5 half-lives of the drug, whichever is longest, prior to the start of screening

Antidepressant (eg, escitalopram) or anti-psychotic agents (eg, chlorpromazine) must not 
be started during the course of the study.

Systemic corticosteroids by oral, intravenous, intra-articular, or intramuscular route are 
prohibited within 3 months prior to screening and during the study unless prescribed for a 
very brief period of less than 7 days.

Concurrent use of aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily 
and within the last 72 hours prior to the start of the study (Visit 2)

Concurrent use of paracetamol (acetaminophen) at a total daily dose greater than 3000 mg 
once daily and within the last 72 hours prior to the start of the study (Visit 2)

Concurrent use of ascorbic acid (vitamin C) at a total daily dose of > 1000 mg and within 
the last 72 hours prior to the start of the study (Visit 2)

Concurrent use of medications (other than metformin) for control of blood glucose within 
4 weeks prior to the start of the study (Visit 2) unless it is deemed necessary by the   
investigator for safety reasons. 

Antimicrobials within the quinolone (eg, ciprofloxacin), macrolide (eg, clarithromycin) or 
azole class (eg, ketoconazole)

Metoclopramide or domperidone for the treatment of emesis should only be considered if 
the subject is unable to tolerate a 5HT3 antagonists (eg, ondansetron)
This is not a comprehensive listing. If the exclusion status of any concomitant medication is in 
question, the study physician should be contacted for discussion. The sponsor or designee 
should be contacted if the investigator is informed of any restriction violations. The sponsor 
will decide whether a subject with restriction violations will be allowed to continue study 
participation.
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.
The as-treated population is defined as all subjects who are randomized and receive any 
investigational product analyzed according to treatment received. All analyses will be based 
on the as-treated population.


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Two analyses are planned for this study as follows:
1
A primary analysis after the up-titration period for Cohort 2, and
2
A final analysis after the safety follow-up period for Cohort 2.
Analyses will be conducted for each cohort and for two cohorts combined. Formal statistical 
modeling analysis for certain efficacy endpoints will only be conducted for two-cohort 
combined analyses.
4.8.2
Sample Size
The total study sample size is 20 subjects, who will be randomized by 2 cohorts: 8 subjects in 
Cohort 1 and 12 subjects in Cohort 2. For each cohort, subjects will be randomized in a 3:1 
ratio to the MEDI0382 arm or the placebo arm. The sample size for this study was empirically 
determined to obtain adequate safety and tolerability evaluation. 
 
 
 
4.8.3
Efficacy
4.8.3.1
Primary Efficacy Analysis
There are no primary efficacy objectives or analyses planned for this study.
4.8.3.2
Secondary Efficacy Analyses
The continuous secondary efficacy endpoints for two cohorts combined analysis will be 
compared between the MEDI0382 and placebo arms using an analysis of covariance model 
adjusting for baseline value and treatment arm. For the secondary proportion-related efficacy 
endpoints, a logistic regression model will be used with baseline value and treatment arm. 
Same endpoints for each cohort analysis will only be summarized without formal statistical 
comparisons.
4.8.3.3
Exploratory Analyses
Exploratory efficacy endpoints will be summarized without formal statistical comparisons and 
testing.
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 


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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.
Additionally, the incidence and event rate of nausea and vomiting will be summarized weekly 
during the treatment period.
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.
Other safety data such as vital signs, ECG and physical examination findings will be 
descriptively summarized at each time point by treatment. Mean ambulatory BP and heart rate 
measurements recorded over 24 hours at different time points will be analyzed using an 
analysis of covariance model, adjusting for treatment and measurement at baseline. 
 
 
 
 
 
 
 
4.8.5
Analysis of MEDI0382 Immunogenicity/Pharmacokinetics 
PK parameters such as MEDI0382 Cmax, Tmax, and AUCtau will be estimated (if data allow) 
from plasma concentration time data for MEDI0382 at each dose level separately except for 
the 
evels by cohort. Additional PK parameters such as AUCinf and 
terminal half-life may be derived if data allow, at the HCTD from samples collected at the end 
of extension period
Descriptive statistics including mean, standard deviations, median, minimum, and maximum 
will be generated for all PK parameters for MEDI0382 at each dose level separately, and for 
the Ctrough. Subjects who have at least one measurable concentration time point of 
investigational product will be used for this analysis.


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Individual Ctrough will be listed by cohort, treatment and day and will be summarized as 
maximum, minimum, arithmetic mean, and geometric mean.
The incidence and impact of ADA to MEDI0382 will be evaluated. The number and 
percentage of subjects with confirmed positive serum antibodies to MEDI0382 will be 
reported by dose level. Data on titers and cross-reactivity to GLP-1 and glucagon (where 
applicable) will be listed. If warranted by the data, the association of ADA positive with 
observed PK data may be explored.
 
 
 
 
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented preexisting 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 


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
Is a congenital anomaly/birth defect in offspring of the subject

Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; or development of drug dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An 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 MedImmune. An AESI may be serious or nonserious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product.
There are no AESIs defined for 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 MedImmune (see Section 5.5). See 
Section 5.2 for the definition of SAEs and Section Appendix B 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.
5.4.1
Time Period for Collection of Adverse Events
All AEs regardless of severity will be collected from randomization throughout the treatment 
period and including the follow-up period. All SAEs and any AEs related to study procedures 
will be recorded from the time of informed consent.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment 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.


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5.4.3
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
5.4.4
Adverse Events Based on Examination and Tests
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the CSR. An abnormal laboratory finding (including ECG finding) that requires medical 
intervention by the investigator, or a finding judged by the investigator as medically 
significant should be reported as an AE. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cell 
increased)
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE
5.4.5
Hy’s Law
Cases in which a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need 
to be reported as SAEs. Please refer to Appendix D further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
5.5
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
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.


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The designated study representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor’s patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform sponsor 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed. 
The reference document for definition of expectedness/listedness is the IB.
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 should inform appropriate sponsor representatives 
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.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.5. 
For other overdoses (ie, those not associated with an AE or SAE), reporting must occur within 
30 days.


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5.6.2
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor except for:

If the pregnancy is discovered before the study subject has received any investigational 
product.

Pregnancies in the partner of male subjects
5.6.2.1
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 study 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.
5.6.3
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for a MedImmune study drug that either causes harm to the subject or 
has the potential to cause harm to the subject. 
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or subject.
Medication error includes situations where an error: 

Occurred


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
Was identified and intercepted before the subject received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion (ie, instead of receiving the investigational product, the subject 
received a drug that has a similar-sounding name)

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature 

Wrong subject received the medication 

Wrong drug administered to subject 
Examples of events that do not require reporting as medication errors in clinical studies:

Subject accidentally missed drug dose(s), eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ or MedImmune product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate MedImmune representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated MedImmune representative works with the investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 5.5) and within 30 days for all other medication errors. 
Medication errors should be reported using a Medication Error Report Form.


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


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inconsistency between this protocol and the Clinical Study Agreement, the terms of the 
protocol shall prevail with respect to the conduct of the study and the treatment of subjects; in 
all other respects not relating to study conduct or the treatment of subjects, the terms of the 
Clinical Study Agreement shall prevail.
Agreements between MedImmune and the principal investigator must be in place before any 
study-related procedures can take place or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through their last protocol-specified visit/assessment (including telephone contact) 
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 Sections 4.1.5 and 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (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.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 


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requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID number to ensure that personally identifiable information 
is kept separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc. will only be collected with the subject’s informed consent. The informed consent 
form will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that describes how subject data will be collected, used, and distributed 
in compliance with relevant data protection and privacy legislation.
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. MedImmune will not provide individual genotype results 
to subjects, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law.
7.2
Ethics and Regulatory Review
The IEC responsible for each site must review and approve the final study protocol, including 
the final version of the informed consent form and any other written information and/or 
materials to be provided to the subjects. The IEC must also approve all advertising used to 
recruit subjects for the study. The investigator is responsible for submitting these documents 
to the applicable IEC, and distributing them to the study site staff.
The opinion of the IEC must be given in writing. The investigator must provide a copy of the 
written approval to MedImmune before enrollment of any subject into the study. 
MedImmune should approve any substantive modifications to the informed consent form that 
are needed to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IEC annually.
Before the study is initiated, MedImmune will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. MedImmune 
will provide safety updates/reports according to local requirements, including suspected 
unexpected serious adverse reactions where relevant, to regulatory authorities, IEC, and 
principal investigators.


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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 center will:

Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study

Ensure each subject is notified that they are free to discontinue from the study at any time

Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study

Ensure the original, signed informed consent form(s) is/are stored in the Investigator’s 
Study File

Ensure a copy of the signed informed consent form is given to the subject

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an IEC
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune. Any changes must be documented in a study protocol 
amendment. 
For a substantial change to the protocol, MedImmune will distribute amended versions of the 
protocol to the principle investigator(s). Before implementation, amended protocols must be 
approved by relevant IEC (see Section 7.2) and reviewed as per local regulatory authority 
requirements. The 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.
Any non-substantial changes will be communicated to or approved by each IEC.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IEC may perform 
audits or inspections at the center, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 


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documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP, ICH guidelines , 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
Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L et al. MEDI0382, 
a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 
diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet. 
2018;391(10140):2607-18.
Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M et al. Effects of 
liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. 
Lancet. 2009;374(9701):1606-16.
Cegla J, Troke RC, Jones B, Tharakan G, Kenkre J, McCullough KA et al. Coinfusion of low-
dose GLP-1 and glucagon in man results in a reduction in food intake. Diabetes. 
2014;63(11):3711-20.
Center for Drug Evaluation and Research. Byetta Pharmacology Review. 2005.
Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjoth TV et al. Efficacy of 
Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes 
Randomized Clinical Trial. JAMA. 2015;314(7):687-99.
Habegger KM, Stemmer K, Cheng C, Muller TD, Heppner KM, Ottaway N et al. Fibroblast 
growth factor 21 mediates specific glucagon actions. Diabetes. 2013;62(5):1453-63.
Henderson SJ, Konkar A, Hornigold DC, Trevaskis JL, Jackson R, Fritsch Fredin M et al. 
Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist 
in rodents and non-human primates. Diabetes Obes Metab. 2016;18(12):1176-90.
Lynch AM, Pathak N, Pathak V, O’Harte FP, Flatt PR, Irwin N et al. A novel DPP IV-
resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-
protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor 
activation. Diabetologia. 2014;57(9):1927-36.
Nauck M, Marre M. Adding liraglutide to oral antidiabetic drug monotherapy: efficacy and 
weight benefits. Postgrad Med. 2009;121(3):5-15.
Shulman ST. Obesity and type 2 diabetes. Pediatr Ann. 2005;34(9):668.
Victoza. 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.  2016.
Wynne K, Park A, Small C, Meeran K, Ghatei M, Frost G et al. 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.
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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9
CHANGES TO THE PROTOCOL
9.1
Protocol Amendment 3, 16Apr2019
The administrative change described below has been incorporated into the current version of 
the protocol. Table numbering in the appendices was also corrected, and the Table of Contents 
was reformatted and updated.
Summary of Revision to the Protocol (Amendment 3)
Key Detail of the Amendment
Reason for Amendment
Amendment 3 (16Apr2019)
Title Page
The medical monitor has changed for the study, and new contact 
information has been provided.
Appendix A
The numbering of the table in this section was corrected.
9.2
Protocol Amendment 2, 17Dec2018
All changes described below have been incorporated into the current version of the protocol.
Summary of Revisions to the Protocol (Amendment 2)
Key Details of the Amendment
Reason for Amendment
Amendment 2 (17Dec2018)
Section 4.1.2 (Inclusion Criteria)
Typos (μg to mg and blood to plasma) were corrected.
Added the need for female subjects of childbearing potential to 
have a negative pregnancy test at screening and randomization
Section 4.1.3 (Exclusion Criteria)
The definition of excessive alcohol intake was revised.
Table 5 (Schedule of Screening and 
Run-in Procedures)
Fasting was removed from plasma glucose as subjects cannot be 
fasting prior to consent.
Footnote added to clarify when follicle-stimulating hormone
should be collected.
Table 6 (Schedule of 
Treatment/Up-titration Period Study 
Procedures)
Text was added to correct the footnotes to the table. 
The optional inpatient or daily visit was corrected for dose period 
20-50 μg to state “from Day 2”.
Table 7 (Schedule of Procedures for 
Treatment Extension at HCTD and 
Follow-up Periods)
Added clarification of the metformin PK sample collection 
timepoints to footnote
 
 
 
Section 4.3.1.2 (Standardized Meals)
Instructions on when meals should be given were clarified.
Section 4.3.2.4 (Vital Signs)
Incorrect text was removed


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Summary of Revisions to the Protocol (Amendment 2)
Key Details of the Amendment
Reason for Amendment
Amendment 2 (17Dec2018)
Section 4.5.1.2 (Dose Preparation)
Text was added to clarify that substitution of other specific needle
gauges was allowed. 
Appendix D (Actions Required in 
Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s 
Law)
Updated in response to Sponsor’s new process
9.3
Protocol Amendment 1, 31October2018
All changes described below have been incorporated into the current version of the protocol. 
 
Other minor corrections 
(typos, grammatical revisions) were made.
Summary of Revisions to the Protocol (Amendment 1)
Key Details of the Amendment
Reason for Amendment
Amendment 1 (31Oct2018)
Section 3.1.3.2 (Dose Escalation 
Stopping Criteria)
Text was revised to clarify actions the DEC will take if any of the 
dose escalation stopping criteria are met (ie, recommending that 
the study proceed to 3-week treatment extension at the HCTD or 
requesting for review and decision by the MedImmune Safety 
Review Board on how to proceed or whether to suspend or stop 
the study).  
Section 4.1.3 (Exclusion Criteria)
Criterion 7 amended to reduce the acceptable upper limit of 
pancreatic amylase and lipase to 3 × ULN.
Section 4.1.5 (Withdrawal from the 
Study) and Table 7 (Schedule of 
Procedures for Treatment Extension at 
HCTD and Follow-up Periods)
Text was added specifying that subjects who withdraw their 
consent to participate in the study, if willing, will be seen and 
assessed by the investigator at an early discontinuation visit.
Table 7 (Schedule of Procedures for 
Treatment Extension at HCTD and 
Follow-up Periods)
The table was revised for accuracy, including correcting visit 
numbers, deletion of medical and disease history, and correcting 
visits for ABPM and ECG procedures.


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Appendix A
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) or those who are not postmenopausal (defined as 12 months with no 
menses) without an alternative medical cause and have follicle-stimulating hormone 
levels in the normal range for postmenopausal phase (25.8-134.8 IU/L) in previous 
laboratory results.

A highly effective method of contraception is defined as one that results in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly. The acceptable 
methods of contraception are described in Table 10.

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
Highly Effective Methods of Contraception 
•
Tubal occlusion
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system or implant; eg, Mirena®) a
•
Medroxyprogesterone injections (eg, Depo-Provera®)
•
Etonogestrel implants (eg, Implanon®, Norplan®)
•
Norelgestromin/ethinyl estradiol transdermal system
•
Intravaginal device (eg, NuvaRing®)
a
This is also considered a hormonal method.


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Appendix B
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).
Hospitalization
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, hospitalization, 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
A guide to Interpreting the Causality Question
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 aetiology 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 aetiology other than the procedure/ 
intervention that was described in the protocol (the alternative aetiology 
must be documented in the study subject’s medical record).


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Appendix C
National Institute of Allergy and Infectious Disease and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Disease (NAID) and Food Allergy and 
Anaphylaxis Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in 
onset and may cause death. They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for 
all 3 categories). 
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), 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 
subject (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnoea, 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 subject (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 mmHg or greater than 30% decrease from that 
person’s baseline


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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 1
Introduction
This appendix describes the process to be followed to identify and appropriately report 
Potential Hy’s Law (PHL) cases and of Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets PHL
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated alanine aminotransferase (ALT) from a central laboratory 
and/or elevated total bilirubin (TBL) from a local laboratory. 
The investigator will also review adverse event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry for possible PHL events.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL 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 PHL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
D 2
Definitions
D 2.1
Potential Hy’s Law
Aspartate transaminase (AST) or ALT ≥ 3 × upper limit of normal (ULN) together with TBL 
≥ 2 × ULN at any point during the study following the start of investigational product
irrespective of an increase in alkaline phosphatase (ALP).
D 2.2
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.


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For potential Hy’s Law and Hy’s Law, the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur.
D 3
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 potential Hy’s Law criteria (see Section D 2) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
D 4
Follow-up
D 4.1
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.
D 4.2
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

Within 1 day of PHL criteria being met, the investigator will report report the case as an 
SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to the Clinical Study Protocol process for SAE 
reporting.


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
For subjects that met PHL criteria prior to starting investigational product, the 
investigator is not required to submit a PHL SAE unless there is a significant change in 
the subject’s condition.
The medical monitor 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. 

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
D 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law 
criteria are met.
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, to ensure timely analysis and reporting to health 
authorities within 15 calendar days from date PHL criteria were met. The medical monitor and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate.
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE CRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following 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:


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
Send updated SAE (report term ‘Hy’s Law’) according to sponsor standard processes 

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for Hy’s Law, then it is assumed 
that there is no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of PHL (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to investigational product and 
seriousness criteria is medically important, according to clinical study protocol (CSP) 
process for SAE reporting

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
D 6
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended when using a central laboratory. For individual studies, the list may be reduced 
to a subset of tests after consultation with the Hepatic Safety Knowledge Group.
Some of the tests may also be considered for use with local laboratories that have respective 
testing capabilities. Any test results need to be recorded in the CRF.
Hy’s Law Lab Kit for Central Laboratories
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgM and IgG anti-HCV
HCV RNA


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IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
Food and Drug Administration (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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Appendix E
Genetic Research
Rationale and Objectives
MedImmune intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic Research Plan and Procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit. The subject will 
not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, subjects must fulfill all inclusion criteria described in 
the main body of the Clinical Study Protocol and:

Provide informed consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study 
Discontinuation of subjects from this genetic research
Specific reasons for discontinuing a subject from this genetic research are:
Withdrawal of consent for genetic research: Subjects may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study. Voluntary discontinuation will not prejudice further treatment. Procedures for 
discontinuation are outlined in Section 4.1.8 of the protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Day -2. Although 
DNA is stable, early sample collection is preferred to avoid introducing bias through 


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excluding subjects who may withdraw due to an AE, such subjects would be important to 
include in any genetic analysis. If for any reason the sample is not drawn at Day -2, it may be 
taken at any visit until the last study visit. Only one sample should be collected per subject for 
genetics during the study. Samples will be collected, labelled, stored and shipped as detailed 
in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  Samples will be stored for a maximum of 15 
years, from the date of last subject last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable by the second, unique number only. This number is used to identify the sample 
and corresponding data at the MedImmune genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(MedImmune employee or designated organizations working with the DNA).
The link between the subject enrollment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at MedImmune or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit 
and to trace samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 7 of the 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 center. 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.


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


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SAP_001.pdf: 
MedImmune 
Statistical Analysis Plan for Protocol D567C00030 
MEDI0382 
 
22JAN2019; version 1.0 
CONFIDENTIAL AND PROPRIETARY 
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SAP template version 3.0 
Statistical Analysis Plan 
A Phase 2a Randomized, Blinded, Placebo-controlled Study to 
Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of 
MEDI0382 in Overweight/Obese Subjects with Type 2 Diabetes 
Mellitus 
 
Protocol Number: D5670C00030 


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MEDI0382 
 
22JAN2019; version 1.0 
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TABLE OF CONTENTS 
1 
INTRODUCTION ...........................................................................................................5 
2 
STUDY OVERVIEW .....................................................................................................5 
2.1 
Study Objectives ...................................................................................................5 
2.1.1Primary Study Objective(s) ..........................................................................5 
2.1.2Secondary Study Objectives .........................................................................5 
2.1.3Exploratory Study Objectives .......................................................................5 
2.2 
Study Design .........................................................................................................6 
2.3 
Treatment Assignment and Blinding ....................................................................7 
2.4 
Sample Size...........................................................................................................7 
3 
STATISTICAL METHODS ...........................................................................................8 
3.1 
General Considerations .........................................................................................8 
3.2 
Analysis Populations.............................................................................................8 
3.3 
Study Subjects.......................................................................................................9 
3.3.1Subject Disposition and Completion Status .................................................9 
3.3.2Demographics and Baseline Characteristics .................................................9 
3.3.3Study Drug Exposure ....................................................................................9 
3.3.4Concomitant Medications .............................................................................9 
3.4 
Efficacy Analyses ...............................................................................................10 
3.4.1Primary Efficacy Endpoint(s) and Analyses ...............................................10 
3.4.2Secondary Efficacy Endpoint(s) and Analyses ...........................................10 
3.4.2.1 
Secondary Efficacy Endpoint(s) ...............................................10 
3.4.2.2 
Handling of Dropouts and Missing Data ..................................11 
3.4.2.3 
Secondary Efficacy Analyses ...................................................11 
3.4.3Other Efficacy Analyses .............................................................................11 
3.4.3.1 
Other Efficacy Endpoints ..........................................................11 
3.4.3.2 
Other Efficacy Analyses ...........................................................11 
3.5 
Safety Analyses...................................................................................................12 
3.5.1Adverse Events and Serious Adverse Events .............................................12 
3.5.2Adverse Events of Special Interest .............................................................12 
3.5.3Deaths and Treatment Discontinuations due to Adverse Events ................12 
3.5.4Clinical Laboratory Evaluation ...................................................................12 
3.5.5Other Safety Evaluations ............................................................................13 
3.5.5.1 
Vital Signs .................................................................................13 
3.5.5.2 
Ambulatory Blood Pressure Measurements .............................13 
3.5.5.3 
Electrocardiogram .....................................................................13 
3.6 
Immunogenicity ..................................................................................................13 
3.7 
Pharmacokinetics ................................................................................................14 


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3.8 
Protocol Deviations.............................................................................................15 
4 
INTERIM ANALYSIS..................................................................................................15 
5 
REFERENCES ..............................................................................................................15 
6 
VERSION HISTORY ...................................................................................................15 
 
LIST OF TABLES 
Table 3.2-1 
Analysis Populations ..............................................................................8 
 
 


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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve  
BMI 
body mass index 
CI 
confidence interval 
 
 
Cmax 
maximum-observed plasma drug concentration 
Ctrough 
trough concentrations from the pre-dose plasma concentration data  
C 
trough concentrations (Ctrough) from the pre-dose plasma drug concentration data 
CV 
coefficient of variation 
DEC 
dose escalation committee 
ECG 
electrocardiogram 
GLP-1 
glucagon-like peptide 1 
HbA1c 
hemoglobin A1c 
HCTD 
highest clinically tolerated dose 
ITT 
Intent-to-Treat 
PK 
pharmacokinetics 
PR 
ECG PR interval 
PT 
MedDRA preferred term or WHO-DDE preferred term 
QRS 
ECG QRS interval 
QT 
ECG QT interval 
QTc 
ECG QT interval corrected for heart rate 
QTcF 
ECG QT interval corrected for heart rate using Fridericia’s formula 
RR 
ECG RR interval 
SAE 
serious adverse event 
SD 
standard deviation 
SOC 
MedDRA system organ class 
SPP 
statistical programming plan 
t1/2 
apparent terminal elimination half-life 
T2DM 
type 2 diabetes mellitus 
TEAE 
treatment-emergent adverse event 
WHO-DDE 
World Health Organization drug dictionary enhanced 


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1 
INTRODUCTION 
This document describes the statistical analysis methodology for protocol D5670C00030, a 
randomized, blinded, placebo-controlled study designed to evaluate the safety, tolerability, 
pharmacokinetics (PK), and efficacy of ascending doses of MEDI0382 in overweight or 
obese subjects with type 2 diabetes mellitus (T2DM). This document details the statistical 
summaries relating to each study objective and describes the general conventions and 
definitions that will be used. In addition, a set of table templates and specifications will be 
included in a statistical programming plan (SPP) to complement this document. 
2 
STUDY OVERVIEW 
2.1 
Study Objectives 
2.1.1 
Primary Study Objective(s) 
Assess the safety and tolerability of MEDI0382 titrated up to a dose of 
 or to the 
highest clinically tolerated dose (HCTD) from a starting dose of 
 
2.1.2 
Secondary Study Objectives 
 To characterize the PK profile of MEDI0382 titrated up to a dose of 
 or to the 
highest clinically tolerated dose (HCTD) 
 To characterize the immunogenicity of MEDI0382 titrated up to a dose of 
 or 
to the HCTD 
 To assess the effects of MEDI0382, titrated up to a dose of 
 or to the HCTD, 
 
 
 To assess the effects of MEDI0382, titrated up to a dose of 
 or to the HCTD, 
on additional measures of glucose control 
 To assess the effects of MEDI0382, titrated up to a dose of 
 or to the HCTD, 
on body weight 
 
 
 
 
 
 


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2.2 
Study Design 
This is a randomized, blinded, placebo-controlled study designed to evaluate the safety, 
tolerability, PK and efficacy of ascending doses of MEDI0382 in overweight or obese 
subjects with T2DM. This study will enroll subjects aged 18 to 74 years with a body mass 
index (BMI) 27 to 35 kg/m2. Subjects will have a diagnosis of T2DM and inadequate blood 
glucose control as defined by a hemoglobin A1c (HbA1c) of 6.5% to 8.5% and will be on 
metformin monotherapy. 
Twenty subjects will be enrolled to 2 cohorts: Cohort 1 (n = 8) and Cohort 2 (n = 12). For 
each cohort, subjects will be randomly assigned in a 3:1 ratio to receive MEDI0382 at doses 
titrated 
or placebo. The study has a run-in 
period of 10 days and an up to 8-week up-titration treatment period (for the primary analysis) 
followed by a 3-week treatment extension period at the HCTD followed by a 28-day follow-
up period. 
In Cohort 1, MEDI0382 or matched placebo will be administered daily starting at 
 with 
the dose up-titrated weekly to 
, or until the HCTD is 
established (whichever occurs first). The dose escalation committee (DEC) will review 72-
hour safety data when subjects reach the 
 dose levels to determine if the 
HCTD is established as these doses have not been previously studied in T2DM subjects and 
the safety profile is unknown. If the DEC determines that the current dose level is not being 
tolerated and does not approve progression to the next dose level, the preceding one will be 
declared as the HCTD. 
Subjects in Cohort 2 will follow the up-titration schedule defined by Cohort 1, with the 3-
week treatment extension period being conducted at the HCTD; thus, the duration of Cohort 
2 subjects’ participation in the study will be determined by the results obtained from Cohort 
1. Dosing in Cohort 2 will occur ≥ 7 days after initiation of Cohort 1 (Figure 2.2-1). 
Figure 2.2-1 Study Flow Diagram 


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2.3 
Treatment Assignment and Blinding 
Subjects will be randomized using a 3:1 ratio to receive either MEDI0382 or placebo via 
manual randomization. 
This is a blinded study in which the subjects and investigator and staff performing 
evaluations are blinded to the identity of investigational product, while MedImmune staff 
involved in the study are unblinded. Investigational product and placebo are indistinguishable 
in appearance, identically labelled, and supplied as fully blinded kits. 
2.4 
Sample Size 
The total study sample size is 20 subjects, who will be randomized by 2 cohorts: 8 subjects in 
Cohort 1 and 12 subjects in Cohort 2. For each cohort, subjects will be randomized in a 3:1 
ratio to the MEDI0382 arm or the placebo arm. The sample size for this study was 
empirically determined to obtain adequate safety and tolerability evaluation. 
 
 
 


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3 
STATISTICAL METHODS 
3.1 
General Considerations 
Data will be presented in data listings sorted by treatment, dose, subject number, and date 
collected, where appropriate. Tabular summaries will be presented by treatment arm. 
Categorical data will be summarized by the number and percentage of subjects in each 
category. Continuous variables will be summarized with descriptive statistics (eg, n, mean, 
median, SD, minimum, and maximum).  
Analyses will be conducted for each cohort and for the two cohorts combined. Formal 
statistical modeling analysis for the secondary efficacy endpoints will be conducted for the 
two-cohort combined analyses. In general, unless stated otherwise, baseline will be defined 
as the last value prior to dosing. 
Two analyses are planned for this study as follows: 
1 
A primary analysis after the up-titration period for Cohort 2, and 
2 
A final analysis after the safety follow-up period for Cohort 2. 
Data analyses will be conducted using the SAS® System Version 9.4 or higher (SAS Institute 
Inc., Cary, NC) in a UNIX platform. 
3.2 
Analysis Populations 
The analysis populations are defined in Table 3.2-1. 
Table 3.2-1 
Analysis Populations 
Population 
Description 
As-treated 
population 
Subjects who receive any study investigational product will be included in 
the As-treated population and subjects will be analyzed according to the 
treatment they actually receive. 
Intent-to-treat 
population (ITT) 
Subjects who receive any study investigational product will be included in 
the ITT population and subjects will be analyzed according to the 
treatment they were randomized 


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Table 3.2-1 
Analysis Populations 
Population 
Description 
PK population 
Subjects who have at least one measurable concentration time point of 
MEDI0382 
Immunogenicity 
Population 
Subjects in the As-treated population who have at least one serum sample 
for immunogenicity testing 
 
3.3 
Study Subjects 
3.3.1 
Subject Disposition and Completion Status 
A summary of subject eligibility and randomization (including a summary of subjects 
randomized but not treated with investigational product as well as treatment administered) 
will be provided. In addition, disposition of subjects throughout the study with respect to 
dose administered and completion of treatment and follow-up will be provided. This 
summary will include the number of subjects who discontinued treatment. 
3.3.2 
Demographics and Baseline Characteristics 
Demographic information related to sex, age, race, ethnicity, weight, height, and BMI will be 
summarized by treatment group and for all subjects for the As-treated population. A 
summary of baseline characteristics may include, but is not limited to, duration of diabetes, 
diabetes complications, baseline fasting plasma glucose, and baseline HbA1c. 
3.3.3 
Study Drug Exposure 
The duration of exposure (number of days dosed) of MEDI0382 will be summarized by 
treatment group with descriptive statistics and frequencies. 
3.3.4 
Concomitant Medications 
Concomitant medications will be coded using the current World Health Organization Drug 
Dictionary Enhanced (WHO-DDE). The number and percentage of subjects who took 
concomitant medications for the highest anatomical therapeutic chemical class and preferred 
term will be summarized by treatment for the As-treated population. The summary of 
concomitant medications will include all concomitant medications taken on or after the date 
of first dose of investigational product or any concomitant medication started prior to first 
dose of investigational product that continued beyond the date of first dose of investigational 
product. 


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3.4 
Efficacy Analyses 
3.4.1 
Primary Efficacy Endpoint(s) and Analyses 
There are no primary efficacy endpoints in this study. 
3.4.2 
Secondary Efficacy Endpoint(s) and Analyses 
3.4.2.1 
Secondary Efficacy Endpoint(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Change in estimated HbA1c (eA1c) from baseline to the end of each week of the up-
titration period and the end of the treatment extension period 
 Change in plasma fasting glucose from Day -1 versus each week of the up-titration 
period, the end of the up-titration period, and the end of the treatment extension 
period 
 Change in HbA1c from Day -1 to the end of the treatment extension period 


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 Percentage and absolute change in body weight from baseline to the end of the up-
titration period and the end of the treatment extension 
 Percentage and absolute change in body weight from baseline to the end of each week 
of the up-titration period 
 Proportion of subjects achieving > 5% body weight loss from baseline to the end of 
the treatment extension period. 
3.4.2.2 
Handling of Dropouts and Missing Data 
Last observation carried forward approach will be used to handle missing data for all 
secondary efficacy analyses. 
 
 
3.4.2.3 
Secondary Efficacy Analyses 
The secondary efficacy analyses will be based on the ITT population. The continuous 
secondary efficacy endpoints for the two-cohort combined analysis will be compared 
between the MEDI0382 and placebo arms using an analysis of covariance (ANCOVA) 
model adjusting for baseline value and treatment arm. For the secondary proportion-related 
efficacy endpoints, a logistic regression model will be used adjusting for baseline value and 
treatment arm. For each cohort, the secondary efficacy endpoints will be summarized without 
formal statistical comparisons. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.5 
Safety Analyses 
All safety analyses will be based on the As-treated population. 
3.5.1 
Adverse Events and Serious Adverse Events 
Adverse events (AEs) will be coded with Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.0 or later. Analysis of AEs will include the type, incidence, severity, 
and relationship to investigational product summarized by MedDRA system organ class 
(SOC) and preferred term (PT) by treatment group as well as overall. The AEs summarized 
will include only treatment-emergent AEs (TEAEs), ie, those starting after the first 
administration of investigational product. Subjects will be counted once for specific PT or 
MedDRA SOC when calculating incidence rates. If the same AE PT occurs multiple times 
within a subject, the highest severity and level of relationship observed will be reported. If 
any associations of interest between AEs and baseline characteristics are observed, additional 
stratified results may be presented. Non-TEAEs and serious adverse events (SAEs) will be 
presented in the listings.  
The incidence and event rate of nausea, vomiting, and nausea/vomiting on each study day 
during the titration period 
 
will be summarized.  Note that this is not just onset of a new event but includes each day the 
subject experiences the event excluding the AE stop day. A similar analysis including event 
rates will be performed for each titration dosing periods: 
 
 
 
3.5.2 
Adverse Events of Special Interest 
No adverse events of special interest are identified in the protocol. 
3.5.3 
Deaths and Treatment Discontinuations due to Adverse Events 
A listing of any death will be provided and will include the MedDRA SOC and PT. AEs 
resulting in permanent discontinuation of investigational product will be summarized by 
treatment. The summary will include results summarized overall and by MedDRA SOC and 
PT. 
3.5.4 
Clinical Laboratory Evaluation 
Hematology, serum chemistry, and urinalysis laboratory evaluations will be performed 
during the study. The hematology and serum chemistry (including lipase and amylase) 
parameters as well as their changes from baseline and percent changes from baseline will be 


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summarized with descriptive statistics by treatment group. Other laboratory parameters 
collected will be summarized in a similar manner. The hematology and serum chemistry 
results (within reference range), or high (above upper limit of reference range). The 
urinalysis results will also be classified as low (below lower limit of reference range), and 
normal results will be classified as normal or abnormal. The shift from baseline for 
hematology, serum chemistry, and urinalysis results will be summarized by treatment at each 
evaluation time. 
3.5.5 
Other Safety Evaluations 
3.5.5.1 
Vital Signs 
Vital signs including pulse rate (beats/min), systolic and diastolic blood pressure (mmHg), 
temperature (oC), and respiratory rate (breaths/min), as well as their change from baseline 
will be descriptively summarized by treatment at each visit. 
3.5.5.2 
Ambulatory Blood Pressure Measurements 
Mean systolic blood pressure, diastolic blood pressure, and heart rate over the 24-hour 
collection for 3 periods (awake, asleep, and complete) will be descriptively summarized by 
treatment at each visit. Mean change from baseline of these parameters will be analyzed 
using an ANCOVA model adjusting for treatment and baseline value at end of dosing period 
and treatment extension. 
3.5.5.3 
Electrocardiogram 
Triplicate electrocardiogram (ECG) will be performed using a digitally recorded standard 12-
lead electrocardiograph. For each ECG parameter (heart rate, RR, PR, QRS, QT interval, and 
the derived parameter QT corrected interval QTcF (Fridericia’s formula 
𝑄𝑇
√𝑅𝑅
3
), the average of 
the 3 values will be analyzed. The change from baseline (Day -1) to each post-baseline 
evaluation will be summarized with descriptive statistics. Results for the qualitative ECG 
interpretation (normal or abnormal) will be summarized with frequencies and percentages at 
each evaluation. 
 
 
 
3.6 
Immunogenicity 
Analysis of immunogenicity will be based on the Immunogenicity population. The incidence 
and impact of anti-drug antibody (ADA) to MEDI0382 will be evaluated. The number and 
percentage of subjects with confirmed positive serum antibodies to MEDI0382 will be 


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reported by treatment. Titer data and cross-reactivity to glucagon-like peptide 1 (GLP-1) and 
glucagon (if applicable) will be listed. 
The following categories will be utilized to describe the ADA response: 
 ADA prevalence: subjects who are ADA positive at any visit (including baseline) 
 Subjects who are ADA positive at baseline only 
 Subjects who are ADA positive at baseline and positive post baseline 
 Subjects who are ADA positive post-baseline only (treatment-induced ADA) 
 Proportion of subjects who are treatment-boosted ADA; treatment-boosted ADA is 
defined as baseline ADA titer that was boosted to a 4-fold or higher level following 
drug administration 
 ADA incidence (treatment-emergent ADA), defined as the sum of treatment-induced 
ADA (post-baseline positive only) and treatment-boosted ADA 
A similar summary will be performed for ADA cross-reactivity to GLP-1 and/or glucagon 
(as data allows and if applicable). 
3.7 
Pharmacokinetics 
PK parameters will be calculated from plasma drug concentration-time data for MEDI0382 
for subjects in the PK population. Descriptive statistics will be generated for PK parameters. 
However, the results of these analyses will be provided in the bioanalytical report that is 
prepared by the bioanalyst and pharmacokineticist; therefore, no tables, figures, or listings of 
PK data will be specified in the SPP. 
Actual time of sampling, rather than nominal (planned) sampling time, will be used to derive 
PK parameters. Nominal sampling time will be used for the summary of PK concentrations 
and will be utilized in the descriptive summaries in mean and median plots. Missing PK 
parameters will not be imputed. 
The PK parameters will be calculated by standard non-compartmental analysis according to 
current working practices and using Phoenix 64 or equivalent. All calculations of non-
compartmental parameters will be based on actual sampling times. 
The following PK parameters of MEDI0382 will be determined, if data allow, for each 
subject from the plasma concentration-time data: 
1. Cmax: The first occurrence of the maximum observed plasma concentration determined 
directly from the raw concentration-time data. 
2. tmax: The first time at which Cmax is observed will be determined directly from the raw 
concentration-time data. 


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3. C: trough concentrations from the plasma concentration-time data defined as pre-
dose samples. 
4. t1/2: The apparent terminal elimination half-life obtained as the ratio of ln2/z, where 
z is the terminal phase rate constant estimated by linear regression analysis of the log 
transformed concentration-time data. 
5. AUC following the last dose until the last measurable concentration (AUC0-last). 
6. AUCτ: AUC at the end of the dosage interval τ. 
7. Ro: observed accumulation ratio will be calculated using both the AUC and Ctrough 
methods, where data allows, as follows: Ro = AUCdayi/AUCday1 and Ro = 
Cdayi/Cday1. 
All derived parameters described above will be listed. For each of these parameters, except 
tmax, the following summary statistics will be calculated for each dose group: median, 
maximum, minimum, arithmetic mean, standard deviation, coefficient of variation (CV), 
geometric mean. For tmax the following summary statistics will be calculated: median, 
maximum, minimum, arithmetic mean and geometric mean. Individual Ctrough will be listed 
by day and will be summarized as maximum, minimum, arithmetic mean, median, and 
geometric mean. 
 
 
  
3.8 
Protocol Deviations 
A listing of important protocol deviations will be provided. 
4 
INTERIM ANALYSIS 
No interim analyses are planned; however, the DEC will be evaluating the data periodically 
to determine whether to escalate the dose. 
5 
REFERENCES 
None 
6 
VERSION HISTORY 
Version 
Date 
Summary of Changes 
Reason for Change 
1.0 
19JAN2019 
Initial document 
Initial document 
 


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