Clinical trial NCT02548585
Conditions: Type 2 Diabetes Mellitus
Keywords: MEDI0382, diabetes
Sponsor: MedImmune LLC
Start date: 2015-12-09; Completion date: 2017-02-24
Enrollment: 113 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 1/2, multiple dose study with 6 cohorts of ascending doses designed to evaluate the efficacy, safety and pharmacokinetics (PK) of MEDI0382 in participants with Type 2 Diabetes Mellitus (T2DM).

Detailed description:
This is a randomized, double-blind, placebo controlled study designed to evaluate the efficacy, safety, and PK of MEDI0382 administered as multiple daily SC doses to participants with T2DM. Approximately one hundred and seven participants will be enrolled across 6 cohorts. In cohorts 1-3 the participants will be randomized to MEDI0382 or placebo (2:1). In Cohort 4, participants will be randomized to MEDI0382 or placebo (1:1). In cohort 5 and 6 participants will be randomized to MEDI0382 or placebo (3:1).

Arms: arm 1: Participants will receive placebo (matched to either 100 micrograms \[mcg\], or 150 mcg or 200 mcg or 300 mcg of MEDI0382) subcutaneously (SC) once daily from Day 1 to Day 7 (Cohort 1); or Day 1 to Day 11 (Cohort 2); or Day 1 to Day 15 (Cohort 3); or Day 1 to Day 41 (Cohort 4); or Day 1 to Day 22 (Cohort 5); or Day 1 to Day 17 (Cohort 6). arm 2: Participants will receive MEDI0382 100 mcg SC once daily from Day 1 to Day 7. arm 3: Participants will receive MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4) and thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 7 days (Day 5 to Day 11). arm 4: Participants will receive MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 7 days (Day 9 to Day 15). arm 5: Participants will receive MEDI0382 100 mcg SC once daily for at least 4 days (Day 1 to Day 4); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 4 days (Day 5 to Day 8); followed by second up titrated dose of MEDI0382 200 mcg SC once daily for 4 days (Day 9 to Day 12), then a further MEDI0382 200 mcg SC once daily for 28 days (Day 13 to Day 40) at home-dosing; followed by MEDI0382 200 mcg SC once daily for 1 day in hospital (Day 41). arm 6: Participants will receive MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 150 mcg SC once daily for 5 days (Day 6 to Day 10); then a second up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 11 to Day 15); followed by third up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 16 to Day 22). arm 7: Participants will receive MEDI0382 100 mcg SC once daily for at least 5 days (Day 1 to Day 5); thereafter, an up titrated dose of MEDI0382 200 mcg SC once daily for 5 days (Day 6 to Day 10); followed by a second up titrated dose of MEDI0382 300 mcg SC once daily for 7 days (Day 11 to Day 17).
Interventions: intervention 1: MEDI0382 intervention 2: Placebo
Intervention descriptions: intervention 1: MEDI0382 administered subcutaneously. intervention 2: Placebo administered subcutaneously.

Protocol documents:
Prot_000.pdf: 
MedImmune
Protocol D5670C00002
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A Phase 1/2, Randomized, Double-blind,
Placebo-controlled, Multiple-ascending-dose Study
to Evaluate the Efficacy, Safety, and Pharmacokinetics
of MEDI0382 in Overweight and Obese Subjects
with a History of Type 2 Diabetes Mellitus
Sponsor Protocol Number: D5670C00002
Application Number:
EudraCT Number 2014-003716-36
Investigational Product:
MEDI0382
Sponsor:
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca PLC
Milstein Building, Granta Park
Cambridge, CB21 6GH
United Kingdom
Medical Monitor:
, MedImmune
Phone: 
; Fax: 
Contract Research Organization: Covance, Inc.
Protocol History, Date:
Original Protocol, 25Nov2014, 
Amendment 1, 26Feb2015
Amendment 2, 14Aug2015
Amendment 3, 10Oct2015
Administrative Change 1, 05Nov2015
Amendment 4, 18Mar2016
Amendment 5, 27Apr2016
Amendment 6, 21Jul2016
Amendment 7, 25Aug2016
Amendment 8, 23Sep2016


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ..........................................................................................................8
LIST OF ABBREVIATIONS..................................................................................................13
1
INTRODUCTION.........................................................................................................16
1.1
Disease Background ...........................................................................................16
1.2
MEDI0382 Background......................................................................................16
1.3
Summary of Nonclinical Experience..................................................................17
1.5
Rationale for Conducting the Study ...................................................................20
1.6
Research Hypotheses ..........................................................................................22
1.6.1Primary Hypothesis.....................................................................................22
1.6.2Secondary Hypotheses................................................................................22
2
OBJECTIVES ...............................................................................................................22
2.1
Objectives ...........................................................................................................22
2.1.1Primary Objective.......................................................................................22
2.1.2Secondary Objectives .................................................................................22
2.1.3Exploratory Objectives ...............................................................................23
2.2
Study Endpoints..................................................................................................23
2.2.1Primary Endpoints ......................................................................................23
2.2.2Secondary Endpoint(s)................................................................................23
2.2.3Exploratory Endpoint(s) .............................................................................24
3
STUDY DESIGN..........................................................................................................25
3.1
Description of the Study .....................................................................................25
3.1.1Overview 25
3.1.2Treatment Regimen.....................................................................................28
3.1.3Cohort Progression .....................................................................................29
3.1.3.1
Progression of Cohorts within this MAD Study.......................29
3.1.3.2
Cardiac Stopping Criteria .........................................................31
3.1.4Management of Toxicities and Dose Modification ....................................32
3.2
Study Design 
3.2.2Rationale for Study Population...................................................................37
3.2.3Rationale for Endpoints ..............................................................................38
4
MATERIALS AND METHODS..................................................................................40
4.1
Subjects...............................................................................................................40
4.1.1Number of Subjects ....................................................................................41
4.1.2Inclusion Criteria ........................................................................................41


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4.1.3Exclusion Criteria .......................................................................................42
4.1.4Subject Enrollment and Randomization .....................................................45
4.1.5Withdrawal from the Study.........................................................................46
4.1.6Discontinuation of Investigational Product ................................................46
4.1.7Replacement of Subjects.............................................................................47
4.1.8Withdrawal of Informed Consent for Data and Biological Samples..........47
4.2
Schedule of Study Procedures ............................................................................48
4.2.1Enrollment/Screening Period......................................................................48
4.2.2Randomized Treatment Period ...................................................................50
4.2.3Follow-up Period ........................................................................................86
4.2.4Early Discontinuation or Unscheduled Study Visit....................................86
4.3
Description of Study Procedures ........................................................................87
4.3.1Efficacy
87
4.3.1.1
Mixed-meal Test.......................................................................87
4.3.1.2
Weight 87
4.3.2Medical History, Physical Examination, Electrocardiograms, and Vital 
Signs..........................................................................................87
4.3.2.1
Medical History and Physical Examination..............................87
4.3.2.2
Assessment of the Injection Site...............................................88
4.3.2.3
Electrocardiograms ...................................................................88
4.3.2.4
Vital Signs.................................................................................89
4.3.3Clinical Laboratory Tests............................................................................90
4.3.4Estimate of Volume of Blood to Be Collected ...........................................92
4.3.5Glucometer Blood Glucose Readings during the Inpatient Period.............92
4.3.6Pharmacokinetic Evaluation and Methods .................................................92
4.3.7Pharmacodynamic Evaluation and Methods...............................................93
4.3.8Combined Pharmacokinetic and Pharmacodynamic Blood Sampling 
Example Schedule.....................................................................94
4.3.9Immunogenicity Evaluation and Methods..................................................95
4.3.10Exploratory Endpoints Evaluations and Methods 
, 
 Magnetic Resonance Imaging)......................96
 
 
 
96


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4.3.10.6
Magnetic Resonance Imaging of the 
Liver/Abdomen (Cohort 4).........................................97
4.3.11Questionnaires ..........................................................................................97
4.3.11.1
Columbia-Suicide Severity Rating Scale (Cohorts 
4, 5, and 6)..................................................................97
4.3.12Training of Cohorts 4, 5, and 6 Subjects for At-home Activities.............97
4.3.12.1
Training for Self-administration and At-home 
Preparation of Investigational Product.......................97
4.3.12.2
Training during the Inpatient Period for Using the 
Standardized Glucometers during the Inpatient and 
Outpatient Periods......................................................98
4.3.12.3
Training for Completing the Daily Diaries during 
the At-home Self-administration Period ....................98
4.3.12.4
Training for Application and Wearing of ABPM 
Device.........................................................................99
4.4
Study Suspension or Termination.....................................................................100
4.5
Investigational Products....................................................................................101
4.5.1Identity of Investigational Product(s) .......................................................101
4.5.1.1
Identity of Investigational Product(s) .....................................101
4.5.1.2
Investigational Product Handling ...........................................102
4.5.1.3
Investigational Product Inspection..........................................102
4.5.1.4
Dose Preparation Steps ...........................................................103
4.5.1.5
Treatment Administration.......................................................106
4.5.1.6
Monitoring of Dose Administration .......................................107
4.5.1.7
Reporting Product Complaints................................................107
4.5.2Additional Study Medications ..................................................................108
4.5.3Labeling
108
4.5.4Storage
108
4.5.5Treatment Compliance..............................................................................108
4.5.6Accountability...........................................................................................108
4.6
Treatment Assignment and Blinding................................................................109
4.6.1Methods for Assigning Treatment Groups ...............................................109
4.6.2Methods for Ensuring Blinding ................................................................109
4.6.3Methods for Unblinding............................................................................110
4.6.3.1
Unblinding in the Event of a Medical Emergency .................110
4.7
Restrictions during the Study and Concomitant Treatment(s)..........................110
4.7.1Permitted Concomitant Medications ........................................................110
4.7.2Prohibited Concomitant Medications .......................................................110
4.8
Statistical Evaluation ........................................................................................111


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4.8.1General Considerations.............................................................................111
4.8.2Sample Size and Power Calculations........................................................112
4.8.3Efficacy
112
4.8.3.1
Primary Efficacy Analysis......................................................112
4.8.3.2
Secondary Efficacy Analysis..................................................113
4.8.4Safety
113
4.8.5Pharmacokinetics/Immunogenicity ..........................................................114
4.8.6Pharmacodynamics Analyses ...................................................................114
4.8.7Subject Diaries and Glucometer Blood Glucose (Cohorts 4, 5, and 6) ....114
4.8.8Exploratory Analyses................................................................................115
4.8.9Dose Escalation Committee......................................................................115
4.8.10Interim Analysis......................................................................................115
5
ASSESSMENT OF SAFETY .....................................................................................116
5.1
Definition of Adverse Events ...........................................................................116
5.2
Definition of Serious Adverse Events ..............................................................116
5.3
Definition of Adverse Events of Special Interest .............................................117
5.4
Recording of Adverse Events ...........................................................................118
5.4.1Time Period for Collection of Adverse Events.........................................118
5.4.2Follow-up of Unresolved Adverse Events................................................118
5.5
Reporting of Serious Adverse Events...............................................................118
5.6
Other Events Requiring Immediate Reporting .................................................119
5.6.1Overdose...................................................................................................119
5.6.2Hepatic Function Abnormality .................................................................120
5.6.3Pregnancy..................................................................................................120
5.6.3.1
Maternal Exposure..................................................................120
5.6.3.2
Paternal Exposure ...................................................................120
6
STUDY AND DATA MANAGEMENT....................................................................120
6.1
Training of Study Site Personnel......................................................................120
6.2
Monitoring of the Study....................................................................................121
6.2.1Source Data...............................................................................................121
6.2.2Study Agreements.....................................................................................121
6.2.3Archiving of Study Documents ................................................................122
6.3
Study Timetable and End of Study...................................................................122
6.4
Data Management.............................................................................................122
6.5
Medical Monitor Coverage...............................................................................122
7
ETHICAL AND REGULATORY REQUIREMENTS ..............................................123
7.1
Ethical Conduct of the Study............................................................................123
7.2
Subject Data Protection ....................................................................................123


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7.3
Ethics and Regulatory Review..........................................................................123
7.4
Informed Consent .............................................................................................124
7.5
Changes to the Protocol and Informed Consent Form......................................125
7.6
Audits and Inspections......................................................................................125
8
REFERENCES............................................................................................................126
9
CHANGES TO THE PROTOCOL.............................................................................129
9.1
Amendment 8, 23Sep2016................................................................................129
9.2
Amendment 7, 25Aug2016...............................................................................133
9.3
Amendment 6, 21Jul2016.................................................................................133
9.4
Amendment 5, 27Apr2016 ...............................................................................136
9.5
Amendment 4, 18Mar2016...............................................................................136
9.6
Administrative Change 1, 05Nov2015 .............................................................144
9.7
Amendment 3, 10Oct2015................................................................................144
9.8
Amendment 2; 14Aug2015...............................................................................145
9.9
Amendment 1; 26Feb2015................................................................................150
LIST OF IN-TEXT TABLES
Table 3.2.1-1
Proposed Study Doses and Predicted Safety Margins Based on Rat and 
Cynomolgus Monkey Data ..................................................................36
Table 4.1.2-1
Highly Effective Methods of Contraception........................................42
Table 4.2.1-1
Schedule of Screening Procedures.......................................................48
Table 4.2.2-1
Schedule of Treatment Period Procedures: Cohort 1...........................51
Table 4.2.2-2
Schedule of Treatment Period Procedures: Cohort 2...........................54
Table 4.2.2-3
Schedule of Treatment Period Procedures: Cohort 3...........................58
Table 4.2.2-4
Schedule of Treatment Period Procedures: Cohort 4 Overview..........62
Table 4.2.2-5
Schedule of Treatment Period Procedures: Cohort 4 Self-
administration Dosing Period Detail....................................................69
Table 4.2.2-6
Schedule of Treatment Period Procedures: Cohort 5 Overview..........73
Table 4.2.2-7
Schedule of Treatment Period Procedures: Cohort 6 Overview..........79
Table 4.2.3-1
Schedule of Follow-up Procedures: All Cohorts .................................86
Table 4.3.8-1
Example Schedule for MEDI0382 PK and for PD Blood Sample 
Collections on Day 7 (Cohort 1), Day 11 (Cohort 2), Day 15 (Cohort 
3), and Day 41 (Cohort 4), Day 22 (Cohort 5), and Day 17 (Cohort 6)94
Table 4.5.1.1-1
Identification of Investigational Products..........................................101
Table 4.5.1.4-1
Cohorts 1–3 MEDI0382 and Placebo Dose Preparation....................103
Table 4.5.1.4-2
Cohort 4 MEDI0382 and Placebo Dose Preparation.........................104
Table 4.5.1.4-3
Cohort 5 MEDI0382 and Placebo Dose Preparation.........................104
Table 4.5.1.4-4
Cohort 6 MEDI0382 and Placebo Dose Preparation.........................105


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LIST OF IN-TEXT FIGURES
Figure 3.1.1-1
Study Flow Diagram............................................................................28
Figure 3.2.1-1
Predicted Activity on GLP-1 Receptor for Liraglutide and MEDI038235
LIST OF APPENDICES
Appendix 1
Signatures...........................................................................................153
Appendix 2
Additional Safety Guidance...............................................................156
Appendix 3
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis .....159
Appendix 4
Columbia-Suicide Severity Rating Scale...........................................160
Appendix 6
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s law ......................................................................168


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PROTOCOL SYNOPSIS
TITLE  
A Phase 1/2, Randomized, Double-blind, Placebo-controlled, Multiple-ascending-dose Study to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Overweight and Obese Subjects with a History of 
Type 2 Diabetes Mellitus
HYPOTHESES  
Primary Hypothesis:
MEDI0382 will achieve an improvement in glucose control equivalent to at least that achieved by oral therapies
in addition to metformin (≥20% reduction in glucose area under the concentration-time curve [AUC] after a 
mixed-meal test [MMT]), and at least comparable weight loss to that expected of liraglutide at the 1.8 mg dose
(ie, between 1.3 and 2.0 kg) versus placebo following 4 weeks of repeat once-daily dosing in subjects with type 
2 diabetes mellitus (T2DM) managed on metformin.
Secondary Hypotheses:
•
MEDI0382 will achieve an improvement in glucose control as measured by hemoglobin A1c (HbA1c) and 
fructosamine following 4 weeks of repeat once-daily dosing.
•
Gastrointestinal symptoms will be manageable during up-titration of MEDI0382, no adverse changes in 
cardiac and hemodynamic parameters will be observed, and the overall safety profile of MEDI0382 will be 
acceptable over up to 4 weeks of repeat once-daily dosing.
OBJECTIVES
Primary Objective:
The primary objective of this study is to assess the effect of MEDI0382 on glucose control (as measured by the 
standardized MMT glucose data) and body weight from baseline to the end of a 4-week treatment period at a 
stable dose.
Secondary Objectives: 
1.
To assess the effect of MEDI0382 on glucose control as measured by the standardized MMT, HbA1c,
and fructosamine data from baseline through end of treatment
2.
To characterize the safety profile of MEDI0382 following subcutaneous (SC) administration of 
multiple-ascending doses
3.
To characterize the pharmacokinetics (PK) and immunogenicity of MEDI0382
4.
To characterize the pharmacodynamics (PD) effect of MEDI0382 on glucose metabolism following a 
MMT
Exploratory Objectives:
 
5.
To explore the effect of MEDI0382 on the volume and fat/water content of the liver 
6.
To explore the effect of MEDI0382 on visceral and subcutaneous fat
STUDY ENDPOINTS
Primary Endpoints (Cohort 4 only):
•
Percent change from baseline in MMT glucose AUC (up to 240 minutes post-MMT) to end of treatment 
•
Change from baseline in body weight in kg to end of treatment
Secondary Endpoints (all cohorts unless stated otherwise): 
•
Change from baseline in HbA1c and fructosamine, and percent change from baseline in 24-hour glucose 
AUC post-MMT, through end of treatment (Cohort 4)
•
Percent change from baseline in MMT glucose AUC (up to 240 minutes post-MMT) to end of treatment 
•
Change from baseline in body weight in kg to end of treatment


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•
Adverse events
•
Blood pressure
•
Pulse
•
Safety laboratory test results
•
Electrocardiograms (ECGs)
•
Columbia-Suicide Severity Rating Scale score (Cohorts 4, 5, and 6 only)
•
PK endpoints for MEDI0382: AUC over a dosing duration, maximum observed concentration, minimum 
observed concentration, time to maximum observed concentration (all cohorts); terminal half-life and 
accumulation ratio (Cohorts 1 to 3 only)
•
Concentration of metformin
•
Development of antidrug antibody (ADA) and titer (if positive) 
•
PD endpoints (glucose metabolism panel): 
◦
Glucose
◦
Beta cell health: insulin, pro-insulin, and c-peptide
◦
Incretins: glucagon-like peptide-1, glucagon, gastric inhibitory peptide
◦
Cohorts 5 and 6: insulin and glucose only
Exploratory Endpoints (Cohort 4 only unless stated otherwise):
•
•
Lipid endpoints: fasting high-density lipoprotein, low-density lipoprotein, triglycerides, non-esterified fatty 
acids, and beta-hydroxybutyrate (Cohorts 4, 5, and 6)
•
 
 
 
•
Change from baseline to Week 4 in:
◦
Liver fat (%)
◦
Liver volume (L)
◦
Visceral adipose tissue (L)
◦
Subcutaneous adipose tissue (L)
◦
Liver diffusion
◦
Sagittal diameter (image based)
◦
Transversal diameter (image based)
as determined by magnetic resonance imaging (MRI) to be conducted if MRI is available to the site and 
the subject is suitable for and consents to scan


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STUDY DESIGN
This is a randomized, double-blind (subjects and investigators/site staff blinded; MedImmune unblinded), 
placebo-controlled study in 3 parts (A, B, and C) with approximately 107 overweight or obese subjects with 
relatively well controlled T2DM (without significant late diabetic complications) planned for enrollment across 
approximately 12 study sites. 
Part A is designed to establish a dose titration regimen for MEDI0382 and a maximal effective dose after 
titration, in T2DM subjects maintained on metformin therapy, over a period of approximately 12 days that can 
then be utilized over an extended dosing period (Part B) to establish the efficacy of MEDI0382 on weight and 
glycemic control. Part C is designed to establish the safety and tolerability of a 300 μg dose of MEDI0382, and 
to explore 2 possible up-titration schedules from 100 to 300 μg from a tolerability, safety, and PK/PD 
perspective.
•
Part A consists of 3 cohorts: Cohort 1 consists of a stable dose of investigational product administered daily 
for 7 days (9 subjects), Cohort 2 consists of an initial dose of investigational product for at least 4 days and 
an up-titration step (titration dose 1) for 7 days (9 subjects), and Cohort 3 consists of an initial dose of 
investigational product for at least 4 days, an up-titration step (titration dose 1) for 4 days, and a second up-
titration step (titration dose 2) for 7 days (9 subjects). 
•
Part B consists of 1 cohort. Subjects in Cohort 4 will be dosed at an initial dose of investigational product 
for at least 4 days, an up-titration step (titration dose 1) for 4 days, a second up-titration step (titration 
dose 2) for 4 days, then titration dose 2 for 28 days thereafter at home (approximately 48 subjects).
Progression to Cohort 4 will occur following review of relevant data from Cohorts 1 through 3 
(safety/tolerability, PK, and PD).
•
Part C consists of 2 cohorts: Cohort 5 consists of 16 subjects (12 active, 4 placebo) who will begin dosing at
100 μg for 5 days followed by 5 days at 150 μg, 5 days at 200 μg, and 7 days at 300 μg. Cohort 6 consists 
of a further 16 subjects (12 active, 4 placebo) who will begin dosing at 100 μg for 5 days followed by 
5 days at 200 μg, and 7 days at 300 μg. Cohorts 5 and 6 may run concurrently.
Screening procedures must be performed within the Day -60 to Day -3 window prior to randomization. The 
screening evaluations may be carried out over more than 1 day. Written informed consent and any locally 
required privacy act document authorization must be obtained prior to performing any protocol-specified 
procedures, including screening evaluations. Following screening, the study duration for each subject varies by 
cohort and consists of an inpatient multiple-ascending dose (MAD) or up-titration evaluation period (beginning 
on Day -2 and ending after Day 8 for Cohort 1, Day 12 for Cohort 2, Day 16 for Cohort 3, and Day 13 for 
Cohort 4, and Day 3 for Cohorts 5 and 6) and an outpatient follow-up period.
Cohort 4 will have a 28-day period of at-home self-administration of investigational product (with weekly site 
visits) after the second inpatient up-titration step and before the end of study visit.
Cohorts 5 and 6 will have an initial inpatient period ending on Day 3 followed by at-home self-administration of 
investigational product with a clinic visit at each dose up-titration step until initiation of the 300 μg dose. 
Subjects will have a second inpatient period for the initiation of the 300 μg dose, ending the fourth day at that 
dose, followed by at-home self-administration of investigational product. Subjects will be re-admitted to the 
clinic on the evening prior to the final dose and ending approximately 24 hours after the final dose.
In the event that subjects are not assessed as competent with respect to self-administration of investigational 
product, alternative arrangements will be made for it to be administered by a qualified study site professional.
Subjects will be admitted to and remain in the unit for all doses and all dose levels during the up-titration period
for Cohorts 1 to 4.
Subjects will be admitted to the unit two evenings prior to receiving investigational product to allow for repeat 
assessment of eligibility criteria, measurement of baseline MMT, and to standardize the level of physical 
activity before dosing the following morning. Cohort 4 subjects only will undergo a predose MRI scan of the 
liver/abdomen (if MRI is available to the site and the subject is suitable for and consents to the scan) between 
Day -7 and Day -1. On Day 1, following an overnight fast for a minimum of 8 hours, baseline blood samples 
will be drawn for safety, efficacy, PK, PD, and ADA laboratory tests; 12-lead ECGs will be recorded, and the 
subject will be administered a single subcutaneous (SC) dose of either MEDI0382 or placebo.
The subject will undergo safety tests including ECGs, telemetry, monitoring of vital signs, and assessments of 


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the injection site for potential reactions throughout the day and during the treatment period. Additionally, for 
Cohorts 4, 5, and 6, 24-hour ambulatory blood pressure monitoring will be performed according to the schedule 
of events. Adverse events will be collected throughout the duration of the study.
MMT procedures will be performed on Day -1 and on the last day of the highest dose level achieved for all 
cohorts. Additional time points will include the first day at titration dose 1 (Cohort 2), the first day at titration 
dose 2 (Cohort 3), the day of discharge from the up-titration inpatient period (the fifth day of titration dose 2; 
Cohort 4), the weekly clinic visits during the 28-day period of at-home self-administration (Cohort 4), and at 
baseline (Day -1) and at the start (Day 16 for Cohort 5 and Day 11 for Cohort 6) and end (Day 22 for Cohort 5 
and Day 17 for Cohort 6) of the 300 μg dosing schedule. For the MMT, the subject will consume a standardized 
meal (Ensure Plus®) within 5 minutes, and timed serial blood samples will be obtained for measurement of 
glucose and parameters related to glucose metabolism just before and through 240 minutes after consumption of 
the standardized meal. During the inpatient period, finger prick glucose samples will be collected 15 minutes
(±10 minutes) prior to and 2 hours (±10 minutes) after breakfast, mid-day, and evening meals, and prior to going 
to bed.
Cohort 4 subjects will be re-admitted for an overnight inpatient stay at the end of the at-home 
self-administration period to collect the final endpoints including repeat MRI scan. This postdose MRI scan may 
be done on Day 39, 40, 41, or 42.
Body weight will be measured at multiple time points including (but not limited to) prior to the first dose, during
the inpatient dosing period (and during the outpatient period for Cohort 4), at discharge from the unit, and at the 
7- to 14-day follow-up visit.
Pharmacokinetics samples for MEDI0382 will be obtained pre- and postdose and at various time points by 
cohort up until 48 hours after the last dose of MEDI0382 (for Cohorts 4 to 6 the last sample will be collected 
approximately 24 hours after the last dose). Samples for metformin concentration will be obtained prior to 
MEDI0382 dosing. Antidrug antibodies samples will be obtained predose and at various time points up through 
28 days post final dose.
Subjects will be discharged from the unit the day after their final dose is administered in the study.
A follow-up visit will be performed for final safety assessments approximately 28 days after the last dose of 
investigational product. 
TARGET SUBJECT POPULATION  
The study population will consist of male or female adults, 18 through 65 years of age with T2DM and body 
mass index 27 to 40 kg/m2 (inclusive), without significant late diabetic complications. Subjects should have 
been treated with a stable dose of oral blood glucose lowering therapy for 3 months prior to screening
(metformin monotherapy or metformin plus dipeptidyl peptidase-4 [DPPIV], sulphonylurea [50% of the 
licensed dose], or a sodium-glucose co-transporter 2 [SGLT2]; and DPPIV inhibitor, sulphonylurea, or SGLT2 
inhibitor is washed out prior to randomization). Females of childbearing potential and lactating females will be 
excluded.
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION  
MEDI0382 or matched placebo will be administered once daily via SC injection. 
PART A:
•
Cohort 1, 9 subjects (6 active, 3 placebo) dosed for 7 days at stable dose
•
Cohort 2, 9 subjects (6 active, 3 placebo) dosed for at least 4 days at initial dose, 7 days at titration dose 1
•
Cohort 3, 9 subjects (6 active, 3 placebo) dosed for at least 4 days at initial dose, 4 days at titration dose 1, 
7 days at titration dose 2
PART B:
•
Cohort 4, approximately 48 subjects (24 active, 24 placebo are planned to be dosed) dosed for at least 
4 days at initial dose, 4 days at titration dose 1, 4 days at titration dose 2, then a further 28 days at titration 
dose 2 for at-home dosing followed by 1 day at titration dose 2 as inpatient
The proposed initial dose is 100 μg. Titration doses 1 and 2 have been determined according to emergent data 
on safety, tolerability, PK, and glycemic efficacy. The maximum dose is set at 200 μg/day for Cohort 4 (Part B 
of the study).
PART C:


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!
Cohort 5, 16 subjects (12 active, 4 placebo) dosed for 5 days at 100 μg, 5 days at 150 μg, 5 days at 
200 μg followed by 7 days at 300 μg
!
Cohort 6, 16 subjects (12 active, 4 placebo) dosed for 5 days at 100 μg, 5 days at 200 μg followed by
7 days at 300 μg
The maximum dose of MEDI0382 in Part C is set at 300 μg/day. 
The first 3 dosing days will occur as an inpatient, as will the first 4 days and the final day of 300 μg dosing. The 
first dose of each up-titration step will be administered in the clinic, otherwise dosing on the remaining days will 
occur at home if the investigator is satisfied the subject can accurately self-administer the dose as instructed. 
STATISTICAL ANALYSIS PLAN  
The sample size of 6 subjects in the MEDI0382 group and 3 subjects in the placebo group for Cohorts 1, 2, and 
3 was empirically determined to obtain adequate safety and tolerability evaluation. Under a two-sided 10% 
significance level, a sample size of 44 evaluable subjects (22 per arm) for Cohort 4 will provide 80% power to 
detect weight loss of 1.5 kg versus placebo (assuming a standard deviation of 1.9 kg), and 98% power to detect a 
20% relative reduction in MMT glucose AUC (up to 240 minutes post-MMT) versus placebo at the end of 
treatment (assuming a coefficient of variation [CV] of 17%). (Internal data from another investigational agent 
for T2DM showed a CV of 17% for 24-hour glucose AUC, and the CV for glucose AUC [up to 240 minutes 
post-MMT] is expected to be similar.) The sample size for Cohort 4 is adjusted to 48 subjects (24 per arm) to 
account for a 10% drop-out rate. For Cohorts 5 and 6, under a one-sided 2.5% significance level the 
combination of 24 subjects on MEDI0382 and 8 subjects on placebo from both cohorts will provide 80% power 
to rule out more than 20% of MEDI0382 subjects having > 5 mm Hg increase from baseline in diastolic blood 
pressure (BP) on the seventh day of the 300 μg dose level (Day 22 for Cohort 5 and Day 17 for Cohort 6) 
relative to that of placebo subjects, under the assumption that both placebo and MEDI0382 subjects have a true 
rate of 1% with > 5 mm Hg increase from baseline in diastolic BP. Moreover, under a one-sided 2.5% 
significance level, this sample size will provide 88% power to rule out > 20 beats per minute (bpm) pulse rate 
increase from baseline on the seventh day of the 300 μg dose level in MEDI0382 subjects relative to that of 
placebo subjects with assumed standard deviation of 15 bpm.
Efficacy endpoints including the percent change in MMT glucose AUC and the change in HbA1c, fructosamine,
and weight, from baseline to the end of treatment will be compared between the MEDI0382 and placebo groups 
using analysis of covariance by adjusting for measurement at baseline and treatment group. Descriptive analyses 
will be provided for safety endpoints in each cohort.
Pharmacokinetic parameters such as maximum concentration (Cmax), time to maximum observed concentration 
(Tmax), AUC, elimination half-life, and accumulation ratio will be estimated from plasma concentration-time 
data for MEDI0382 if data permit. Descriptive statistics will be generated for PK parameters for the MEDI0382 
group in each cohort. Subjects who have at least one measurable concentration time point of investigational 
product will be used for this analysis.
With respect to metformin PK, changes in metformin levels over time will be evaluated, as will any association 
between baseline metformin dose and change in metformin levels over time in the clinical study. In the event 
that a reduction in metformin levels is seen in Cohorts 1-3, an exploratory analysis will be performed to examine 
the relationship between changes in metformin level and glucose control over time.
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 cohort. If warranted by the data, the 
association of ADA positivity with observed PK data and safety may be explored.


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ABPM
ambulatory blood pressure monitoring
ADA
antidrug antibody
AE
adverse event
AESI
adverse event of special interest
ALT
alanine transaminase
AST
aspartate transaminase
AUC
area under the concentration-time curve
AV
atrioventricular
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CDER
Center for Drug Evaluation and Research
Cmax
maximum observed concentration
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
coefficient of variation
DEC
Dose Escalation Committee
dECG
digital electrocardiogram
DIO
diet-induced obese
DPPIV
dipeptidyl peptidase-4
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
 
FTIH
first-time-in-human
GFR
glomerular filtration rate
GI
gastrointestinal
GIP
gastric inhibitory peptide
GLP-1
glucagon-like peptide-1
GMP
Good Manufacturing Practice
HbA1c
hemoglobin A1c (glycated hemoglobin)
HDL
high-density lipoprotein
Hg
mercury
HIV
human immunodeficiency virus
HL
Hy’s Law


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Abbreviation or 
Specialized Term
Definition
HOMA
Homeostasis Model Assessment
HR
heart rate
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IR
insulin resistance
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous(ly)
IXRS
interactive voice or web response system
LDL
low-density lipoprotein
MAD
multiple-ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MDRD
Modification of Diet in Renal Disease
MMT
mixed-meal test
MRI
magnetic resonance imaging
NASH
non-alcoholic steatohepatitis
NOAEL
no-observed-adverse-effect level
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PR (PQ)
electrocardiogram interval measured from the onset of the P wave to the onset of 
the QRS complex
QRS
electrocardiogram interval measured from the onset of the QRS complex to the J 
point
QT
electrocardiogram interval measured from the onset of the QRS complex to the 
offset of the T wave
QTc
cardiac QT interval corrected for heart rate
QTcF
cardiac QTc interval corrected for heart rate by the formula of Fridericia
RR
the time between corresponding points on 2 consecutive R waves on the 
electrocardiogram
SAD
single-ascending dose
SAE
serious adverse event
SGLT2
sodium-glucose co-transporter 2
SID
subject identification
SC
subcutaneous(ly)
SPC
Summary of Product Characteristics
T2DM
type 2 diabetes mellitus


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Abbreviation or 
Specialized Term
Definition
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TG
triglycerides
TSH
thyroid-stimulating hormone
Tmax
time to maximum observed concentration
ULN
upper limit of normal
USA
United States of America
VT
ventricular tachycardia
w/v
weight per volume


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1
INTRODUCTION
1.1
Disease Background
Type 2 diabetes mellitus (T2DM) is a disease characterized by insulin resistance (IR) related 
to central obesity and weight gain, coupled with later progressive beta-cell failure, resulting 
in a steady worsening of glycemic control. Whilst a range of therapies is available for the 
control of blood glucose, none currently achieve substantial weight loss, which remains a 
significant unmet need for patients. Fifty percent of patients progress from oral monotherapy 
for glucose control (usually with metformin) to initiation of insulin within 10 years
(Taylor, 2013), often taking multiple oral combination therapies before initiating insulin. The 
use of insulin exacerbates weight gain, which can be as great as 6 kg in the first year after 
starting insulin therapy (Douek et al, 2005). This weight gain can lead to increased insulin 
resistance, which is associated with hypertension, dyslipidemia, and an increased risk of 
major adverse cardiovascular events. With respect to reducing insulin resistance, significant 
weight reduction (> 5%) is the optimal intervention, although this can only be achieved 
reliably at present through intensive dietary and lifestyle interventions and/or bariatric 
surgery.
1.2
MEDI0382 Background
MEDI0382 is briefly described below. Refer to the current Investigator’s Brochure for 
additional details. 
MEDI0382 is a synthetic peptide with both glucagon-like peptide-1 (GLP-1) and glucagon 
receptor co-agonist activity. MEDI0382 is being developed to address the unmet need for 
patients with T2DM to achieve both blood glucose control and weight reduction. The 
combination of GLP-1 and glucagon activity is expected to improve glycemic control and 
lipid profiles, and cause significant weight loss. These effects are hypothesized to be 
mediated through stimulation of glucose-mediated insulin release (the incretin effect), 
delayed gastric emptying, and increased fatty acid oxidation. Glucagon-like peptide-1 and 
glucagon agonists may also exert central effects on appetite, and glucagon agonism has 
been shown to drive increased energy expenditure in animal models and humans 
(Lynch et al, 2014; Habegger et al, 2013). Furthermore, appetite suppression and increased 
energy expenditure in humans has been demonstrated with the use of oxyntomodulin, a 
peptide with weak GLP-1 and glucagon co-agonist activity (Wynne et al, 2006).


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1.3
Summary of Nonclinical Experience
MEDI0382 injected subcutaneously (SC) in diet-induced obese (DIO) mice robustly and 
dose-dependently reduced body weight gain compared with vehicle-treated mice. A sustained 
lowering of body weight was observed over a 4-week treatment period with a reduction of 
approximately 25% at the highest dose tested (41 μg/kg, twice daily). MEDI0382 
significantly improved glucose control in DIO mice following dosing of up to 4 weeks. 
MEDI0382-treated DIO mice showed reduced blood glucose excursion following an oral 
glucose challenge as compared with vehicle-treated mice. In diabetic db/db mice, acute and 
subchronic treatment with MEDI0382 reduced blood glucose excursion following an 
intraperitoneal glucose challenge.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.5
Rationale for Conducting the Study
Studies that have examined changes in small bowel peptide hormones following bariatric 
surgery revealed that increases in GLP-1 and oxyntomodulin are associated 
with improvements in both glycemic control and weight loss (Falkén et al, 2011; 
Ionut et al, 2013). Nonclinical studies that have examined the effect of glucagon and GLP-1 
co-agonism on blood glucose and body weight suggest that a co-agonist such as MEDI0382, 
delivering potent GLP-1 and some glucagon agonism, can cause more significant weight loss 
through combined action on delayed gastric emptying, appetite suppression, and increased 
energy expenditure than GLP-1 agonist therapy alone (Tan et al, 2013). Glucagon agonism is 
thought to improve the lipid profile via increased fatty acid oxidation. Although glucagon 
agonism would normally be expected to cause an increase in glucose, the effect is 
counterbalanced by the GLP-1 effect on reducing blood glucose and significant weight loss 
driven by GLP-1 and glucagon agonism.
Available nonclinical data suggest that the affinity profile of MEDI0382 is optimized to 
achieve enhanced weight reduction via glucagon receptor agonism without adversely 
impacting the expected glycemic control associated with the GLP-1 agonist component (up 
to 20% weight loss, with effects on blood glucose control comparable to that of liraglutide, a 
GLP-1 agonist). MEDI0382 is therefore a potential breakthrough therapy for T2DM, 
achieving both significant weight loss and glycemic control.
This study is designed to assess the efficacy, safety/tolerability, and PK of MEDI0382 and 
the pharmacodynamic (PD) effect on blood glucose, following SC administration of 
multiple-ascending doses. Cohorts 1 through 3 (Part A of the study) are designed to establish 
an up-titration schedule for MEDI0382 and a maximal effective repeat dose. Subjects in 
Cohort 4 will be dosed for an extended period (33 days) with this maximal effective dose 
(Part B of the study) to assess the effect of MEDI0382 on glucose control and body weight.
 
 
 
 
 
 


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The design of the MAD study has taken into account the known benefits and risks of GLP-1 
receptor agonists and glucagon receptor agonists as well as the translatable effects observed 


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in nonclinical studies of MEDI0382, such that benefit-risk balance for the subjects with 
T2DM in this study is considered favorable.
1.6
Research Hypotheses
1.6.1
Primary Hypothesis
MEDI0382 will achieve an improvement in glucose control equivalent to at least that 
achieved by oral therapies in addition to metformin (≥20% reduction in glucose area under 
the concentration-time curve [AUC] after a mixed-meal test [MMT]), and at least 
comparable weight loss to that expected of liraglutide at the 1.8 mg dose (ie, between 1.3 and 
2.0 kg) versus placebo following 4 weeks of repeat once-daily dosing in subjects with T2DM
managed on metformin.
1.6.2
Secondary Hypotheses
•
MEDI0382 will achieve an improvement in glucose control as measured by hemoglobin 
A1c (HbA1c) and fructosamine following 4 weeks of repeat once-daily dosing.
•
Gastrointestinal (GI) symptoms will be manageable during up-titration of MEDI0382, no 
adverse changes in cardiac and hemodynamic parameters will be observed, and the
overall safety profile of MEDI0382 will be acceptable over up to 4 weeks of repeat once-
daily dosing.
2
OBJECTIVES
2.1
Objectives
2.1.1
Primary Objective
The primary objective of this study is to assess the effect of MEDI0382 on glucose control 
(as measured by the standardized MMT glucose data) and body weight from baseline to the 
end of a 4-week period at a stable dose.
2.1.2
Secondary Objectives
1. To assess the effect of MEDI0382 on glucose control as measured by the standardized 
MMT, HbA1c, and fructosamine data from baseline through end of treatment
2. To characterize the safety profile of MEDI0382 following SC administration of multiple-
ascending doses
3. To characterize the PK and immunogenicity of MEDI0382
4. To characterize the PD effect of MEDI0382 on glucose metabolism following a MMT


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2.1.3
Exploratory Objectives
 
 
 
5. To explore the effect of MEDI0382 on the volume and fat/water content of the liver 
6. To explore the effect of MEDI0382 on visceral and subcutaneous fat
2.2
Study Endpoints
2.2.1
Primary Endpoints
The primary endpoints apply to Cohort 4 only:
1. Percent change from baseline in MMT glucose AUC (up to 240 minutes post-MMT) to 
end of treatment 
2. Change from baseline in body weight in kg to end of treatment
2.2.2
Secondary Endpoint(s)
Secondary endpoints apply to all cohorts unless stated otherwise.
1. Change from baseline in HbA1c and fructosamine, and percent change from baseline in 
24-hour glucose AUC post-MMT, through end of treatment 
2. Percent change from baseline in MMT glucose AUC (up to 240 minutes post-MMT) to 
end of treatment 
3. Change from baseline in body weight in kg to end of treatment
4. AEs
5. BP
6. Pulse
7. Safety laboratory test results
8. Electrocardiograms (ECGs)
9. Columbia-Suicide Severity Rating Scale (C-SSRS) score (Cohorts 4, 5, and 6 only)
10. PK endpoints for MEDI0382: AUC over a dosing duration, maximum observed 
concentration (Cmax), minimum observed concentration, time to maximum observed 
concentration (Tmax)(all cohorts); terminal half-life, and accumulation ratio (Cohorts 1 to 
3 only)
11. Concentration of metformin
12. Development of antidrug antibody (ADA) and titer (if positive) 


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13. PD endpoints (glucose metabolism panel): 
◦
Glucose
◦
Beta cell health: insulin, pro-insulin, and c-peptide
◦
Incretins: GLP-1, glucagon, gastric inhibitory peptide (GIP)
◦
Cohorts 5 and 6 insulin and glucose only
2.2.3
Exploratory Endpoint(s)
Unless otherwise stated, the exploratory endpoints apply to Cohort 4 only.
1.
 
 
8. Change from baseline to Week 4 in:
◦
Liver fat (%)
◦
Liver volume (L)
◦
Visceral adipose tissue (L)
◦
Subcutaneous adipose tissue (L)
◦
Liver diffusion
◦
Sagittal diameter (image based)
◦
Transversal diameter (image based)
as determined by magnetic resonance imaging (MRI) to be conducted if MRI is 
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3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
This is a randomized, double-blind (subjects and investigators/site staff blinded; MedImmune 
unblinded), placebo-controlled study in 3 parts (A, B, and C) with approximately 107
overweight or obese subjects with relatively well controlled T2DM (without significant late 
diabetic complications) planned for enrollment across approximately 12 study sites. 
Part A is designed to establish a dose titration regimen for MEDI0382 and a maximal 
effective dose after titration, in T2DM subjects maintained on metformin therapy, over a 
period of approximately 12 days that can then be utilized over an extended dosing period 
(Part B) to establish the efficacy of MEDI0382 on weight and glycemic control. 
•
Part A consists of 3 cohorts: Cohort 1 consists of a stable dose of investigational product
administered daily for 7 days (9 subjects), Cohort 2 consists of an initial dose of 
investigational product for at least 4 days and an up-titration step (titration dose 1) for 7
days (9 subjects), and Cohort 3 consists of an initial dose of investigational product for at 
least 4 days, an up-titration step (titration dose 1) for 4 days, and a second up-titration 
step (titration dose 2) for 7 days (9 subjects). 
•
Part B consists of 1 cohort. Subjects in Cohort 4 will be dosed at an initial dose of 
investigational product for at least 4 days, an up-titration step (titration dose 1) for 4 days, 
a second up-titration step (titration dose 2) for 4 days, then titration dose 2 for 28 days 
thereafter at home (approximately 48 subjects).
•
Progression to Cohort 4 will occur following review of relevant data from Cohorts 1 
through 3 (safety/tolerability, PK, and PD).”Part C consists of 2 cohorts: Cohort 5 
consists of 16 subjects (12 active, 4 placebo) who will begin dosing investigational 
product at 100 μg for 5 days followed by 150 μg for 5 days, 200 μg for 5 days, and
300 μg for 7 days. Cohort 6 consists of a further 16 subjects (12 active, 4 placebo) who 
will begin dosing investigational product at 100 μg for 5 days followed by 200 μg for 
5 days, and 300 μg for 7 days (approximately 32 subjects in total). Cohorts 5 and 6 will 
be run in parallel.
The endpoints to be measured in this study are described in Section 2.2.
Screening procedures (Table 4.2.1-1) must be performed within the Day -60 to Day -3 
window prior to randomization. The screening evaluations may be carried out over more than 
1 day. Written informed consent and any locally required privacy act document authorization 
must be obtained prior to performing any protocol-specified procedures, including screening 
evaluations. Following screening, the study duration for each subject varies by cohort (refer 


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to Table 4.2.2-1, Table 4.2.2-2, Table 4.2.2-3, Table 4.2.2-4, Table 4.2.2-5, Table 4.2.2-6, 
and Table 4.2.2-7), and consists of an inpatient MAD or up-titration evaluation period 
(beginning on Day -2 and ending after Day 8 for Cohort 1, Day 12 for Cohort 2, Day 16 for 
Cohort 3, Day 13 for Cohort 4, and Day 3 for Cohorts 5 and 6) and an outpatient follow-up 
period. For Cohorts 5 and 6, the first 4 days and the final day of dosing at 300 μg are also 
inpatient periods. Additionally, only for Cohort 4, a 28-day period of at-home self-
administration of investigational product (with weekly site visits) is included after the second 
inpatient up-titration step and before the end of study visit. For Cohorts 5 and 6, in the event 
that subjects are not assessed as competent with respect to self-administration of 
investigational product, alternative arrangements will be made for it to be administered by a 
qualified study site professional.
For Cohorts 1 to 4, subjects will be admitted to and remain in the unit for all doses and dose 
levels during the up-titration period. Subjects will be admitted to the unit two evenings prior 
to receiving investigational product to allow for repeat assessment of eligibility criteria and 
baseline MMT, and to standardize the level of physical activity before dosing the following 
morning. Cohort 4 subjects only will undergo a predose MRI scan of the liver/abdomen (if 
MRI is available to the site and the subject is suitable for and consents to scan) between 
Day -7 and Day -1. This may require a separate visit at the subject’s discretion if not carried 
out on Day -2 or Day -1. On Day 1, following an overnight fast for a minimum of 8 hours, 
baseline blood samples will be drawn for safety, efficacy, PK, PD, and ADA laboratory tests, 
12-lead ECGs will be recorded, and the subject will be administered a single SC dose of 
either MEDI0382 or placebo. 
For Cohorts 5 and 6, subjects will be admitted to the clinic per the other cohorts; however, 
they will have an initial inpatient period ending on Day 3 followed by at-home 
self-administration of MEDI0382 with a clinic visit at each dose up-titration step until 
initiation of the 300 μg dose. Subjects will have a second inpatient period for the initiation of
the 300 μg dose ending on the fourth day at that dose followed by at-home 
self-administration. The subject will undergo safety tests including ECGs, telemetry, 
monitoring of vital signs, and assessments of the injection site for potential reactions 
throughout the day and during the treatment period. Additionally, for Cohorts 4, 5, and 6,
24-hour ambulatory blood pressure monitoring (ABPM) will be performed. Adverse events 
will be collected throughout the duration of the study.
MMT procedures will be performed on Day -1 and on the last day of the highest dose level 
achieved for all cohorts. Additional time points will include the first day at titration dose 1
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up-titration inpatient period (the fifth day of titration dose 2; Cohort 4), the weekly clinic
visits during the 28-day period of at-home self-administration (Cohort 4), before 
commencing the 300 μg dose (Day 16 for Cohort 5 and Day 11 for Cohort 6), and at the end 
of dosing (Day 22 for Cohort 5 and Day 17 for Cohort 6). For the MMT, the subject will 
consume a standardized meal (Ensure Plus®) within 5 minutes, and timed serial blood 
samples will be obtained for measurement of glucose and parameters related to glucose 
metabolism just before and through 240 minutes after consumption of the standardized meal. 
During the inpatient period, finger prick glucose samples will be collected 15 minutes ( prior 
to and 2 hours ( after breakfast, mid-day, and evening meals, and prior to going to bed.
Cohort 4 subjects will be re-admitted for an overnight inpatient stay at the end of the at-home 
self-administration period to collect the final endpoints including repeat MRI scan. This 
postdose MRI scan may be done on Day 39, 40, 41, or 42. Cohort 5 and 6 subjects will also
be re-admitted to the clinic for an overnight inpatient stay at the end of their final at-home 
self-administration period to collect the final endpoints.
Body weight will be measured at multiple time points including (but not limited to) prior to 
the first dose, during the inpatient dosing period (and during the outpatient period for 
Cohorts 4, 5, and 6), at discharge from the unit, at the 7- to 14-day follow-up visit, and at the 
28-day End of Study Visit. 
Pharmacokinetics samples for MEDI0382 will be obtained pre- and postdose and at various 
time points by cohort up until 48 hours after the last dose of MEDI0382 (for Cohorts 4 to 6
the last sample will be collected approximately 24 hours after the last dose). Samples for 
metformin concentration will be obtained prior to MEDI0382 dosing. Antidrug antibodies
samples will be obtained predose and at various time points up through 28 days post final 
dose.
Subjects will be discharged from the unit the day after their final dose is administered in the 
study.
A follow-up visit (End of Study Visit) will be performed for final safety assessments 
(Table 4.2.3-1) approximately 28 days after the last dose of investigational product.
The study schematic presented below (Figure 3.1.1-1) describes the sizing and treatment 
duration for Cohorts 1 through 6. Refer to Section 3.1.3.1 for restrictions on dose escalation, 
cohort expansion, and when enrollment in Cohort 4 (Part B) of this MAD study may begin.




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The proposed initial dose is 100 μg. Titration doses 1 and 2 have been determined according 
to emergent data on safety, tolerability, PK, and glycemic efficacy. The maximum dose is set 
at 200 μg/day for Cohort 4, (Part B of the study).
PART C:
•
Cohort 5, 16 subjects (12 active, 4 placebo) dosed for 5 days at 100 μg, 5 days at 150 μg, 
5 days at 200 μg followed by 7 days at 300 μg
•
Cohort 6, 16 subjects (12 active, 4 placebo) dosed for 5 days at 100 μg, 5 days at 200 μg 
followed by 7 days at 300 μg
The maximum dose is set at 300 μg/day for Cohorts 5 and 6 (Part C of the study).
3.1.3
Cohort Progression
3.1.3.1
Progression of Cohorts within this MAD Study
The proposed initial dose level for Cohort 1 is 100 μg. Titration doses 1 and 2 will be 
determined according to emergent data on safety, tolerability, PK and glycemic efficacy. 
This study is designed to establish the titration schedule for MEDI0382 and a maximal 
effective repeat dose for MEDI0382 over an extended dosing period. 
A sentinel dosing approach is planned for Cohorts 1, 2, and 3. Only 2 subjects in a given 
cohort will be dosed on Day 1, and the randomization schedule will ensure that these consist 
of 1 active and 1 placebo subject. A minimum of 3 days of dosing at the target dose level (ie, 
initial dose for Cohort 1, titration dose 1 for Cohort 2, and titration dose 2 for Cohort 3) will
occur before additional subjects in the cohort are dosed. Dosing is proposed to continue 
based on a lack of significant safety findings in the first 2 subjects dosed. The overall 
randomization schedule will ensure a 2:1 randomization (active:placebo) for Cohorts 1 to 3.
A sentinel dosing approach is also planned for Cohort 5 and 6. Three subjects from Cohort 5 
and 3 subjects from Cohort 6 will be dosed initially, and the randomization schedule will 
ensure that these consist of 2 active subjects and 1 placebo subject. The rest of the cohort will 
continue dosing once dosing is complete for the last sentinel subject in each cohort. This will 
ensure that a minimum of 7 days of dosing at the 300 μg dose will occur before additional 
subjects are dosed at this level. Dosing will continue based on a review of the data, and the 
lack of significant findings in these 6 subjects dosed.
For progression from Cohort 1 to Cohort 2, and from Cohort 2 to Cohort 3, the decision 
whether or not to progress will be made by DEC composed of members from the clinical 


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study team and the coordinating investigator. The decision to dose escalate will be based on 
safety/tolerability (safety laboratory test results including lactate, vital signs, ECGs, and AEs 
through 24 hours post final dose), PK data (for MEDI0382, through 24 hours after the Day 3
dose at the target dose level), and PD data (MMT glucose data post final dose) for each 
subject in the cohort. If the PK profile from Cohort 1 is as predicted, PK data from Cohort 2 
may not be reviewed for the dose escalation decision.
Cohort 4 of this MAD study may begin only after relevant data from Cohorts 1 through 3
have been analyzed (safety/tolerability, PK for MEDI0382 and for metformin, and PD) and 
reviewed by the DEC: data for Cohorts 1 and 2 through the end of study visit, and data for 
Cohort 3 through Day 16 (24 hours post final dose). These data will also be summarized and 
provided to the appropriate regulatory body and central ethics committee. The target dose 
level for Cohort 4 (dosed according to the up-titration scheme described above for Cohort 3) 
will be decided by the DEC and will not exceed 200 μg/day (Section 3.2.1). Approval to
proceed with Cohort 4 will be obtained from the appropriate regulatory body prior to 
initiating dosing.
Dose escalation will be stopped if, within the given cohort, DEC review determines that any 
of the following criteria are met. If any of these criteria are met, then data will be reviewed 
by a MedImmune safety review board to determine whether to continue the study and/or 
escalate the dose.
•
Grade 2 or higher AEs assessed as possibly, probably, or definitely related to MEDI0382
occur in more than 50 % of MEDI0382 subjects in a dosing cohort, or
•
One serious adverse event (SAE) occurs in a MEDI0382 subject that is assessed as
possibly, probably, or definitely related to MEDI0382
Based on a review of the safety and PD data from Cohorts 1, 2, and 3, the 300 μg dose level 
will be explored to fully characterize the dose-response with respect to safety and tolerability. 
The up-titration scheme described for Cohorts 5 and 6 differs from previous cohorts to 
determine the optimal up-titration schedule of the 300 μg dose from a perspective of 
tolerability, safety and PK/PD data. 
Cohorts 5 and 6 may run concurrently and the sponsor will conduct an ongoing review of 
safety data and AEs throughout Part C. In addition, given that telemetry will be in place for 
prolonged periods, arrhythmia findings will be expected to occur as part of the study 
population’s normal background incidence (Min et al, 2010). Subjects will be randomized 
2:1 (Cohorts 1 to 3), 1:1 (Cohort 4), or 3:1 (Cohorts 5 and 6) to receive MEDI0382 or 
placebo, and the sparse occurrence makes any such finding a priori more likely to be seen on 


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active treatment. If 1 or more subjects have a documented arrhythmia of concern, this may be 
reviewed by an external expert (or group) for opinion prior to the dose escalation decision. 
Study stopping criteria (including specific cardiac stopping criteria) are detailed in 
Section 3.1.3.2.
Based on prior clinical data from this class of agents, ADA formation is not considered to 
pose a high safety risk (eg, liraglutide is reported to have ADA rates of 8.6% with no clinical 
safety/efficacy consequence); therefore, ADA data will not be considered in dose-escalation 
decisions, but will be presented in the clinical study report.
After reviewing the data from a given cohort, the DEC will make one of the following 
recommendations:
•
Escalate to the next cohort as per the protocol.
•
Escalate to the next cohort with an intermediate (lower than planned) initial dose and/or 
titration dose increment, or expand the number of subjects dosed at a particular dose
level.
•
Escalate to the next cohort but extend the number of dosing days at a particular dose level 
before dose up-titration occurs.
•
Request for review and decision by the sponsor’s safety review board on how to proceed, 
or whether to suspend or stop the study.
Study suspension and termination are discussed in Section 0. Further details on the DEC are 
provided in Section 4.8.9.
3.1.3.2
Cardiac Stopping Criteria
The following criteria apply to stopping an individual from continuation in the study:
•
In any subject: an average absolute (regardless of baseline value) cardiac QTc interval 
corrected for HR by the formula of Fridericia (QTcF) > 500 milliseconds (msec), or an 
increase of QTcF > 60 msec above the baseline value, confirmed (persistent for 
≥5 minutes) on a repeat 12-lead ECG
•
In a subject receiving MEDI0382: tachycardia, defined as resting supine pulse rate 
> 125 beats per minute persisting for at least 10 minutes (measured at 5 timepoints in the
10 minute period)
•
In a subject receiving MEDI0382: symptomatic bradycardia, defined as resting supine 
pulse rate < 40 beats per minute while awake, persisting for at least 10 minutes; or 
asymptomatic bradycardia defined as resting supine pulse rate < 30 beats per minute 


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while awake persisting for at least 10 minutes (measured at 5 timepoints in the 10 minute 
period)
•
In a subject receiving MEDI0382: hypertension, defined as an increase in resting supine 
systolic BP > 40 mm Hg or above 180 mm Hg and persisting for at least 10 minutes, or 
an increase in resting supine diastolic BP > 20 mm Hg or above 100 mm Hg and 
persisting for at least 10 minutes
The following criteria apply to stopping the study when observed in 2 or more subjects 
receiving MEDI0382:
•
A QTc prolongation defined as QTcF > 500 msec, or an increase of QTcF > 60 msec
above baseline, confirmed (persistent for ≥5 minutes) and determined postdose on a 
repeat 12-lead ECG
•
Tachycardia, as defined above
•
Symptomatic or asymptomatic bradycardia, as defined above
•
Hypertension, as defined above
If 1 or more subjects have a documented arrhythmia of concern, this may be reviewed by an 
external expert (or group) for opinion prior to the DEC decision (see Section 5.3).
 
 
 
 
 
 
 
 
 
 
Prior clinical experience with both GLP-1 and glucagon agonist mechanisms (eg, liraglutide, 
oxyntomodulin, and human glucagon) indicates that AEs are primarily gastrointestinal, easily 


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observable, treatable, and reversible upon cessation of dosing (Victoza Summary of Product 
Characteristics [SPC], 2014; Wynne et al, 2005; GlucaGen® SPC, 2013).
In human studies, symptoms of nausea and vomiting are likely to precede significant weight 
loss. Timing of dose up-titration and the magnitude of dose level increase between Cohorts 1 
and 2 and Cohorts 2 and 3, 4, 5, and 6 are expected to be limited by GI tolerability, 
specifically with respect to nausea and vomiting. Subjects will be instructed to manage 
nausea by reducing food intake or by eating smaller portions of food spaced more regularly 
throughout the day. Significant vomiting for the purposes of this study is defined as 3 or 
more episodes of vomiting on a single day or across 2 consecutive days, despite adjustment 
to diet having been made. Subjects who fulfil the criteria for significant vomiting will have 
their electrolytes monitored and the medical monitor will be contacted regarding further 
follow-up and to discuss any need for supplementation of electrolytes by the oral or IV route. 
If investigational product is withdrawn, then follow up for safety and efficacy evaluations 
would be maintained. 
In Cohort 1, subjects will be treated at an initial dose level for a period of 7 days. Based on 
data from other GLP-1 agonist studies, it is likely that the effect of the first dose of 
MEDI0382 with respect to GI stasis will wane with repeat dosing, and thus initial symptoms 
of nausea and/or vomiting will decline after Day 1. An objective for all cohorts is to 
determine how rapidly initial symptoms of nausea and vomiting decline with repeated once-
daily administration, and thus define the optimal timing for dose up-titration in future studies. 
In addition to the formal dose escalation decision, SAEs and significant laboratory 
abnormalities will be reviewed by the DEC on a case-by-case basis to determine if 
discontinuation of dosing is required. In addition, criteria will be included to limit dose 
escalation progression, if needed, following data review by the DEC as described in 
Section 3.1.3. Expansion of a cohort and exploration of the effect of a lower intermediate 
dose level may be considered.
Up-titration for Cohort 2 is proposed after at least 4 days of dosing with the initial dose used 
in Cohort 1. Up-titration for Cohort 3 is proposed after at least 4 days of dosing with the 
initial dose used in Cohort 1 with a further up-titration after 4 days of dosing with the dose 
used in Cohort 2 (8 days total for up-titration). This 4-day up-titration schedule may be 
increased according to observed safety/tolerability, ie, if the GI tolerability profile with up-
titration after 4 days is unacceptable, the time to up-titration may be extended for future 
cohorts. A similar up-titration schedule is proposed for Cohort 4 before continuing stable 
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will be at 5-day intervals. If unacceptable tolerability with respect to nausea and vomiting is 
seen in Cohort 6 in 3 or more subjects, any remaining subjects to be randomized to Cohort 6 
may be switched to the Cohort 5 up-titration schedule after discussion with the medical 
monitor. 
3.2
Study Design and Dose Rationale
Rationale for the study and study design are presented in Section 1.5.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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150.03 (118.44-190.04) ng•hr/mL and median (range) half-life of 12.0 (9.58-15.20) hours in 
the SAD study. 
The safety margin between the predicted Cmax after multiple doses at the 100 μg dose in 
human and the observed Cmax at the cynomolgus monkey NOAEL is approximately 25. This 
dose will allow confirmation of the PK predictions for MEDI0382 after multiple doses, while 
being at the lower end of the potentially relevant pharmacological range.
Four dose levels are proposed for repeat once-daily dosing in this study (100, 150, 200, and 
300 μg).
3.2.2
Rationale for Study Population
Recruitment of Subjects with Body Mass Index 27 to 40 kg/m2
A significant level of unmet clinical need exists with respect to both weight loss and glucose 
control in patients with T2DM who are overweight or obese. While patients with a 
BMI > 40 kg/m2 are usually offered bariatric surgery, those with BMI in the range of 
27-40 kg/m2 are offered medical management of their weight. Current licensed therapies for 
glucose control in this population (GLP-1 agonists) achieve a mean weight loss of 3% over 
1 year, and high-dose GLP-1 agonist therapy (3 mg liraglutide) achieves weight loss of up to 
8% versus baseline. It is anticipated that MEDI0382 will achieve weight loss > 10% versus
baseline over 1 year, and a greater reduction in HbA1c control than 1.8 mg liraglutide. The 
entry criteria with respect to BMI of 27-40 kg/m2 both maximizes recruitment potential and 
provides efficacy, safety, and tolerability data in the likely population of clinical use.
Recruitment of Subjects with T2DM on Metformin
MEDI0382 is a GLP-1 and glucagon receptor co-agonist. Early evaluation of the relative 
effects on blood glucose control of the GLP-1 versus glucagon component is crucial in 
modeling the overall effect on HbA1c in patients with T2DM, and data on the effects of 
incretin hormones on glucose homeostasis are much more robust when collected in the target 
T2DM population. 
Metformin forms the basis of initial and continuing oral therapy for a significant proportion 
of patients with T2DM. Metformin is associated with GI tolerability issues, including nausea, 
abdominal bloating, and diarrhea. Treatment with MEDI0382 concomitant with metformin 
will allow assessment of GI tolerability in the likely clinical-use setting early in the 
development pathway. Metformin concentration will be measured during this study to 
determine whether there is an interaction with MEDI0382 dosing.


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Recruitment of Subjects in the 18 through 65 Years Age Range
This MAD study will be conducted in subjects with T2DM managed by metformin. 
Recruitment of adults up through age 65 years both ensures that recruitment to the MAD 
study is feasible and subject safety is appropriately safeguarded. The age range chosen is a 
balance between the significant fall off in prevalence of T2DM (below age 18 years), and the 
increase in comorbidities seen in patients with T2DM above age 65 years. Female subjects 
will not be lactating and not of childbearing potential. There is no requirement for a given 
number of subjects in each gender to be enrolled.
Selection of Subjects with Stable HbA1c in the Range of 6.5 to 8.5 Percent
The specified HbA1c ranges permit feasible recruitment while ensuring that any acute effect 
on glucose metabolism can be robustly assessed in the target clinical population. Further 
intervention to lower blood glucose levels should not be delayed by entry into the MAD 
study for those with an HbA1c > 8.5%. 
3.2.3
Rationale for Endpoints
Rationale for Endpoints Supporting the Primary Objectives of Glucose Control 
and Body Weight Loss
The goal for this MAD study is to ensure that MEDI0382 provides a reliable measure of 
glucose control and leads to at least comparable body weight loss relative to that achieved by 
liraglutide at the 1.8 mg dose (Victoza SPC, 2014) to support investment in further 
development.
Rationale for the Endpoints Supporting the Secondary Objective of Change 
from Baseline in HbA1c and Fructosamine Levels
Both fructosamine and HbA1c tests are used primarily as monitoring tools to help patients
with diabetes control their blood sugar. For the HbA1c test there are firm data that a 
chronically elevated HbA1c level predicts an increased risk for certain diabetic 
complications. Fructosamine is the product of a reaction between glucose and albumin. This 
test is used to evaluate the average amount of glucose in blood over a period of 2 to 3 weeks.
The American Diabetes Association recognizes both tests and states that fructosamine may 
be more useful in situations where HbA1c cannot be reliably measured. These secondary 
endpoints for glucose control, namely change from baseline through end of treatment in 
HbA1c and fructosamine (Cohort 4), should enable modeling for longer-term Phase 2b study 
design.


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Rationale for Endpoints Supporting the Secondary Objectives of 
Safety/Tolerability and PK/Immunogenicity
The goal is to ensure that repeated dosing with MEDI0382 has a suitable safety profile for 
further clinical development, particularly with respect to GI AE profile and effect on HR and 
BP. Given the mechanism of action of MEDI0382, GI events including nausea, vomiting, 
abdominal bloating and diarrhea may be seen with increased frequency. Elevations in HR
and BP may also be seen and effects on the QTcF interval will be evaluated.
Food and Drug Administration Guidance suggests assessment of suicidality for agents 
recognised to cause weight loss where central nervous system penetration is predicted
(Food and Drug Administration, CDER, 2012). Therefore the C-SSRS instrument is included 
in the study procedures.
The incidence and impact of ADA formation to MEDI0382 will be assessed. Antidrug 
antibodies formation to other GLP-1 receptor agonist peptides has generally been of low titer 
and non-neutralizing. There were no confirmed ADA responses following single 
administration of up to and including 300 μg MEDI0382 in the SAD study. The goal for PK 
endpoints is to ensure that MEDI0382 has a suitable PK profile for further development and 
to evaluate any interactions with metformin to determine the relevance of observations seen 
in rodents with respect to co-administration of metformin with MEDI0382, and evaluate 
combination therapy in the likely clinical use population.
 
 
 
 
 
 
 
 


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Rationale for Endpoints Supporting the Exploratory Objective for Hepatic, 
Visceral, and Subcutaneous Fat Volume in T2DM Patients on a 33-day Stable 
Dose of MEDI0382 (Cohort 4)
Abdominal obesity and T2DM are associated with chronic liver disorders resulting from the 
accumulation of fat in the liver (steatosis). As weight loss is expected over the 4-week dosing 
period, relative changes in liver and abdominal visceral/subcutaneous fat compared to 
baseline will be investigated at sites which have the technical capability to perform the MRI 
assessment. Reductions in liver fat 
 will allow
initial exploration of the utility of MEDI0382 as a treatment for NASH.
4
MATERIALS AND METHODS
4.1
Subjects
The study population will consist of male or female adults, 18 through 65 years of age with 
T2DM and BMI 27 to 40 kg/m2 (inclusive), without significant late diabetic complications. 


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Subjects should have been treated with a stable dose of oral blood glucose lowering therapy 
for 3 months prior to screening, (metformin monotherapy or metformin plus dipeptidyl 
peptidase-4 [DPPIV], sulphonylurea [50% of the licensed dose], or a sodium-glucose 
co-transporter 2 [SGLT2]; and DPPIV inhibitor, sulphonylurea, or SGLT2 inhibitor is 
washed out prior to randomization). Females of childbearing potential and lactating females 
will be excluded.
4.1.1
Number of Subjects
A total of approximately 107 subjects are planned as described in Section 3.1.2.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Male or female age 18 through ≤65 years at the time of screening.
2. Written informed consent and any locally required authorization (eg, European Union 
Data Privacy Directive) obtained from the subject/legal representative prior to performing 
any protocol-related procedures, including screening evaluations.
3. Ability to complete and meet all eligibility requirements for randomization within 
60 days after signing the informed consent form (ICF). 
4. Body mass index 27 to 40 kg/m2 (inclusive).
5. Diagnosis of T2DM and glucose control managed with metformin monotherapy where no 
significant dose change (increase or decrease ≥ 500 mg/day) has occurred in the 3 months 
prior to screening. 
a.
The screening HbA1c value should be within the target range of 6.5% to 8.5%.
b. Subjects prescribed a DPPIV inhibitor in addition to metformin monotherapy may be 
eligible to enter the study following a 4-week DPPIV inhibitor washout period.
c.
Subjects who are prescribed less than 50% of the licensed dose of sulphonylurea in 
addition to metformin monotherapy may be eligible to enter the study following a 
4-week sulphonylurea washout period.
d. Subjects prescribed a sodium-glucose co-transporter 2 (SGLT2) inhibitor in addition 
to metformin monotherapy may be eligible to enter the study following a 4-week 
SGLT2 inhibitor washout period.
Note: Subjects may be re-tested for the HbA1c entry criterion only once.
6. Venous access suitable for multiple cannulations.
7. For subjects in Cohorts 4, 5, and 6: Willing and able to self-administer daily SC 
injections following an initial self-injection of placebo (or normal saline in Cohorts 5 
and 6 only) during the screening period.
8. Females must be not lactating and not of childbearing potential, defined as those who are 
surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or are postmenopausal (defined as at least 1 year since last menses and 


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having an elevated [> 40 mIU/mL] follicle stimulating hormone laboratory value at
screening).
If sexually active with a female partner of childbearing potential, nonsterilized males and 
their partner must practice 2 effective contraceptive measures (see Table 4.1.2-1) from 
screening through at least 28 days after the last dose of investigational product has been 
administered. NOTE: Male condom plus spermicide is only considered an effective 
contraceptive measure when used together with another method in Table 4.1.2-1. None of 
the methods in Table 4.1.2-1 are intended to be used alone.
Table 4.1.2-1
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Male condom plus spermicide
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system (eg, 
Mirena®) a
•
Implants
•
Hormone shot or injection
•
Combined pill
•
Minipill
•
Patch
a
This is also considered a hormonal method.
4.1.3
Exclusion Criteria
Any of the following would exclude a subject from participation in the study:
1. Any condition that, in the opinion of the investigator, would interfere with evaluations of 
the investigational product or interpretation of subject safety or study results. Specific 
examples are:
a.
Past history of acute or chronic pancreatitis, or pancreatic amylase or lipase greater 
than twice the upper limit of normal (ULN) of the laboratory reference range at 
screening.
b. Past history of gastroparesis requiring treatment.
c.
Past history of surgery affecting the upper GI tract likely to affect the interpretation of 
safety and tolerability data.
d. History of cholelithiasis leading to episodes of acute cholecystitis not treated by 
cholecystectomy, or known biliary disease.
e.
Serum calcitonin suggestive of thyroid C-cell hyperplasia (calcitonin level 
> 50 ng/L), medullary thyroid carcinoma, or history or family history of multiple 
endocrine neoplasia at screening.
2. History or presence of GI, renal, or hepatic disease (with the exception of Gilbert’s 
syndrome), or any other condition known to interfere with absorption, distribution, 
metabolism, or excretion of drugs.
3. History of cancer within the last 10 years, with the exception of non-melanoma skin 
cancer.
4. History or presence of diabetic foot ulcers.
5. Any clinically important illness (apart from T2DM for subjects with known diabetes), 
medical/surgical procedure, or trauma within 4 weeks prior to Day 1 dosing.


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6. Symptoms of insulinopenia or poor blood glucose control (eg, significant thirst, nocturia, 
polyuria, polydipsia, or weight loss).
7. Fasting blood glucose ≥ 200 mg/dL (11.11 mmol/L).
8. Positive hepatitis B surface antigen or hepatitis C virus antibody serology at screening.
9. Positive human immunodeficiency virus (HIV) test at screening or subject taking 
antiretroviral medications as determined by medical history or subject’s verbal report.
10. At screening blood tests, any of the following: 
a.
Aspartate transaminase (AST) ≥2.5 × ULN
b. Alanine transaminase (ALT) ≥2.5 × ULN
c.
Total bilirubin ≥ 2 × ULN
d. Hemoglobin below the lower limit of the normal range
e.
Neutrophils < 1.5 × 109/L
f.
Thyroid-stimulating hormone (TSH) level above the normal range
Note: Subjects may be re-tested for the AST and ALT criteria only once.
11. Impaired renal function defined as glomerular filtration rate (GFR) 
≤60 mL/minute/1.73m2 (GFR estimated according to Modification of Diet in Renal 
Disease (MDRD) using MDRD Study Equation IDMS-traceable [SI units]).
12. Persistent (defined as documented on ≥2 prior occasions by the subject’s usual 
physician) macroalbuminuria (> 300 mg/L).
13. Significant late diabetic complications (macroangiopathy with symptoms of congestive 
heart disease or peripheral arterial disease, microangiopathy with symptoms of 
neuropathy, gastroparesis, retinopathy, nephropathy).
14. Cardiac conduction defect (eg, Wolff-Parkinson-White syndrome, sick sinus syndrome) 
during the screening period.
15. Abnormal vital signs, after 10 minutes of supine rest, defined as any of the following:
a.
Cohorts 1 to 4:
▪
If < 60 years old, systolic BP < 90 mm Hg or ≥140 mm Hg; if ≥60 years old, 
systolic BP < 90 mm Hg or ≥150 mm Hg
▪
Diastolic BP < 50 mm Hg or ≥90 mm Hg
▪
HR < 45 or > 85 bpm
Note: At the investigator’s discretion, subjects who fail BP screening criteria may be 
considered for 24-hour ABPM. Subjects who maintain 24-hour BP at a mean of less than 
140/90 mm Hg with a preserved nocturnal dip of > 15% will be considered eligible to 
enter Cohorts 1 to 4.
b. Cohorts 5 and 6:
▪
If systolic BP < 90 mm Hg or ≥140 mm Hg
▪
Diastolic BP < 50 mm Hg or ≥90 mm Hg
▪
HR < 45 or > 85 bpm
Note: At the investigator’s discretion, subjects who fail BP screening criteria may be 
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140/90 mm Hg with a preserved nocturnal dip of > 15% will be considered eligible to 
enter Cohorts 5 and 6.
Subjects may be re-tested for the vital signs criteria only once if, in the investigator’s 
judgment, they are not representative of the subject.
16. Any clinically important abnormalities in rhythm, conduction or morphology of the 
resting ECG and any abnormalities in the 12-lead ECG that, as considered by the 
investigator, may interfere with the interpretation of QTc interval changes, including 
abnormal ST-T-wave morphology or left ventricular hypertrophy.
17. Prolonged QTcF > 450 msec (for both genders) or shortened QTcF < 340 msec, or family 
history of long QT syndrome.
18. PR (PQ) interval shortening < 120 msec (PR < 120 msec but > 110 msec is acceptable if 
there is no evidence of ventricular pre-excitation).
19. PR (PQ) interval prolongation (> 240 msec), intermittent second or third degree AV 
block, or AV dissociation.
20. QRS duration > 120 msec including persistent or intermittent bundle branch block.
Note: Subjects with QRS duration > 120 msec in the presence of right bundle branch 
block, which is not in the opinion of the investigator associated with significant 
respiratory or cardiovascular disease, may be enrolled in the study.
21. Subjects with implantable cardiac defibrillator or a permanent pacemaker, and subjects 
with symptomatic ventricular and/or atrial tachyarrhythmias
22. Subjects with unstable angina pectoris or stable angina pectoris classified higher than 
Canadian Cardiovascular Society class II:
a.
or a myocardial infarction or stroke (Cohorts 1 to 4). 
b. or any previous medical history of myocardial infarction or stroke, or a history of a 
transient ischemic attack within the prior 12 months (Cohorts 5 and 6).
23. History of hospitalization caused by heart failure or a diagnosis of heart failure.
24. Known or suspected history of drug abuse within the past 3 years as judged by the 
investigator.
25. History of alcohol abuse or excessive intake of alcohol within the past 3 years as judged 
by the investigator.
26. Positive screen for drugs of abuse at screening or admission to the study unit, or positive 
screen for alcohol on admission to the unit prior to the administration of investigational 
product. Patients who utilize benzodiazepines for chronic anxiety or sleep disorders may 
be permitted to enter the study.
27. History of severe allergy/hypersensitivity or ongoing clinically important 
allergy/hypersensitivity as judged by the investigator.
28. Whole blood or red blood cell donation, or any blood loss > 500 mL during the 2 months 
prior to screening.
29. Received another new chemical entity (defined as a compound that has not been 
approved for marketing), or has participated in any other clinical study that included drug 
treatment within at least 30 days or 5 half-lives prior to the first administration of 
investigational product in this study (whichever is longer). The period of exclusion to 
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last visit, whichever is longest. Subjects consented and screened, but not randomized into 
this study or a previous Phase 1 study, are not excluded.
30. Concurrent participation in another study of any kind is prohibited.
31. Use of any of the following medicinal products:
a.
Concurrent or previous use of a GLP-1 agonist.
b. Use of systemic corticosteroids within 28 days prior to screening.
c.
Use of compounds known to prolong the QTc interval.
d. Use of any herbal preparations or medicinal products licensed for control of body 
weight or appetite within 1 week prior to Day 1.
32. Psychiatric illness such that subjects have been committed to an institution by way of 
official or judicial order.
33. History of lactic acidosis or ketoacidosis
34. The subject is an employee, or close relative of an employee, of AstraZeneca, 
MedImmune, the contract research organization (CRO), or the study site, regardless of 
the employee’s role.
35. Ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents, unless the diet 
or treatment has been stopped at least 3 months prior to screening and the subject has had 
a stable body weight (± 3 kg) during the 3 months prior to screening.
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 subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice or web response system [IXRS]), and 
the screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria.
The SID number will be used to identify the subject during the screening process and 
throughout study participation. 
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 to a treatment arm by the IXRS. 
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; a determination 
whether or not to replace the subject will be made jointly between the investigator and 
medical monitor. 
Subjects may be rescreened only once


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4.1.5
Withdrawal from the Study
Subjects are at any time free to withdraw from the study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent). Such subjects 
will always be asked about the reason(s) and the presence of any AEs. If possible, they will 
be seen and assessed by an investigator. Adverse events will be followed up. 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 or lost to 
follow-up
2. An AE that, in the opinion of the investigator or the sponsor, warrants discontinuation 
from further dosing
3. More than 2 symptomatic hypoglycemic events (symptoms of hypoglycemia with 
documented finger prick glucose < 50.4 mg/dL [2.8 mmol/L]); or persistent 
hyperglycemia (> 260 mg/dL [14.4 mmol/L] measured with 2 laboratory fasting blood
glucose samples more than 3 days apart).
4. Dose-limiting symptoms with respect to GI tolerability, even after measures are taken to 
reduce the risk of vomiting, after discussion with the medical monitor
5. Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation at study entry and continuing 
investigational product, in the decision of the investigator dosing might constitute a 
safety risk
6. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)
7.
Subject develops a resting supine systolic BP of ≥ 180 mm Hg or a resting supine 
diastolic BP of ≥ 100 mm Hg sustained for more than 10 minutes, or a sustained resting 
tachycardia which is symptomatic and requires urgent medical intervention (Cohorts 5 
and 6)
Subjects who are permanently discontinued from receiving investigational product will be 
followed for safety and PK/PD unless consent is withdrawn specifically from further study 
participation (Section 4.1.5) or the subject is lost to follow-up.
Subjects who have not received investigational product, regardless of the reason, will not be 
followed.


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4.1.7
Replacement of Subjects
Additional subjects may be screened and available to ensure that a sufficient number of 
subjects are randomized into each cohort. Subjects who withdraw from the study may be
replaced, if deemed necessary by the medical monitor, to ensure that safety, PK and PD data 
are collected on a sufficient number of subjects.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.2
Schedule of Study Procedures
Separate schedules of procedures are provided for the screening period, treatment period, and 
follow-up period.
4.2.1
Enrollment/Screening Period
Table 4.2.1-1 shows all procedures to be conducted at the screening visit. Assessments
should be performed in the order shown in the table.
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the blood draws should occur last. 
Table 4.2.1-1
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure/Study Day
Day -60 to Day -3
Written general 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
Verify eligibility criteria
X
Demographics
X
Medical and disease history (including smoking and alcohol history)
X
Full physical examination (including structured neurological examination) a
X
Vital signs
X
12-lead digital ECG (also printed on paper)
X


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Table 4.2.1-1
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure/Study Day
Day -60 to Day -3
Body height
X
Body weight
X
Calculate GFR to confirm eligibility
X
Collect blood for:
Pancreatic amylase, lipase, calcitonin, and TSH
X
HIV-1 and -2 antibodies; hepatitis B and C serology
X
HbA1c
X
Serum chemistry panel
X
Hematology and coagulation panels
X
FSH levels (females only)
X
Total Ig and subsets (Ig A/E/G/M)
X
Collect urine for:
Urinalysis (dipstick)
X
Drug and alcohol screen b
X
Assessment of AEs/SAEs
X
Concomitant medications
X
 c
X
Cohort 4, 5, and 6 only: Check ability to self-administer investigational 
productd
X
AE = adverse event; ECG = electrocardiogram; FSH = follicle-stimulating hormone; GFR = glomerular 
filtration rate; HbA1c = glycated hemoglobin; HIV = human immunodeficiency virus; Ig = immunoglobulin; 
SAE = serious adverse event; SID = subject identification; TSH = thyroid-stimulating hormone; V = visit.
a
Only the screening physical examination will be a full examination including a structured neurological 
examination. For all time points thereafter, only a targeted physical examination is required (see 
Section 4.3.2.1).
b
Breath alcohol testing is acceptable as an alternative to urine testing. 
 
.
d
Subject’s ability to self-administer investigational product will be verified using placebo or normal saline 
subcutaneous injections.


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4.2.2
Randomized Treatment Period
Procedures to be conducted during the treatment period are shown as itemized by cohort(s) 
below:
•
Cohort1 (Table 4.2.2-1)
•
Cohort 2 (Table 4.2.2-2)
•
Cohort 3 (Table 4.2.2-3)
•
Cohort 4 Overview (Table 4.2.2-4)
•
Cohort 4 Self-administration Dosing Period Detail (Table 4.2.2-5)
•
Cohort 5 (Table 4.2.2-6)
•
Cohort 6 (Table 4.2.2-7)


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Table 4.2.2-1
Schedule of Treatment Period Procedures: Cohort 1
Study Period
Residential Inpatient
Outpatient
Visit Number
V2
V3
Dose Level 1
V5
V6
V7
V4.1
V4.2
V4.3
V4.4
V4.5
V4.6
V4.7
Study Day
-2
-1
1
2
3
4
5
6
7
8
9
7 to 14 Days
Post Last 
Dose
Procedure
Verify eligibility criteria
X
Admit to clinic
X
Medical and disease history
X
Targeted physical examination
X
X
X
Body weight a
X
X
X
X
Randomization
X b
X b
Collect blood for:
Hematology panel (predose as applicable)
X
X
X
X
X
X
X
X
X
X
Serum chemistry panel (predose as applicable)
X
X
X
X
X
X
X
X
X
X
Amylase and lipase (predose)
X
X
X
Lactate (predose as applicable)
X
X
X
X
X
HbA1c
X
Optional future genetic research c
X
Optional future non-genetic research c
X
X
Collect urine sample for: 
Urinalysis (dipstick; predose as applicable)
X
X
X
Pregnancy test 
X
Drug and alcohol screen d
X
ECG e
X
X
X
X
X
X
X
X
X
X
Telemetry f
X
X
X
X
X
X
X
X
X
Vital signs (BP, pulse, body temperature, RR) g
X
X
X
X
X
X
X
X
X
X
X


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Table 4.2.2-1
Schedule of Treatment Period Procedures: Cohort 1
Study Period
Residential Inpatient
Outpatient
Visit Number
V2
V3
Dose Level 1
V5
V6
V7
V4.1
V4.2
V4.3
V4.4
V4.5
V4.6
V4.7
Study Day
-2
-1
1
2
3
4
5
6
7
8
9
7 to 14 Days
Post Last 
Dose
IP administration
X
X
X
X
X
X
X
PK for MEDI0382 h
X
X
X
X
X
X
PK for metformin (prior to MEDI0382 dose as 
applicable)
X
X
X
X
X
X
MMT and blood samples for glucose metabolism 
panel i
X
X
Record start time of breakfast, mid-day, and evening 
meals
X
X
X
X
X
X
X
PD samples for glucose j
X
X
X
X
X
X
X
X
ADA k
X
X
X
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
Injection site assessment l
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Discharge from clinic
X
ADA = antidrug antibody; AE = adverse event; BP = blood pressure; ECG = electrocardiogram; eCRF = electronic case report form; 
 
; GIP = gastric inhibitory peptide; GLP-1 = glucagon-like peptide-1; HbA1c = glycated hemoglobin; IP = investigational product; min = minutes; MMT 
= mixed-meal test; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
RR = respiration rate; SAE = serious adverse 
event; V = Visit.
Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood draws 
should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (eg, for PK and PD) to occur as close as possible to 
the scheduled time. Ten minutes of supine rest should precede these assessments.
a
Except Day -2, body weight measurement should be taken in the morning before breakfast.


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b
Randomization may occur on either Day -1 or Day 1. 
c
There are separate consent forms for the genetic future research sample and the non-genetic future research sample. Only sample(s) for which the subject has 
consented will be taken.
d
Breath alcohol testing is acceptable as an alternative to urine testing. 
e
Digital ECGs will be captured on Day -1; predose on Day 1; at 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min); and 24 hours (± 60 min) postdose on each day of 
dosing (Days 1 through 8); additionally at 0.5 hours (± 15 min) postdose on Day 1 and Day 7; and at the 7 to 14 days post last dose visit (V7). All ECGs 
should be printed. Whenever possible, meals should be scheduled such that at least 2 hours elapse between the meal and the next scheduled ECG time point.
f
On Day -1, a minimum of 4 hours of cardiac telemetry will be performed, and any rhythm disturbance is to be recorded in the eCRF. Throughout the 
inpatient period, cardiac telemetry will be monitored continuously as tolerated, ie, balanced in consideration of potential skin abrasion AEs.
g
Vital Signs Schedule: On Day 1, vital signs are to be recorded predose and at 15, 30, 60 and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose, as well 
as before the mid-day meal and before the evening meal (approximately 5 minutes before each meal), and at 24 hours postdose (prior to next dose). 
Thereafter, vital signs will be recorded on each inpatient day at 4, 12, and 24 hours postdose (prior to next dose or the morning of discharge).
h
PK Sampling Schedule for MEDI0382: 
Day 1: Predose and at 0.5, 1, and 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 2: 24 hours (± 60 min) post Day 1 dose (prior to Day 2 dose).
Day 4: 24 hours (± 60 min) post Day 3 dose (prior to Day 4 dose); then 2 hours (± 15 min) and 8 hours (± 30 min) postdose.
Day 7: 24 hours (± 60 min) post Day 6 dose (prior to Day 7 dose); then 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 8: 24 hours (± 60 min) post Day 7 dose.
Day 9: 48 hours (± 2 hours) post Day 7 dose.
i
MMT Schedule: Following a minimum 8-hour fast and after collection of the 2-hour postdose PK sample (except on Day -1), a blood sample for glucose 
metabolism panel (glucose, insulin, pro-insulin, c-peptide, GLP-1, glucagon, and GIP) will be taken immediately prior to the subject drinking 1 entire can of 
Ensure Plus as a standardized meal (ie, “0 minutes”). Blood samples for glucose metabolism panel will additionally be drawn at 15, 30, 45, 60, 90, 120, 180, 
and 240 minutes (±5 min) after consumption of the standardized meal.
j
Using the glucometer (ie, by finger-prick), except for Day -1, the PD glucose will be taken 15 minutes prior to and 2 hours after breakfast, mid-day, and 
evening meals, and prior to going to bed. The time of the meal start will be recorded in the eCRF every day the subject is an inpatient. For Day -1, PD 
glucose will be taken only at 15 minutes before the evening meal.
k
ADA Sampling Schedule: Day 1 predose; Day 8; and 7 to 14 days after administration of the last dose in the study.
l
Injection Site Assessment Schedule: On Day 1, the injection site will be assessed postdose at 4, 12, and 24 hours (prior to next dose). Thereafter, the
injection site will be assessed predose on the morning of every inpatient day and on the morning of discharge.
m
 
.


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Table 4.2.2-2
Schedule of Treatment Period Procedures: Cohort 2
Study Period
Residential Inpatient
Outpatient
Visit Number
V2
V3
Dose Level 1
Dose Level 2
V6
V7
V8
V4.1
V4.2
V4.3, 
V4.4
V5.1
V5.2
V5.3-
V5.6
V5.7
Study Day
-2
-1
1
2
3, 4
5
6
7-10
11
12
13
7 to 14 Days
Post Last 
Dose
Procedure
Verify eligibility criteria
X
Admit to clinic
X
Medical and disease history
X
Targeted physical examination
X
X
X
Body weight a
X
X
X
X
X
Randomization
X b
X b
Collect blood for:
Hematology panel (predose as applicable)
X
X
X
X
X
X
X
X
X
X
Serum chemistry panel (predose as applicable)
X
X
X
X
X
X
X
X
X
X
Amylase and lipase (predose)
X
D4
D8
X
Lactate (predose as applicable)
X
X
X
D8
X
X
HbA1c
X
Optional future genetic research c
X
Optional future non-genetic research c
X
X
Collect urine sample for: 
Urinalysis (dipstick; predose as applicable)
X
X
X
X
X
Pregnancy test
X
Drug and alcohol screen d
X
ECG e
X
X
X
X 
X
X
X
X
X
X
Telemetry f
X
X
X
X
X
X
X
X
X


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Table 4.2.2-2
Schedule of Treatment Period Procedures: Cohort 2
Study Period
Residential Inpatient
Outpatient
Visit Number
V2
V3
Dose Level 1
Dose Level 2
V6
V7
V8
V4.1
V4.2
V4.3, 
V4.4
V5.1
V5.2
V5.3-
V5.6
V5.7
Study Day
-2
-1
1
2
3, 4
5
6
7-10
11
12
13
7 to 14 Days
Post Last 
Dose
Vital signs (BP, pulse, body temperature, RR) g
X
X
X
X
X
X
X
X
X
X
X
IP administration
X
X
X
X
X
X
X
PK for MEDI0382 h
X
X
X
D8
X
X
X
PK for metformin (prior to MEDI0382 dose as 
applicable)
X
X
X
D8
X
X
X
MMT and blood samples for glucose metabolism 
panel i
X
X
X
Record start time of breakfast, mid-day, and 
evening meals
X
X
X
X
X
X
X
PD samples for glucose j
X
X
X
X
X
X
X
X
ADA k
X
X
X
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
Injection site assessment l
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
Discharge from clinic
X
ADA = antidrug antibody; AE = adverse event; BP = blood pressure; D = day; ECG = electrocardiogram; eCRF = electronic case report form; 
 
; GIP = gastric inhibitory peptide; GLP-1 = glucagon-like peptide-1; HbA1c = glycated hemoglobin; IP = investigational product; min 
= minutes; MMT = mixed-meal test; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
; RR = respiration rate; SAE = 
serious adverse event; V = Visit.


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Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood draws 
should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (eg, for PK and PD) to occur as close as possible to 
the scheduled time. Ten minutes of supine rest should precede these assessments.
a
Except Day -2, body weight measurement should be taken in the morning before breakfast.
b
Randomization may occur on either Day -1 or Day 1.
c
There are separate consent forms for the genetic future research sample and the non-genetic future research sample. Only sample(s) for which the subject has 
consented will be taken.
d
Breath alcohol testing is acceptable as an alternative to urine testing. 
e
Digital ECGs will be captured on Day -1; predose on Day 1; at 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min); and 24 hours (± 60 min) postdose on each day of 
dosing (Days 1 through 12); additionally at 0.5 hours (± 15 min) post dose on Day 5 and Day 11; and at the 7 to 14 days post last dose visit (V8). All ECGs 
should be printed. Whenever possible, meals should be scheduled such that at least 2 hours elapse between the meal and the next scheduled ECG time point.
f
On Day -1, a minimum of 4 hours of cardiac telemetry will be performed, and any rhythm disturbance is to be recorded in the eCRF. Throughout the 
inpatient period, cardiac telemetry will be monitored continuously as tolerated, ie, balanced in consideration of potential skin abrasion AEs.
g
Vital Signs Schedule: On Day 1 and the first day of each new dose level, vital signs are to be recorded predose, and at 15, 30, 60 and 90 minutes postdose; 2, 
4, 6, 8, and 12 hours postdose, as well as before the mid-day meal and before the evening meal (approximately 5 minutes before each meal), and at 24 hours 
postdose (prior to next dose). Thereafter (but not on up-titration days), vital signs will be recorded on each inpatient day at 4, 12, and 24 hours postdose 
(prior to next dose or the morning of discharge). 
h
PK Sampling Schedule for MEDI0382: 
Day 1: Predose and at 2 hours (± 15 min) postdose.
Day 5: Predose and at 0.5, 1, and 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 6: 24 hours (± 60 min) post Day 5 dose (prior to Day 6 dose).
Day 8: 24 hours (± 60 min) post Day 7 dose (prior to Day 8 dose); then 2 hours (± 15 min) and 8 hours (± 30 min) postdose.
Day 11: 24 hours (± 60 min) post Day 10 dose (prior to Day 11 dose); then 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (±30 min) postdose.
Day 12: 24 hours (± 60 min) post Day 11 dose.
Day 13: 48 hours (± 2 hours) post Day 11 dose.
i
MMT Schedule: Following a minimum 8-hour fast and after collection of the 2-hour postdose PK sample (except on Day -1), a blood sample for glucose 
metabolism panel (glucose, insulin, pro-insulin, c-peptide, GLP-1, glucagon, and GIP) will be taken immediately prior to the subject drinking 1 entire can of 
Ensure Plus as a standardized meal (ie, “0 minutes”). Blood samples for glucose metabolism panel will additionally be drawn at 15, 30, 45, 60, 90, 120, 180, 
and 240 minutes (± 5 min) after consumption of the standardized meal.
j
Using the glucometer (ie, by finger-prick), except for Day -1, the PD glucose will be taken 15 minutes prior to and 2 hours after breakfast, mid-day, and 
evening meals, and prior to going to bed. The time of the meal start will be recorded in the eCRF every day the subject is an inpatient. For Day -1, PD 
glucose will be taken only at 15 minutes before the evening meal.
k
ADA Sampling Schedule: Day 1 predose; Day 12; and 7 to 14 days after administration of the last dose in the study.


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l
Injection Site Assessment Schedule: On Day 1 and the first day of each new dose level, the injection site will be assessed postdose at 4, 12, and 24 hours 
(prior to next dose). Thereafter (but not on up-titration days), the injection site will be assessed predose on the morning of every inpatient day and on the 
morning of discharge. 
m
 


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Table 4.2.2-3
Schedule of Treatment Period Procedures: Cohort 3
Study Period
Residential Inpatient
Outpatient
Visit Number
V2
V3
Dose Level 1
Dose Level 2
Dose Level 3
V7
V8
V9
V4.1
V4.2
V4.3, 
V4.4
V5.1
V5.2
V5.3, 
V5.4
V6.1
V6.2
V6.3-
V6.6
V6.7
Study Day
-2
-1
1
2
3, 4
5
6
7, 8
9
10
11-14
15
16
17
7 to 
14 Days
Post Last 
Dose
Procedure
Verify eligibility criteria
X
Admit to clinic
X
Medical and disease history
X
Targeted physical examination
X
X
X
Body weight a
X
X
X
X
X
X
Randomization
X b
X b
Collect blood for:
Hematology panel (predose as 
applicable)
X
X
X
X
X
X
X
D11,
D12
X
X
Serum chemistry panel (predose 
as applicable)
X
X
X
X
X
X
X
D11,
D12
X
X
Amylase and lipase (predose)
X
X
Lactate (predose as applicable)
X
X
X
X
D12
X
X
HbA1c
X
Optional future genetic research c
X
Optional future non-genetic 
research c
X
X
Collect urine sample for: 
Urinalysis (dipstick; predose as 
applicable)
X
X
X
X
X
X
X
Pregnancy test
X


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Table 4.2.2-3
Schedule of Treatment Period Procedures: Cohort 3
Study Period
Residential Inpatient
Outpatient
Visit Number
V2
V3
Dose Level 1
Dose Level 2
Dose Level 3
V7
V8
V9
V4.1
V4.2
V4.3, 
V4.4
V5.1
V5.2
V5.3, 
V5.4
V6.1
V6.2
V6.3-
V6.6
V6.7
Study Day
-2
-1
1
2
3, 4
5
6
7, 8
9
10
11-14
15
16
17
7 to 
14 Days
Post Last 
Dose
Drug and alcohol screen d
X
ECG e
X
X
X
X
X
X
X
X
X
X
X
X
X
Telemetry f
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (BP, pulse, body 
temperature, RR) g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IP administration
X
X
X
X
X
X
X
X
X
X
PK for MEDI0382 h
X
X
X
X
D12
X
X
X
PK for metformin (prior to 
MEDI0382 dose as applicable)
X
X
X
X
D12
X
X
X
MMT i
X
X
X
Blood samples for glucose, 
insulin, pro-insulin, c-peptide i
X
X
X
Blood samples for GLP-1, 
glucagon, GIP i
X
X
Record start time of breakfast,
mid-day and evening meals
X
X
X
X
X
X
X
X
X
X
PD samples for glucose j
X
X
X
X
X
X
X
X
X
X
X
ADA k
X
X
X
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection site assessment l
X
X
X
X
X
X
X
X
X
X
X


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-3
Schedule of Treatment Period Procedures: Cohort 3
Study Period
Residential Inpatient
Outpatient
Visit Number
V2
V3
Dose Level 1
Dose Level 2
Dose Level 3
V7
V8
V9
V4.1
V4.2
V4.3, 
V4.4
V5.1
V5.2
V5.3, 
V5.4
V6.1
V6.2
V6.3-
V6.6
V6.7
Study Day
-2
-1
1
2
3, 4
5
6
7, 8
9
10
11-14
15
16
17
7 to 
14 Days
Post Last 
Dose
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Discharge from clinic
X
ADA = antidrug antibody; AE = adverse event; BP = blood pressure; D = day; ECG = electrocardiogram; eCRF = electronic case report form; 
 
 GIP = gastric inhibitory peptide; GLP-1 = glucagon-like peptide-1; HbA1c = glycated hemoglobin; IP = investigational product; min 
= minutes; MMT = mixed-meal test; PD = pharmacodynamic(s); PK = pharmacokinetic(s);
RR = respiration rate; SAE = 
serious adverse event; V = Visit.
Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood draws 
should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (eg, for PK and PD) to occur as close as possible to 
the scheduled time. Ten minutes of supine rest should precede these assessments.
a
Except Day -2, body weight measurement should be taken in the morning before breakfast.
b
Randomization may occur on either Day -1 or Day 1.
c
There are separate consent forms for the genetic future research sample and the non-genetic future research sample. Only sample(s) for which the subject has 
consented will be taken.
d
Breath alcohol testing is acceptable as an alternative to urine testing. 
e
Digital ECGs will be captured on Day -1; predose on Day 1; at 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min); and 24 hours (± 60 min) postdose on each day of 
dosing (Days 1 through 16); additionally at 0.5 hours (± 15 min) postdose on Day 9 and Day 15; and at the 7 to 14 days post last dose visit (V9). All ECGs 
should be printed. Whenever possible, meals should be scheduled such that at least 2 hours elapse between the meal and the next scheduled ECG time point.
f
On Day -1, a minimum of 4 hours of cardiac telemetry will be performed, and any rhythm disturbance is to be recorded in the eCRF. Throughout the 
inpatient period, cardiac telemetry will be monitored continuously, as tolerated, ie, balanced in consideration of potential skin abrasion AEs.
g
Vital Signs Schedule: On Day 1 and the first day of each new dose level, vital signs are to be recorded predose, and at 15, 30, 60 and 90 minutes postdose; 2, 
4, 6, 8, and 12 hours postdose, as well as before the mid-day meal and before the evening meal (approximately 5 minutes before each meal), and at 24 hours 
postdose (prior to next dose). Thereafter (but not on up-titration days), vital signs will be recorded on each inpatient day at 4, 12, and 24 hours postdose 
(prior to next dose or the morning of discharge).


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23Sep2016, Amendment 8
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Template 16.2
h
PK Sampling Schedule for MEDI0382: 
Day 1: Predose and 2 hours (± 15 min) postdose.
Day 5: Predose and 2 hours (± 15 min) postdose.
Day 9: Predose and 0.5, 1, and 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 10: 24 hours (± 60 min) post Day 9 dose (prior to Day 10 dose).
Day 12: 24 hours (± 60 min) post Day 11 dose (prior to Day 12 dose); then 2 hours (± 15 min) and 8 hours (± 30 min) postdose.
Day 15: 24 hours (± 60 min) post Day 14 dose (prior to Day 15 dose); then 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 16: 24 hours (± 60 min) post Day 15 dose.
Day 17: 48 hours (± 2 hours) post Day 15 dose.
i
MMT Schedule: Following a minimum 8-hour fast and after collection of the 2-hour postdose PK sample (except on Day -1), blood samples for the tests 
indicated will be taken immediately prior to the subject drinking 1 entire can of Ensure Plus as a standardized meal (ie, “0 minutes”). Blood samples for the 
tests indicated will additionally be drawn at 15, 30, 45, 60, 90, 120, 180, and 240 minutes (± 5 min) after consumption of the standardized meal.
j
Using the glucometer (ie, by finger-prick), except for Day -1, the PD glucose will be taken 15 minutes prior to and 2 hours after breakfast, mid-day, and 
evening meals, and prior to going to bed. The time of the meal start will be recorded in the eCRF every day the subject is an inpatient. For Day -1, PD 
glucose will be taken only at 15 minutes before the evening meal.
k
ADA Sampling Schedule: Day 1 predose; Day 16; and 7 to 14 days after administration of the last dose in the study.
l
Injection Site Assessment Schedule: On Day 1 and the first day of each new dose level, the injection site will be assessed postdose at 4, 12, and 24 hours 
(prior to next dose). Thereafter (but not on up-titration days), the injection site will be assessed predose on the morning of every inpatient day and on the 
morning of discharge. 
m
 


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-4
Schedule of Treatment Period Procedures: Cohort 4 Overview
Study Period
Residential Inpatient
Outpatient
with Weekly 
Visits a
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
Dose Level
1
Dose Level
2
Dose Level
3
Dose Level
3
Dose Level
3
V4.1
V4.2
V4.3
V4.4
V5.1
V5.2
V5.3
V5.4
V6.1
V6.2
V6.3
V6.4
V7a
(V8-
V10) a
V11a
V12
V13
V14
Study Day
-2
-1
1
2
3, 4
5
6
7, 8
9
10
11
12
13a
14-39 a
40 a
41
42
7-14 Days
Post Last 
Dose
Procedure
Verify eligibility criteria
X
Admit to clinic
X
X
Return to site for once 
weekly visits b
X
Medical and disease 
history
X
Targeted physical 
examination
X
X
X
X
Body weight c
X
X
X
X
X
X
X
X
X
Randomization
X d
X d
Collect blood for:
Hematology panel
(predose as applicable)
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry panel
(predose as applicable)
X
Xu
X
X
Xu
X
X
Xu
Xu
Xu
X
Amylase and lipase
(predose)
X
X
X
X
X
X
X
Lactate (predose as 
applicable)
X
X
X
X
X
X
X
X
HbA1c (predose as 
applicable)
X
X
X
X
Fructosamine (predose 
as applicable)
X
X
X
X


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-4
Schedule of Treatment Period Procedures: Cohort 4 Overview
Study Period
Residential Inpatient
Outpatient
with Weekly 
Visits a
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
Dose Level
1
Dose Level
2
Dose Level
3
Dose Level
3
Dose Level
3
V4.1
V4.2
V4.3
V4.4
V5.1
V5.2
V5.3
V5.4
V6.1
V6.2
V6.3
V6.4
V7a
(V8-
V10) a
V11a
V12
V13
V14
Study Day
-2
-1
1
2
3, 4
5
6
7, 8
9
10
11
12
13a
14-39 a
40 a
41
42
7-14 Days
Post Last 
Dose
Fasting lipid profile
(before breakfast and 
predose as applicable)
X
X
X
X
Optional future genetic 
research e
X
Optional future non-
genetic research e
X
X
Collect urine sample 
for:
Urinalysis (dipstick)
X
X
X
X
X
X
X
X
X
X
Urinary Ketostix f
X
X
Pregnancy test
X
X
X
Drug and alcohol 
screen g
X
 
ECG h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Telemetry i
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (BP, pulse, 
body temperature, RR) j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
24-hour ABPM
X
X
X
X
Subject completes
Daily Diary
X
X


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23Sep2016, Amendment 8
64 of 171
Template 16.2
Table 4.2.2-4
Schedule of Treatment Period Procedures: Cohort 4 Overview
Study Period
Residential Inpatient
Outpatient
with Weekly 
Visits a
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
Dose Level
1
Dose Level
2
Dose Level
3
Dose Level
3
Dose Level
3
V4.1
V4.2
V4.3
V4.4
V5.1
V5.2
V5.3
V5.4
V6.1
V6.2
V6.3
V6.4
V7a
(V8-
V10) a
V11a
V12
V13
V14
Study Day
-2
-1
1
2
3, 4
5
6
7, 8
9
10
11
12
13a
14-39 a
40 a
41
42
7-14 Days
Post Last 
Dose
Staff review Daily Diary 
with subject
X
X
Accelerometer receipt/
exchange/ collection
X k
X
X
X
Train subject on self-
administration
X
X
X
X
X
X
Train subject on at-home 
dose preparation and 
glucometer use
X
X
X
X
Staff train subject in 
Daily Diary completion
(refer to Section 4.3.12.3)
X
X
IP administration by 
staff
X
X
X
X
X
X
X
IP administration by 
subject
X
X
X
X
X
X
X
PK for MEDI0382 l
X
X
X
X
X
X
X
X
PK for metformin (prior 
to MEDI0382 dosing as 
applicable)
X
X
X
X
X


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MEDI0382
23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-4
Schedule of Treatment Period Procedures: Cohort 4 Overview
Study Period
Residential Inpatient
Outpatient
with Weekly 
Visits a
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
Dose Level
1
Dose Level
2
Dose Level
3
Dose Level
3
Dose Level
3
V4.1
V4.2
V4.3
V4.4
V5.1
V5.2
V5.3
V5.4
V6.1
V6.2
V6.3
V6.4
V7a
(V8-
V10) a
V11a
V12
V13
V14
Study Day
-2
-1
1
2
3, 4
5
6
7, 8
9
10
11
12
13a
14-39 a
40 a
41
42
7-14 Days
Post Last 
Dose
MMT m
X
X
X
X
Blood samples for 
glucose and insulin m
X
X
X
X
Blood samples for 
pro-insulin and 
c-peptide m
X
X
Blood samples for
GLP-1, glucagon, and 
GIP m
X
X
Record start time of
breakfast, mid-day, and 
evening meals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PD samples for glucose n
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA o
X
X
V9
X
X
 
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection site
assessment p
X
X
X
X
X
X
X
X
X
X
X
X
X
MRI q
X r
X r
X s
X s
X s
X s
C-SSRS
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


MedImmune
Protocol D5670C00002
MEDI0382
23Sep2016, Amendment 8
66 of 171
Template 16.2
Table 4.2.2-4
Schedule of Treatment Period Procedures: Cohort 4 Overview
Study Period
Residential Inpatient
Outpatient
with Weekly 
Visits a
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
Dose Level
1
Dose Level
2
Dose Level
3
Dose Level
3
Dose Level
3
V4.1
V4.2
V4.3
V4.4
V5.1
V5.2
V5.3
V5.4
V6.1
V6.2
V6.3
V6.4
V7a
(V8-
V10) a
V11a
V12
V13
V14
Study Day
-2
-1
1
2
3, 4
5
6
7, 8
9
10
11
12
13a
14-39 a
40 a
41
42
7-14 Days
Post Last 
Dose
Discharge from clinic
X
X
ABPM = ambulatory blood pressure monitoring; ADA = antidrug antibody; AE = adverse event; BP = blood pressure; C-SSRS = Columbia-Suicide Severity 
Rating Scale;
 ECG = electrocardiogram; eCRF = electronic case report form; 
 
GIP = gastric inhibitory peptide; GLP-1 = glucagon-like peptide-1; HbA1c = glycated hemoglobin; IP = investigational product; min = minutes; MMT 
= mixed-meal test; MRI = magnetic resonance imaging; 
; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
 
 RR = respiration rate; SAE = serious adverse event; V = Visit.
Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood draws 
should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (eg, for PK and PD) to occur as close as possible to 
the scheduled time. Ten minutes of supine rest should precede these assessments.
a
The time period shown between the thickened black gridlines in this table is expanded with details in Table 4.2.2-5. Note: an “X” in the Study Day 14-39 
column indicates that the procedure in the given row occurs at some time between Days 14 and 39, inclusive (ie, not necessarily on each of these days).
b
The subject will return to the site on Days 20, 27, and 34 for weekly visits. Refer to Table 4.2.2-5 for details of assessments/procedures.
c
Except Day -2, body weight measurement should be taken in the morning before breakfast.
d
Randomization may occur on either Day -1 or Day 1.
e
There are separate consent forms for the genetic future research sample and the non-genetic future research sample. Only sample(s) for which the subject has 
consented will be taken.
f
The subject should do a Ketostix test daily on non-clinic-visit days during the at-home self-administration period; the subject will indicate whether the result 
was negative or positive in the Daily Diary, and be instructed to call the clinic if the result is positive.
g
Breath alcohol testing is acceptable as an alternative to urine testing. 
h
Digital ECGs will be captured on Day -1; predose on Day 1; at 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min); and 24 hours (± 60 min, except Day 12) postdose 
on each day of dosing (Days 1 through 12); additionally at 0.5 hours (± 15 min) post dose on Day 9 and Day 41; predose, 1, 2 hours (± 15 min) and 4 hours 
(± 30 min) postdose at the weekly visits during the at-home dosing period (Day 20, Day 27, Day 34); 24 hours (± 60 min) after the last dose (Day 42); and at 


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23Sep2016, Amendment 8
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Template 16.2
the 7 to 14 days post last dose visit (V14). All ECGs should be printed. Whenever possible, meals should be scheduled such that at least 2 hours elapse 
between the meal and the next scheduled ECG time point.
i
On Day -1, a minimum of 4 hours of cardiac telemetry will be performed, and any rhythm disturbance is to be recorded in the eCRF. Throughout the 
inpatient period, cardiac telemetry will be monitored continuously as tolerated, ie, balanced in consideration of potential skin abrasion AEs.
j
Vital Signs Schedule: On Day 1 and the first day of each new dose level, vital signs are to be recorded predose, and at 15, 30, 60 and 90 minutes postdose; 2, 
4, 6, 8, and 12 hours postdose, as well as before the mid-day meal and before the evening meal (approximately 5 minutes before each meal), and at 24 hours 
postdose (prior to next dose). Thereafter (but not on up-titration days), vital signs will be recorded on each inpatient day at 4, 12, and 24 hours postdose 
(prior to next dose or the morning of final discharge). During the at-home dose administration period, at weekly clinic visits, vital signs are to be recorded 
predose, and at 15, 30, 60 and 90 minutes postdose; then at 2 and 4 hours postdose. Also, vital signs are to be taken at all PK time points.
k
Subjects will return the accelerometer when they return to the clinic for inpatient admission on Day -2.
l
PK Sampling Schedule for MEDI0382: 
Day 1 (V4.1): Predose and 2 hours (± 15 min) postdose.
Day 5 (V5.1): Predose and 2 hours (± 15 min) postdose.
Day 9 (V6.1): Predose and 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 10 (V6.2): 24 hours (± 60 min) post Day 9 dose (prior to Day 10 dose).
Day 13 (V7): Predose.
Day 20 (V8): Predose.
Day 27 (V9): Predose.
Day 34 (V10): Predose.
Day 41 (V12): 24 hours (± 60 min) post Day 40 dose (prior to Day 41 dose); then 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 42 (V13): 24 hours (± 60 min) post Day 41 dose.
m
MMT Schedule: Following a minimum 8-hour fast and after collection of the 2-hour postdose PK sample (except on Day -1), blood samples for the tests 
indicated will be taken immediately prior to the subject drinking 1 entire can of Ensure Plus as a standardized meal (ie, “0 minutes”). On Day -1, and Day 
41, blood samples for the tests indicated will additionally be taken at 15, 30, 45, 60, 90, 120, 180, and 240 minutes (± 5 min) after consumption of the 
standardized meal. On Day 13, Day 20, Day 27, and Day 34, blood samples for the tests indicated will additionally be taken at 30, 60, 120, and 240 minutes
(± 5 min) after consumption of the standardized meal.


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23Sep2016, Amendment 8
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Template 16.2
n
Using the glucometer (ie, by finger-prick), during the in-clinic dosing period and except for Day -1, the PD glucose will be taken 15 minutes (± 10 minutes)
prior to and 2 hours (± 10 minutes) after breakfast, mid-day, and evening meals, and prior to going to bed. The time of the meal start will be recorded in the 
eCRF every day the subject is an inpatient. For Day -1, PD glucose will be taken only at 15 minutes (± 10 minutes) before the evening meal. For the at-home 
dosing period, PD glucose samples are to be taken at home with the standardized glucometer (a) prior to breakfast (ie, fasting)/prior to self-dosing, (b) 
approximately 2 hours after the mid-day meal, (c) within 15 minutes prior to the evening meal, and (d) approximately every other day at bedtime.
o
ADA Sampling Schedule: Day 1 (V4.1) predose; Day 13 (V7) predose; Day 27 (V9) predose; Day 41 (V12) predose; and 7 to 14 days after administration 
of the last dose in the study.
p
Injection Site Assessment Schedule: On Day 1 and the first day of each new dose level, the injection site will be assessed postdose at 4, 12, and 24 hours 
(prior to next dose). Thereafter (but not on up-titration days), the injection site will be assessed predose on the morning of every inpatient day and on the 
morning of final discharge. At weekly clinic visits during the at-home self-administration period, the injection site will be assessed predose in the morning.
q
MRI will only be conducted if MRI is available to the site and the subject is suitable for and consents to scan.  
r
Predose MRI scan may be done anytime between Day -7 to Day -1, as determined by site feasibility. This may require a separate visit at the subject’s
discretion if not carried out on Day -2 or Day -1.
s
Postdose MRI scan may be done on Day 39, 40, 41, or 42.
t
The P/MSS is to be completed by the subject within 30 minutes (+ 10 minutes) prior to starting the MMT and within 30 minutes (+ 10 minutes) after 
collection of the final MMT glucose metabolism panel blood sample for the inpatient period of the study and at the weekly site visits during the outpatient 
period.
u
Sample to be taken following a minimum of 8 hours fasting.


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-5
Schedule of Treatment Period Procedures: Cohort 4 Self-administration Dosing Period Detail
Visit Number
V7
Home
V8
Home
V9
Home
V10
Home
V11
Location
Clinic
Clinic
Clinic
Clinic
Home
Clinic
Procedure / Study Day
13
14-19
20 
(±1 
day)
21-26
27(±1 
day)
28-33
34(±1 
day)
35-39
40 (±1 day)
Admit to clinic
X
Targeted physical examination
X
Body weight a
X
X
X
X
Collect blood for:
Hematology panel (predose)
X
X
X
X
Serum chemistry panel (predose)
Xn
Xn
Xn
Xn
Amylase and lipase (predose)
X
X
X
X


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-5
Schedule of Treatment Period Procedures: Cohort 4 Self-administration Dosing Period Detail
Visit Number
V7
Home
V8
Home
V9
Home
V10
Home
V11
Location
Clinic
Clinic
Clinic
Clinic
Home
Clinic
Procedure / Study Day
13
14-19
20 
(±1 
day)
21-26
27(±1 
day)
28-33
34(±1 
day)
35-39
40 (±1 day)
Lactate (predose)
X
X
X
X
HbA1c (predose)
X
X
X
X
Fructosamine (predose)
X
X
X
X
Fasting lipid panel (predose before breakfast)
X
X
X
X
Collect urine sample for: 
Urinalysis (dipstick; at clinic visits only)
X
X
X
X
Urinary Ketostix (at home only) b
X
X
X
X
X
Pregnancy test (if applicable)
X
X
X
X
ECG c
X
X
X
X
Telemetry
X
Vital signs (BP, pulse, body temperature, RR) d
X
X
X
X
X
24-hour ABPM e
X
D14
X
D21
X
D28
X
D35
X
Subject completes Daily Diary
X
X
X
X
X
X
X
X
Staff review Daily Diary with subject
X
X
X
Staff train subject in Daily Diary completion (refer to 
Section 4.3.12.3)
X
Accelerometer receipt/exchange/collection
X
X
X
X
X
Compliance/accountability for outpatient doses
X
X
X
X
IP administration by subject at the study site
X
X
X
X
IP administration once daily by subject at home
X
X
X
X
X


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MEDI0382
23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-5
Schedule of Treatment Period Procedures: Cohort 4 Self-administration Dosing Period Detail
Visit Number
V7
Home
V8
Home
V9
Home
V10
Home
V11
Location
Clinic
Clinic
Clinic
Clinic
Home
Clinic
Procedure / Study Day
13
14-19
20 
(±1 
day)
21-26
27(±1 
day)
28-33
34(±1 
day)
35-39
40 (±1 day)
PK for MEDI0382f
X
X
X
X
PK for metformin (prior to MEDI0382 dose)
X
X
X
X
MMT g
X
X
X
X
Blood samples for glucose and insulin g
X
X
X
X
Record start time of mid-day and evening meals
X
X
X
X
X
X
PD samples for glucose h
X
X
X
X
ADA i
X
X
AEs/SAEs
X
X
X
X
X
X
Injection site assessment j
X
X
X
X
X
MRI k
X l
X l
X l
 
C-SSRS
Concomitant medications
X
X
X
X
X
X
Discharge from clinic
X
ABPM = ambulatory blood pressure monitoring; ADA = antidrug antibody; AE = adverse event; BP = blood pressure; C-SSRS = Columbia-Suicide Severity 
Rating Scale; D = day; ECG = electrocardiogram; 
 HbA1c = glycated hemoglobin; IP = investigational product; min = 
minutes; MMT = mixed-meal test; MRI = magnetic resonance imaging; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
 
RR = respiration rate; SAE = serious adverse event; V = Visit.


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23Sep2016, Amendment 8
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Template 16.2
Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood draws 
should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (eg, for PK and PD) to occur as close as possible to 
the scheduled time. Ten minutes of supine rest should precede these assessments.
a
Body weight should be taken in the morning before breakfast.
b
The subject should do a Ketostix test daily on non-clinic-visit days; the subject will indicate whether the result was negative or positive in the Daily Diary, 
and will be instructed to call the clinic if the result is positive.
c
Digital ECGs will be captured predose, 1, 2 hours (± 15 min) and 4 hours (± 30 min) postdose at the weekly visits during the at-home dosing period (starting 
with Day 13, then Day 20, Day 27, and Day 34). All ECGs should be printed. Whenever possible, meals should be scheduled such that at least 2 hours elapse 
between the meal and the next scheduled ECG time point.
d
Vital Signs Schedule: At clinic visits, vital signs are to be recorded predose, and at 15, 30, 60 and 90 minutes postdose; then 2 and 4 hours postdose. 
e
Subjects will be fitted with the ABPM device whilst 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. Subjects will return the 
device to the clinic.
f
PK Sampling Schedule for MEDI0382: Predose on Days 13, 20, 27, and 34.
g
MMT Schedule: Following a minimum 8-hour fast and after collection of the PK sample, a blood sample for the tests indicated will be taken immediately 
prior to the subject drinking 1 entire can of Ensure Plus as a standardized meal (ie, “0 minutes”). Blood samples for the tests indicated will additionally be 
drawn at 30, 60, 120, and 240 minutes (± 5 min) after consumption of the standardized meal.
h
PD glucose samples are to be taken at home with the standardized glucometer (a) prior to breakfast (ie, fasting)/prior to self-dosing (b) approximately 2 
hours after the mid-day meal, (c) within 15 minutes prior to the evening meal, and (d) approximately every other day at bedtime..
i
ADA Sampling Schedule: Predose on Days 13 and 27.
j
Injection Site Assessment Schedule: At weekly clinic visits during the at-home self-administration period, the injection site will be assessed predose in the 
morning (except Day 40).
k
MRI will only be conducted if MRI is available to the site and the subject is suitable for and consents to scan
l
Postdose MRI scan may be done on Day 39, 40, 41, or 42.
m
 
n
Sample to be taken following a minimum of 8 hours fasting.


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-6
Schedule of Treatment Period Procedures: Cohort 5 Overview
Dose Level
100 μg
150 μg
200 μg
300 μg
Residential Inpatient
Outpatient
Outpatient
Residential 
Inpatient
Outpatient
Residential
Inpatient
Outpatient
Visit Number
V2
V3
V4
V5
V6
V7
Study Day
-2
-1
1
2
3
4-5
6
7-10
11
12-15
16
17
18
19
20-21
22
23
7-14 days post 
last dose
Procedure
Verify eligibility 
criteria
X
Admit to clinic
X
Xa,b
Xa, b
Discharge home 
Xa
Xa
X
Outpatient clinic visit
Xa, b
Xa,b
X
Medical and disease 
history
X
Targeted physical 
examination
X
X
X
X
X
X
Body weight c
X
X
X
X
X
X
X
Randomization
X
d
Xd
Hematology panel 
(predose as 
applicable)
X
X
X
X
X
X
X
Serum chemistry 
panel (predose as 
applicable)
X
Xr
X
X
Xr
Xr
X
X
X
X
Xr 
X
Amylase and lipase 
(predose)
X
X
X
X
X
X
X
X
Lactate (predose as 
applicable)
X
X
X
X
X
X
X
X
HbA1c (predose as 
applicable)
X
X
Fructosamine 
(predose as 
applicable)
X
X


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-6
Schedule of Treatment Period Procedures: Cohort 5 Overview
Dose Level
100 μg
150 μg
200 μg
300 μg
Residential Inpatient
Outpatient
Outpatient
Residential 
Inpatient
Outpatient
Residential
Inpatient
Outpatient
Visit Number
V2
V3
V4
V5
V6
V7
Study Day
-2
-1
1
2
3
4-5
6
7-10
11
12-15
16
17
18
19
20-21
22
23
7-14 days post 
last dose
Fasting lipid profile 
(before breakfast 
and predose as 
applicable)
X
X
Optional future 
genetic research e
X
Optional future 
non-genetic 
research e
X
X
Urinalysis 
(dipstick)
X
X
X
X
X
X
X
X
X
X
X
X
Urinary Ketostix f
X
X
X
X
Pregnancy test
X
X
X
X
X
X
Drug and alcohol  
screen g
X
X
 
ECG h
X
X
X
X
X
X
X
X
X
X
X
X
Telemetry i
X
X
X
X
X
X
X
X
X
Vital signs (BP, pulse, 
body temperature, 
RR) j
X
X
X
X
X
X
X
X
X
X
X
X
X
24-hour ABPM o
X
X
X
Subject completes
Daily Diary 
X
X
X
X
X
X
X
X
Staff review Daily 
Diary with subject
X
X
X
X


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-6
Schedule of Treatment Period Procedures: Cohort 5 Overview
Dose Level
100 μg
150 μg
200 μg
300 μg
Residential Inpatient
Outpatient
Outpatient
Residential 
Inpatient
Outpatient
Residential
Inpatient
Outpatient
Visit Number
V2
V3
V4
V5
V6
V7
Study Day
-2
-1
1
2
3
4-5
6
7-10
11
12-15
16
17
18
19
20-21
22
23
7-14 days post 
last dose
Train subject on self-
administration, at-
home dose 
preparation and 
glucometer and diary 
use as required (refer 
to Section 4.3.12)
X
X
X
X
X
X
X
X
IP administration by 
staff q
X
IP administration by 
subject q
X
X
X
X
X
X
X
X
X
X
X
X
X
PK for MEDI0382 k
X
X
X
X
X
X
X
X
PK for metformin 
(prior to MEDI0382 
dose as applicable)
X
X
MMT l
X
X
X
Record start time of
breakfast, mid-day,
and evening meals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PD samples for 
glucose m
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA 
X
X
X
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection site
assessment n
X
X
X
X
X
X
X
X
X
X
X
P/MSS p
X
X
C-SSRS
X
X
Concomitant 
medications
Collected on an ongoing basis throughout study
X


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23Sep2016, Amendment 8
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Template 16.2
ABPM = ambulatory blood pressure monitoring; ADA = antidrug antibody; AE = adverse event; BP = blood pressure; C-SSRS = Columbia-Suicide Severity 
Rating Scale;
 ECG = electrocardiogram; eCRF = electronic case report form;  HbA1c = glycated hemoglobin;
IP = investigational product; min = minutes; MMT = mixed-meal test;; 
 PD = pharmacodynamic(s); PK = 
pharmacokinetic(s); P/MSS = Physical/Mental State Scale; RR = respiration rate; SAE = serious adverse event; V = Visit.
Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood draws 
should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (eg, for PK and PD) to occur as close as possible to 
the scheduled time. Ten minutes of supine rest should precede these assessments.
a
Dosing to take place in the clinic 
b
Instruct subject to arrive fasted for a minimum of 8 hours
c
Except Day -2, body weight measurement should be taken in the morning before breakfast.
d
Randomization may occur on either Day -1 or Day 1.
e
There are separate consent forms for the genetic future research sample and the non-genetic future research sample. Only sample(s) for which the subject has 
consented will be taken.
f
The subject should do a Ketostix test daily on non-clinic-visit days during the at-home self-administration period; the subject will indicate whether the result 
was negative or positive in the Daily Diary, and be instructed to call the clinic if the result is positive.
g
Breath alcohol testing is acceptable as an alternative to urine testing. 
h
Digital ECGs will be captured on;
Day -1; No specific time point
Day 1; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 2; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 3; Predose, 1, 2 (± 15 min); hours postdose
Day 6: Predose, 1, 2 (± 15 min); 4, 6 (± 30 min); hours postdose
Day 11; Predose, 1, 2 (± 15 min); 4, 6 (± 30 min); hours postdose
Day 16; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 17; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 18; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min); hours postdose
Day 19; Predose, 1, 2 (± 15 min) hours postdose
Day 22; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) and 24 (± 60 min) hours postdose
7-14 days post last dose visit; No specific timepoint 
24-hour postdose samples may be taken in the next calendar day. Whenever possible, meals should be scheduled such that at least 2 hours elapse between 
the meal and the next scheduled ECG time point.


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23Sep2016, Amendment 8
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Template 16.2
i
On Day -1, a minimum of 4 hours of cardiac telemetry will be performed, and any rhythm disturbance is to be recorded in the eCRF. Throughout the 
inpatient period, cardiac telemetry will be monitored continuously as tolerated, ie, balanced in consideration of potential skin abrasion AEs.
j
Vital Signs Schedule: 
Day -2; No timepoint specified
Day -1; No timepoint specified
Day 1; predose, and at 15, 30, 60, and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
Day 2; predose, 4 and 12 hour postdose 
Day 3; predose and 2 hours postdose. 
Day 6; predose, and at 15, 30, 60 and 90 minutes postdose; then at 2 and 4 hours postdose. 
Day 11; predose, and at 15, 30, 60 and 90 minutes postdose; then at 2 and 4 hours postdose. 
Day 16; predose, and at 15, 30, 60, and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
Day 17; predose, and at 15, 30, 60, and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
Day 18; predose, and at 15, 30, 60, and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
Day 19; predose, and at 15, 30, 60 and 90 minutes postdose; then at 2 hours postdose
Day 22; predose, and at 15, 30, 60 and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
7-14 days post last dose; No timepoint specified
k
PK Sampling Schedule for MEDI0382::
Day 1 (V): Predose
Day 6 (V): Predose
Day 11 (V): Predose 
Day 16 (V): Predose and 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 17 (V): 24 hours (± 60 min) post Day 16 dose (prior to Day 17 dose).
Day 18 (V): Pre-dose
Day 22 (V); Predose and 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose
Day 23 (V); 24 hours (± 60 min) post Day 22 dose
l
MMT Schedule: Following a minimum 8-hour fast and after collection of the 2-hour postdose PK sample (except on Day -1), blood samples for the tests 
indicated will be taken immediately prior to the subject drinking 1 entire can of Ensure Plus as a standardized meal (ie, “0 minutes”). On Day -1, Day 16, 


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23Sep2016, Amendment 8
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Template 16.2
and Day 22, blood samples for the tests indicated will additionally be taken at 15, 30, 45, 60, 90, 120, 180, and 240 minutes (± 5 min) after consumption of 
the standardized meal. 
m
Using the glucometer (ie, by finger-prick), during a full in-patient day in the clinic, the PD glucose will be taken 15 minutes (± 10 minutes) prior to and 
2 hours (± 10 minutes) after breakfast, mid-day, and evening meals, and prior to going to bed. The time of the meal start will be recorded in the eCRF every 
day the subject is an inpatient.. For the at-home dosing period, PD glucose samples are to be taken at home with the standardized glucometer (a) prior to 
breakfast (ie, fasting)/prior to self-dosing, (b) approximately 2 hours after the mid-day meal, (c) within 15 minutes prior to the evening meal, and 
(d) bedtime. On days where patients are both in clinic and at home the 4 point monitoring sequence should be followed
n
Injection Site Assessment Schedule: On Day 1 and the first day of each new dose level, the injection site will be assessed postdose at 4, hours. Thereafter 
(but not on up-titration days), the injection site will be assessed predose on the morning of every inpatient day and on the morning of final discharge.
Subjects will not need to assess injection site reactions, but to report anything unusual to site staff.
o
ABPM device will be fitted at a convenient time on the day stated and worn for 24 hours per period. On Day 22, the ABPM device should be fitted as soon 
as possible after the subject arrives on the unit that morning. Subjects will be given training on how to fit and wear the ABPM device during the day and 
overnight whilst sleeping
p
The P/MSS is to be completed by the subject within 30 minutes (+ 10 minutes) prior to starting the MMT and within 30 minutes (+ 10 minutes) after 
collection of the final MMT glucose metabolism panel blood sample for the inpatient period of the study and at the weekly site visits during the outpatient 
period.
q
Subject will dose themselves on the days indicated as long as the investigator is satisfied the subject is competent to do so, This may involve supervision and 
or assistance being given whilst in clinic, particularly on up-titration days. If not capable of accurately dosing themselves, subjects will be dosed at the unit 
each day or a trained health care professional will attend the home of the subject according to their preference. 
r
Sample to be taken following a minimum of 8 hours fasting.


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23Sep2016, Amendment 8
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Template 16.2
-Cohort 6
Table 4.2.2-7
Schedule of Treatment Period Procedures: Cohort 6 Overview
Dose Level
100 μg
200 μg
300 μg
Residential Inpatient
Outpatient
Outpatient
Residential Inpatient
Outpatient
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
V4
V5
V6
V7
Study Day
-2
-1
1
2
3
4-5
6
7-10
11
12
13
14
15-16
17
18
7-14 days post 
last dose
Procedure
Verify eligibility 
criteria
X
Admit to clinic
X
Xa,b
Xa,b
Discharge home
Xa
Xa
X
Outpatient clinic visit
X a,b
X
Medical and disease 
history
X
Targeted physical 
examination
X
X
X
X
X
X
Body weight c
X
X
X
X
X
X
Randomization
X d
X d
Hematology panel 
(predose as 
applicable)
X
X
X
X
X
X
Serum chemistry 
panel (predose as 
applicable)
X
Xr
X
X
Xr
Xr
X
X
X
Xr
X
Amylase and lipase 
(predose)
X
X
X
X
X
X
X
Lactate (predose as 
applicable)
X
X
X
X
X
X
X
HbA1c (predose as 
applicable)
X
X


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MEDI0382
23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-7
Schedule of Treatment Period Procedures: Cohort 6 Overview
Dose Level
100 μg
200 μg
300 μg
Residential Inpatient
Outpatient
Outpatient
Residential Inpatient
Outpatient
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
V4
V5
V6
V7
Study Day
-2
-1
1
2
3
4-5
6
7-10
11
12
13
14
15-16
17
18
7-14 days post 
last dose
Fructosamine 
(predose as 
applicable)
X
X
Fasting lipid profile 
(before breakfast and 
predose as applicable)
X
X
Optional future 
genetic research e
X
Optional future non-
genetic research e
X
X
X
Urinalysis (dipstick)
X
X
X
X
X
X
X
X
X
X
X
Urinary Ketostix f
X
X
X
Pregnancy test
X
X
X
X
X
Drug and alcohol  
screen g
X
X
 
ECG h
X
X
X
X
X
X
X
X
X
X
X
Telemetry i
X
X
X
X
X
X
X
X
X
Vital signs (BP, pulse, 
body temperature, 
RR) j
X
X
X
X
X
X
X
X
X
X
X
X
24-hour ABPM o
X
X
X
Subject completes
Daily Diary 
X
X
X
X
X
X


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23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-7
Schedule of Treatment Period Procedures: Cohort 6 Overview
Dose Level
100 μg
200 μg
300 μg
Residential Inpatient
Outpatient
Outpatient
Residential Inpatient
Outpatient
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
V4
V5
V6
V7
Study Day
-2
-1
1
2
3
4-5
6
7-10
11
12
13
14
15-16
17
18
7-14 days post 
last dose
Staff review Daily 
Diary with subject
X
X
X
Train subject on self-
administration at-
home dose 
preparation and 
glucometer and diary 
use as required (refer 
to Section 4.3.12)
X
X
X
X
X
X
X
IP administration by 
staff q
X
X
X
X
IP administration by 
subject q
X
X
X
X
X
X
X
X
X
PK for MEDI0382 k
X
X
X
X
X
X
X
PK for metformin
(prior to MEDI0382 
dose as applicable)
X
X
MMT l
X
X
X
Record start time of 
breakfast, mid-day, 
and evening meals
X
X
X
X
X
X
X
X
X
X
X
X
PD samples for 
glucose m
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA 
X
X
X
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection site
assessment n
X
X
X
X
X
X
X
X
X
X
P/MSS p
X
X


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MEDI0382
23Sep2016, Amendment 8
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Template 16.2
Table 4.2.2-7
Schedule of Treatment Period Procedures: Cohort 6 Overview
Dose Level
100 μg
200 μg
300 μg
Residential Inpatient
Outpatient
Outpatient
Residential Inpatient
Outpatient
Residential 
Inpatient
Outpatient
Visit Number
V2
V3
V4
V5
V6
V7
Study Day
-2
-1
1
2
3
4-5
6
7-10
11
12
13
14
15-16
17
18
7-14 days post 
last dose
C-SSRS
X
X
Concomitant 
medications
Collected on an ongoing basis throughout study
X
ABPM = ambulatory blood pressure monitoring; ADA = antidrug antibody; AE = adverse event; BP = blood pressure; C-SSRS = Columbia-Suicide Severity 
Rating Scale;
 ECG = electrocardiogram; eCRF = electronic case report form;  HbA1c = glycated hemoglobin;
IP = investigational product; min = minutes; MMT = mixed-meal test;; 
; PD = pharmacodynamic(s); PK = 
pharmacokinetic(s); 
 RR = respiration rate; SAE = serious adverse event; V = Visit.
Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood draws 
should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (eg, for PK and PD) to occur as close as possible to 
the scheduled time. Ten minutes of supine rest should precede these assessments.
a
Dosing to take place in the clinic
b
Instruct subject to arrive fasted for a minimum of 8 hours
c
Except Day -2, body weight measurement should be taken in the morning before breakfast.
d
Randomization may occur on either Day -1 or Day 1.
e
There are separate consent forms for the genetic future research sample and the non-genetic future research sample. Only sample(s) for which the subject has 
consented will be taken.
f
The subject should do a Ketostix test daily on non-clinic-visit days during the at-home self-administration period; the subject will indicate whether the result 
was negative or positive in the Daily Diary, and be instructed to call the clinic if the result is positive.
g
Breath alcohol testing is acceptable as an alternative to urine testing. 
h
Digital ECGs will be captured on;
Day -1; No specific time point
Day 1; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 2; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 3; Predose, 1, 2 (± 15 min) hours postdose
Day 6; Predose, 1, 2 (± 15 min); 4, 6 (± 30 min) hours postdose


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Template 16.2
Day 11; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 12; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 13; Predose, 1, 2 (± 15 min); 4, 6, 8, and 12 (± 30 min) hours postdose
Day 14; Predose, 1, 2 (± 15 min) hours postdose
Day 17; predose, and at 15, 30, 60 and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
7-14 days post last dose visit; No specific timepoint 
24-hour postdose samples may be taken in the next calendar day. Whenever possible, meals should be scheduled such that at least 2 hours elapse between 
the meal and the next scheduled ECG time point.


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23Sep2016, Amendment 8
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Template 16.2
i
On Day -1, a minimum of 4 hours of cardiac telemetry will be performed, and any rhythm disturbance is to be recorded in the eCRF. Throughout the 
inpatient periods, cardiac telemetry will be monitored continuously as tolerated, ie, balanced in consideration of potential skin abrasion AEs.
j
Vital Signs Schedule: 
Day -2; No timepoint specified
Day -1; No timepoint specified
Day 1; predose, and at 15, 30, 60, and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
Day 2; predose, 4 and 12 hour postdose 
Day 3; predose 2 and 4 hours postdose. 
Day 6; predose, and at 15, 30, 60 and 90 minutes postdose; then at 2 and 4 hours postdose. 
Day 11; predose, and at 15, 30, 60, and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
Day 12; predose, and at 15, 30, 60, and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
Day 13; predose, and at 15, 30, 60, and 90 minutes postdose; 2, 4, 6, 8, and 12 hours postdose
Day 14; predose, and at 15, 30, 60 and 90 minutes postdose; then at 2 and 4 hours postdose
Day 17; predose, and at 15, 30, 60 and 90 minutes postdose; then at 2 and 4 hours postdose
7-14 days post last dose; No timepoint specified
k
PK Sampling Schedule for MEDI0382:: 
Day 1 (V); Predose 
Day 6 (V); Predose 
Day 11 (V); Predose and 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 12 (V); 24 hours (± 60 min) post Day 11 dose
Day 13 (V); Predose
Day 17 (V); Predose and 0.5, 1, 2 hours (± 15 min); 4, 6, 8, and 12 hours (± 30 min) postdose.
Day 18 (V); 24 hours (± 60 min) post Day 17 dose.
l
MMT Schedule: Following a minimum 8-hour fast and after collection of the 2-hour postdose PK sample (except on Day -1), blood samples for the tests 
indicated will be taken immediately prior to the subject drinking 1 entire can of Ensure Plus as a standardized meal (ie, “0 minutes”). On Day -1, Day 11, 
and Day 17, blood samples for the tests indicated will additionally be taken at 15, 30, 45, 60, 90, 120, 180, and 240 minutes (± 5 min) after consumption of 
the standardized meal. 
m
Using the glucometer (ie, by finger-prick), during a full in-patient day in the clinic, the PD glucose will be taken 15 minutes (± 10 minutes) prior to and 
2 hours (± 10 minutes) after breakfast, mid-day, and evening meals, and prior to going to bed. The time of the meal start will be recorded in the eCRF every 
day the subject is an inpatient. For the at-home dosing period, PD glucose samples are to be taken at home with the standardized glucometer (a) prior to 


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breakfast (ie, fasting)/prior to self-dosing, (b) approximately 2 hours after the mid-day meal, (c) within 15 minutes prior to the evening meal, and (d) at 
bedtime. On days where patient is in the unit and at home, the 4 point monitoring schedule should be followed.
n
Injection Site Assessment Schedule: On Day 1 and the first day of each new dose level, the injection site will be assessed postdose at 4, hours. Thereafter 
(but not on up-titration days), the injection site will be assessed predose on the morning of every inpatient day and on the morning of final discharge. 
Subjects will not need to assess injection site reactions, but to report anything unusual to site staff.
o
ABPM device will be fitted at a convenient time on the day stated and worn for 24 hours and subjects with receive training from study site staff on how to fit 
and wear the device during the day and whilst sleeping. On Day 17, the ABPM device should be fitted as soon as possible after the subject arrives on the unit 
that morning
p
The P/MSS is to be completed by the subject within 30 minutes (+ 10 minutes) prior to starting the MMT and within 30 minutes (+ 10 minutes) after 
collection of the final MMT glucose metabolism panel blood sample for the inpatient period of the study and at the weekly site visits during the outpatient 
period.
q
Subject will dose themselves on the days indicated as long as the investigator is satisfied the subject is competent to do so, This may involve supervision and 
or assistance being given whilst in clinic. If not capable of accurately dosing themselves, subjects will be dosed at the clinical unit each day. 
r
Sample to be taken following a minimum of 8 hours fasting


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4.2.3
Follow-up Period
Table 4.2.3-1 shows procedures to be conducted during the follow-up period. Assessments 
should be performed in the order shown in the table.
Table 4.2.3-1
Schedule of Follow-up Procedures: All Cohorts 
Study Period
Follow-up
Visit Number
End of Study Visit
(Visit Number Varies by Cohort)
Procedure / Study Day
28 (± 2) Days Post Last Dose
Targeted physical examination
X
Pregnancy test (if applicable)
X
ECG a
X
Vital signs (BP, pulse, body temperature, RR) a
X
Body weight
X
MEDI0382 ADA b
X
Assessment of AEs/SAEs
X
Concomitant medications
X
AE = adverse event; ADA = antidrug antibody; BP = blood pressure; ECG = electrocardiogram; RR = 
respiration rate; SAE = serious adverse event.
a
Prior to discharge from the clinic, subjects should be assessed with respect to QT interval, HR and BP. If, 
after a period of 10 minutes supine rest, any of these parameters for an individual subject are outside the 
limits specified in the protocol exclusion criteria, or if in the opinion of the investigator any of these 
parameters are clinically significantly different versus baseline measures on an individual subject basis, the 
findings should be discussed with the medical monitor prior to the subjects’ release. Measurements may be 
re-assessed for confirmation.
b
If this sample is ADA positive, the subject will be asked to return to provide another sample at 
approximately 3 months after the end of study visit (post-study sample). If the sample taken at 3 months is
ADA positive, the subject will be asked to return to provide a sample in another 3 months (ie, 6 months 
after the end of study visit).
After the end of the follow-up period, subjects will return to the care of their own physicians 
according to local requirements and local standards.
4.2.4
Early Discontinuation or Unscheduled Study Visit
The following study procedures should be conducted for subjects who prematurely 
discontinue from the study or for subjects who require an unscheduled study visit. 
Assessments should be performed in the order shown.
•
Targeted physical examination
•
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•
Vital signs
•
Body weight
•
PK for MEDI0382 and for metformin
•
Lactate
•
MEDI0382 ADA
•
Assessment of AEs/SAEs
•
Injection site assessment
•
C-SSRS (Cohort 4, 5, and 6 only)
•
Concomitant medications
•
Pregnancy test (Cohort 4, 5, and 6 only)
4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
Mixed-meal Test
Refer to Section 4.3.7.
4.3.1.2
Weight
Weight will be measured at the time points specified in the schedules of procedures by 
cohort(s), after the subject has toileted and removed bulky clothing including shoes. 
Whenever possible, the same (properly calibrated) scale should be used for each 
measurement for any given subject.
4.3.2
Medical History, Physical Examination, Electrocardiograms, and Vital 
Signs
4.3.2.1
Medical History and Physical Examination
Complete medical history will include history and current medical conditions, past or present 
cardiovascular disorders, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, 
lymphatic, hematologic, immunologic, dermatological, psychiatric, genitourinary, drug and 
surgical history, or any other diseases or disorders.
Physical examinations will be performed by a physician or qualified designee and will 
include examination of the following body systems: immunologic/allergy; head, ears, eyes, 
nose, throat; respiratory; cardiovascular; gastrointestinal; musculoskeletal, neurological 
(structured neurological examination to encompass mental status; cranial nerves; nystagmus;


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motor system - muscle strength; sensory system - sensation; bowel and bladder function; 
deep tendon reflexes; gait; station; coordination; fundoscopy; and cerebellar function); 
psychiatric (to the extent of determining whether or not the subject is willing and able to 
cooperate with the required study procedures in the investigator’s judgment); dermatological, 
hematologic/lymphatic; and endocrine.
Any focal deficit identified at baseline should be documented in the electronic case report 
form (eCRF).
The full physical examination including structured neurological examination is required at 
screening. Targeted examinations (evaluation of selective body systems at the judgement of 
the physician or qualified designee based on subject presentation) are sufficient for the 
remaining time points.
Clinically significant abnormal findings will be recorded. Physical examinations will be 
performed at the time points specified in the schedules of procedures. Height will be 
measured at screening. 
4.3.2.2
Assessment of the Injection Site
Site staff will check the injection site for injection site reactions at the times specified in the 
study procedures table. Injection site reactions may include (but are not limited to) local 
erythema, pain, tenderness, induration, swelling, pruritus, ulceration and pigmentation.
4.3.2.3
Electrocardiograms
Electrocardiography will be used in this study to monitor cardiac safety. Digital ECG 
[dECG]/paper printout will be used for each subject at each time point. Telemetry will also 
be utilized, to improve capture of any potential arrhythmias. Date and time settings should be 
checked at the start of each study day and aligned with an official timekeeper for all 
machines used in the study. Skin preparation should be thorough and electrode positions 
should be according to standard 12-lead ECG placement. Electrocardiograms will be 
recorded after the subject has rested for 10 minutes in the supine position. Where significant 
skin irritation exists in response to telemetry electrode placement, subjects may be permitted 
to discontinue telemetry during stable dosing after 48 hours recording, although re-
application of telemetry is to be encouraged for 48 hours after dose up-titration in this 
situation.
The following variables will be reported: RR, PR, QRS and QT intervals. Derived parameters 
(such as HR, QTcF and others as applicable) will be calculated.


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12-lead Electrocardiograms
Electrocardiograms will be digitally recorded and printed on paper according to the schedules
specified for each cohort. Digital ECGs will be captured as triplicate measures in a single 
recording. Printed ECGs will be reviewed by the investigator for assessments of subject 
eligibility related to the ECG criteria and assessment of AEs. The printed ECGs will be used
for the real time bedside ECG assessment made by the investigator, and at minimum, a single 
representative ECG should be printed and archived in the subject’s file.
The investigator may record 12-lead ECGs at other time points if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason.
Digital ECGs will be collected according to the schedules specified for each cohort. These 
will be submitted to the sponsor (or designee) and to the ECG vendor. The ECG vendor will 
perform the dECG analysis and interpretation in this study using their methodology for 
dECG analysis. If the central readers pick up an abnormality that the clinician may have 
missed, they will notify the investigator who will review the ECG and report any AEs as 
necessary.
Telemetry
Telemetry will be used to continuously monitor HR 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 continuous during the 
inpatient treatment period as specified in the schedules by cohort(s). 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 dECG.
4.3.2.4
Vital Signs
Vital sign measurements (BP, pulse, body temperature, and respiration rate) will be obtained
after the subject has rested in the supine position for at least 10 minutes at the time points
specified in the schedules of procedures for each cohort (for time points where ECG 
recording precedes vital sign measurement, the 10 minute rest in the supine position prior to 
the ECG suffices for the rest prior to vital sign measurement). Route of body temperature 
measurement will be according to local custom.


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During the at-home self-administration dosing period for Cohorts 4, 5, and 6, ambulatory BP 
and HR monitoring will be used for the 24-hour period after receipt of the SC dose at the 
clinic visit.
Prior to discharge from the unit, subjects should be assessed with respect to QT interval, HR 
and BP. If, after a period of 10 minutes supine rest, any of these parameters for an individual 
subject are outside the limits specified in the protocol exclusion criteria, or if in the opinion 
of the investigator any of these parameters are clinically significantly different versus 
baseline measures on an individual subject basis, the findings should be discussed with the 
medical monitor prior to the subject’s release. Measurements may be re-assessed for 
confirmation.
4.3.3
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. 
Clinical laboratory safety tests will be performed in a licensed central or licensed local 
clinical laboratory. Abnormal laboratory results considered to be clinically significant should 
be repeated as soon as possible (preferably within 24 to 48 hours). 
The following clinical laboratory tests will be performed (please refer to time points in the 
schedules of procedures by cohort[s]): 
Serum Chemistry Panel
•
Calcium
•
Alkaline phosphatase (ALP)
•
Chloride
•
Total bilirubin
•
Potassium
•
Gamma glutamyl transferase
•
Sodium
•
Creatinine
•
Bicarbonate*
•
Blood urea nitrogen
•
AST
•
Glucose
•
ALT
•
Albumin
•
Magnesium (Cohorts 5 and 6)
Notes for serum chemistries: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently 
and assessed concurrently. * may be measured via serum chemistry sample of blood gas analyzer per local 
procedures. 


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Hematology Panel
•
White blood cell count with differential
•
Platelet count
•
Red blood cell count
•
Mean corpuscular volume
•
Hematocrit
•
Mean corpuscular hemoglobin concentration
•
Hemoglobin
Coagulation Panel
•
Prothrombin time (screening only)
•
Activated partial thromboplastin time (screening only)
Urinalysis
•
Color
•
Leucocyte esterase
•
Appearance
•
Bilirubin
•
Specific gravity
•
Urobilinogen
•
pH
•
Nitrite
•
Protein
•
Urine microscopy and urine casts (as required)
•
Glucose
•
Urine culture (as required)
•
Ketones
•
Urine drug and alcohol screen a (screening and 
Day -2 for all cohorts; at the weekly site visits for 
Cohort 4 and just prior to initiation of the 300 μg 
dose for Cohorts 5 and 6 at the discretion of the 
investigator)
•
Blood
a
Breath alcohol testing is acceptable as an alternative to urine testing.
Note: Urinalysis for specific gravity, pH, protein, glucose, ketones, blood, leucocyte esterase, bilirubin, 
urobilinogen, and nitrite may be performed at the site using a licensed test (dipstick).
Other Tests
•
Calcitonin (screening only), TSH (screening only), pancreatic amylase, lipase
•
Blood lactate
•
HbA1c
•
•
Anti-drug antibodies 
•
Total immunoglobulin (Ig) and subsets (Ig A/E/G/M)
•
Follicle-stimulating hormone (for females at screening only)
•
Urine pregnancy test (females only)
•
Hepatitis B surface antigen, hepatitis C antibody (screening only)
•
HIV-1, -2 antibodies (screening only)
•
Glucose metabolism panel for MMT for Cohort 1 to 4: Timed glucose, insulin, pro-insulin, c-peptide, GLP-
1, glucagon, and GIP
•
Glucose metabolism panel for MMT for Cohorts 5 and 6; Timed glucose and insulin
•
Fructosamine (Cohorts 4, 5, and 6 only)
•
 


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•
4.3.4
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 371 mL for Cohort 1, 490 mL for Cohort 2, 445 mL for 
Cohort 3, 553 mL for Cohort 4, 425 mL for Cohort 5, and 405 mL for Cohort 6. Additional 
blood samples may be collected at the discretion of the investigator in the event of abnormal 
laboratory findings or an adverse event.
4.3.5
Glucometer Blood Glucose Readings during the Inpatient Period
At study start, each subject in every cohort will be issued a standardized glucometer. Subjects 
will be encouraged to follow their normal practice with respect to finger-prick blood testing 
for glucose at normal testing frequency and include extra finger-prick tests if at any time they 
feel unwell and feel the symptoms may be due to hypo- or hyperglycemia during the 
inpatient period. If the investigator/site staff feel that a subject could be experiencing hypo-
or hyperglycemia, blood glucose should be tested with the standardized glucometer issued to 
that subject. Any glucometer blood glucose values of concern should be reported as AEs. The 
PD glucose measurements will be taken with the glucometer (15 minutes [± 10 minutes]
prior to and 2 hours [± 10 minutes] after breakfast, mid-day, and evening meals, and prior to 
going to bed, and for which start time of meal is recorded) and recorded. Other inpatient 
glucometer blood glucose readings are for “real time” safety purposes, and will only be 
captured if reported as AEs.
4.3.6
Pharmacokinetic Evaluation and Methods
Separate PK samples will be collected to measure MEDI0382 concentration and metformin 
concentration. The PK sampling times and windows for collection are specified in the 
schedules of procedures by cohort(s). Sampling within the specified window around the 
specified time will not be considered a protocol deviation but the exact time of sampling 
should be recorded. A sample schedule for Day 1 that depicts the relationship of the 
MEDI0382 PK sampling times relative to dosing and meals is provided in Table 4.3.8-1
together with PD sampling times.


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4.3.7
Pharmacodynamic Evaluation and Methods
Mixed-meal Test
Following a minimum 8-hour overnight fast and after collection of the 2-hour postdose PK 
blood sample (as applicable), the subject will undergo a MMT. For the MMT, the subject
will consume a standardized meal (Ensure Plus, a nutritional supplement containing the 
components of fat, carbohydrate and protein, which make up a standard MMT) within 
5 minutes, and timed serial blood samples will be obtained for measurement of glucose and 
parameters related to glucose metabolism through 240 minutes after consumption of the 
standardized meal (with no additional food intake during this time). The MMT procedures 
will be performed at the time points specified in the schedules of procedures by cohort(s).
The time points are also summarized in Section 3.1.1.
The timed pre- and post-MMT blood sample collections are for measurement of a panel of 
glucose metabolism markers: glucose, insulin, pro-insulin, c-peptide, GLP-1, glucagon, and 
GIP as indicated by the footnotes in the example schedule for PK and PD/efficacy in
Table 4.3.8-1. Glucose measurements from these pre- and post-MMT samples will be used
for the primary efficacy assessment (Cohort 4). All MMT test results will be used to generate 
PD profiles. For Cohorts 5 and 6, only glucose and insulin will be measured.
Blood will be drawn within 15 minutes before consuming the standardized meal (ie, 
“0 minutes”), and at 15, 30, 45, 60, 90, 120, 180, and 240 minutes (± 5 minutes) after 
consumption (except at the weekly visits for Cohort 4, during which the time points will be 
abbreviated to include 0, 30, 60, 120, and 240 minutes [± 5 minutes]). Blood sampling should 
occur as close as possible to the specified times for the MMT. Sampling ± 5 minutes of the 
specified time will not be considered a protocol deviation but the exact time of sampling 
should be recorded.


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4.3.8
Combined Pharmacokinetic and Pharmacodynamic Blood Sampling 
Example Schedule
Table 4.3.8-1
Example Schedule for MEDI0382 PK and for PD Blood 
Sample Collections on Day 7 (Cohort 1), Day 11 (Cohort 2), 
Day 15 (Cohort 3), and Day 41 (Cohort 4), Day 22 (Cohort 5), 
and Day 17 (Cohort 6)
Example Clock Time
Time Relative to 
Dosing
MEDI0382 PK 
Sample
Time Relative to 
MMT
PD Sample
Overnight (minimum 8-hour fast)
5:55 a
Predose
X
6:00                                                                      Administer IP
6:30
0.5 hour postdose
X
7:00
1 hour postdose
X
8:00 
2 hours postdose
X
8:15
15 minutes before 
breakfast
X b
8:25 
Within 15 min 
before ingesting 
Ensure Plus (MMT)
X c
8:30                                                                        Ensure Plus
after collection of the 2-hour post dose PK sample (Ensure Plus to be consumed within 5 minutes);
actual start time to be recorded in eCRF
Or Breakfast
8:45
15 minutes
X c
9:00 
30 minutes
X c
9:15
45 minutes
X c
9:30 
60 minutes
X c
10:00 
4 hours postdose
X
90 minutes
X c
10:30 
120 minutes
X b ,c
11:30 
180 minutes
X c
12:00 
6 hours postdose
X
12:30 
240 minutes
X b,c
12:45                                                                   Mid-day Meal
(after collection of the 240-minute MMT sample; actual start time to be recorded in eCRF)
14:00
8 hours postdose
X
14:45
X b
15:00
2 hours after 
mid-day meal
X b
18:00 
12 hours postdose
X
18:15
Within 15 minutes 
before evening meal
X b


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Table 4.3.8-1
Example Schedule for MEDI0382 PK and for PD Blood 
Sample Collections on Day 7 (Cohort 1), Day 11 (Cohort 2), 
Day 15 (Cohort 3), and Day 41 (Cohort 4), Day 22 (Cohort 5), 
and Day 17 (Cohort 6)
Example Clock Time
Time Relative to 
Dosing
MEDI0382 PK 
Sample
Time Relative to 
MMT
PD Sample
18:30                                                                     Evening Meal
(actual start time to be recorded in eCRF)
20:30
X b
Pre bedtime
X b
Overnight (minimum 8 hours of fasting)
5:55 (next day)
24 hours postdose
X
After a minimum 
8-hours fast
X b
eCRF = electronic case report form; GIP = gastric inhibitory peptide; GLP-1 = glucagon-like peptide-1; IP = 
investigational product; min = minutes; MMT = mixed-meal test; PD = pharmacodynamics(s); PK = 
pharmacokinetic(s).
Notes: For instances in which a PK and PD blood sample are required at the same clock time, every effort 
should be made to take the samples using a single venipuncture.
a
This is an example schedule. Actual start time may vary, but the timing relative to dosing and timing 
relative to MMT should be maintained.
b
Using the glucometer (ie, by finger-prick); for PD glucose only. 
c
For the complete glucose metabolism panel (glucose, insulin, pro-insulin, c-peptide, GLP-1, glucagon, and 
GIP). Note: On MMT days not listed in the title of this table, components of the panel are to be drawn as 
specified in the schedules of procedures by cohort.
Note that ECGs and vital signs immediately precede PK sample times (refer to schedules of 
assessments by cohort). Whenever possible, it is preferable to have meals consumed after 
ECGs or to perform ECGs ≥ 1.5 hours after a meal, to avoid the influence of food intake on 
HR, T-wave morphology, and QT assessment.
4.3.9
Immunogenicity Evaluation and Methods
Antidrug antibody sampling will occur at the time points specified in the schedules of 
procedures by cohort(s). A screening assay will be used to determine ADA-positive samples. 
This will be in the form of a traditional ligand-binding “bridging” assay using 
electrochemiluminescence. Any positive samples will be tested in a confirmatory assay 
whereby the specificity of the ADA response will be confirmed as either positive or negative 
with respect to MEDI0382. Cross reactivity of ADA-positive samples to GLP-1 and 
glucagon may also be assessed in the confirmatory assay. Titer evaluation will be performed 
on samples that are confirmed positive for ADA. For subjects with a positive ADA result, a
qualitative analysis of incretin hormone levels in response to MMT (ie, glucagon, GLP-1, 


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glucose, and insulin) will also be performed to assess whether any correlation exists between 
the response and ADA positivity.
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.
4.3.10
Exploratory Endpoints Evaluations and Methods (Accelerometer,
Biomarkers, and Magnetic Resonance Imaging)
 
 
 
 
 
 
 
 
 


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4.3.10.6
Magnetic Resonance Imaging of the Liver/Abdomen (Cohort 4)
At study sites that have the capacity and if subject is suitable and has consented, MRI of the 
liver/abdomen will be performed at the time points specified in the schedules of procedures 
for Cohort 4 only. Detailed instructions will be provided in the MRI manual. Subject
suitability to be scanned will be determined against local criteria at the scanning site.
4.3.11.1
Columbia-Suicide Severity Rating Scale (Cohorts 4, 5, and 6)
The C-SSRS is a 2-page validated questionnaire that assesses suicidal ideation and behavior.
The Baseline Form will be used on Day -1, and the Since Last Visit Form will be used at the 
time points shown in the schedules of procedures for Cohorts 4, 5, and 6 to assess change 
from baseline (Appendix 4). Site staff will complete the assessment with the subject in a 
private, quiet place.
 
 
 
 
 
4.3.12
Training of Cohorts 4, 5, and 6 Subjects for At-home Activities
4.3.12.1
Training for Self-administration and At-home Preparation of 
Investigational Product
Cohort 4
While the subject is still an inpatient at the unit, qualified study site personnel will train the 
subject about the technique of SC abdominal self-administration for each dose 
administrationat dose level 1 and dose level 2 as shown in Table 4.2.2-4 (8 doses total). 
Beginning with the first dose at dose level 3, while the subject is still an inpatient undergoing 
up-titration (5 doses), qualified site personnel will work daily with the subject to train 


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him/her how to prepare their daily dose and the subject will administer his or her own dose 
under their watchful supervision. 
Cohorts 5 and 6
While the subject is still an inpatient at the clinic, qualified site personnel will train the 
subject about the technique of SC abdominal self-administration during the initial days 3 
days of inpatient dosing, beginning with the first dose. Qualified site personnel will work 
daily with the subject to train him/her how to prepare their daily dose and the subject will 
administer his or her own dose under their watchful supervision.
Subjects will be given an instructions sheet for self-administration and at-home preparation 
of investigational product while in residence at the clinic.
4.3.12.2
Training during the Inpatient Period for Using the Standardized 
Glucometers during the Inpatient and Outpatient Periods
In Clinic
At the beginning of the study, a standardized glucometer will be provided to each subject in 
all cohorts. This glucometer will be used for the PD glucose samples. Site staff will make a 
point of explaining how the glucometer should be used for the purposes of this study (refer to 
Section 4.3.5), and allow the subject to demonstrate that he or she uses it properly (under 
watchful supervision) before the subject is discharged from the clinic after the inpatient 
up-titration period.
At Home
Blood glucose measurements are to be taken with the standardized glucometer supplied for 
this study (a) prior to breakfast (ie, fasting)/prior to self-dosing, (b) approximately 2 hours 
after the mid-day meal, (c) within 15 minutes prior to the evening meal, and 
(d) approximately every other day at bedtime (every bedtime for Cohort 5 and 6). Meal start 
times are to be recorded in the Daily Diary (see Section 4.3.12.3).
At the weekly site visit, relevant data (eg, blood glucose values, dates and times) will be 
collected by site staff. 
4.3.12.3
Training for Completing the Daily Diaries during the At-home Self-
administration Period
Before discharge from the unit, at the time points indicated in the overview schedule of 
procedures for Cohorts 4, 5, and 6, each subject in these cohorts will be trained on how to 


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complete the Daily Diary. At the time points indicated in the at-home schedule of procedures 
for Cohort 4, each subject will be given a Daily Diary for the next week to be completed at 
home, and each subject in Cohorts 5 and 6 will be given a Daily Diary to complete according 
to the schedule outlined in Section 4.2.2. Subjects will be encouraged to complete the Daily 
Diary as accurately as possible.
The following entries will be made daily into the Daily Diary and collected and reviewed by 
site staff at the appropriate visits:
•
Date
•
Confirmation that the acceptable temperature was maintained 
•
Unique kit number of dose
•
Time of self-dose administration
•
Start time of each meal
•
Daily Ketostix® result (negative or positive) (Note: In case a Ketostix [ketone] test result 
is positive, the subject will be instructed to call the site)
•
Any new medications or changes to standard medications (Note: Subjects will be 
instructed to contact the site in the event of any new medications or changes to 
medication)
•
Any symptoms experienced (Note: For data capture purposes, this information will be 
captured in a comment field. Subjects will be instructed to contact the site in the event of 
any symptoms being experienced. Based on the information provided by the subject, the 
investigator will report any AEs, what action was taken, and if no action was taken, why 
no action was taken) 
If the subject forgets to fill in any requested information, it will not be considered a protocol 
deviation.
4.3.12.4
Training for Application and Wearing of ABPM Device
Subjects will be given training at their local study site about how to set up and apply the 
ABPM device. In brief, an appropriate size cuff encircling 80% to 100% of the arm will be 
selected and the device will be fitted to the non-dominant arm of the subject, with the bladder 
placed over the artery and an initial test reading performed. The subjects will be advised that 
for the first reading the device will inflate to a pressure of 180 mm Hg, and thereafter the 
device will adapt to inflate to a pressure just above the last recorded BP. The subject will be 
advised to undergo normal daily activities while wearing the cuff, and he/she will be advised 
to avoid any strenuous form of activity, bathing, or showering while wearing the cuff. The 
subject will be advised to remain still during a measurement with the arm relaxed at heart 


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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, pulse pressure, HR and mean arterial pressure readings will be recorded over a period of 
24 hours.
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include but are not limited 
to the following: 
1. The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects (eg, drug-related SAEs, anaphylactic reaction, hepatic enzyme 
alterations meeting Hy’s law, signs of renal toxicity, QT interval prolongation)
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
5. Sponsor decision to terminate the study
If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Institutional Review Board (IRB) / Independent Ethics Committee (IEC) promptly
and provide the reason(s) for the suspension/termination. If the study is suspended for safety 
reasons and it is deemed appropriate by the sponsor to resume the study, approval from the 
relevant regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to 
resuming the study.


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4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
4.5.1.1
Identity of Investigational Product(s)
MedImmune will provide the investigator(s) with investigational product using designated 
distribution centers. 
Table 4.5.1.1-1
Identification of Investigational Products
Investigational Product
Manufacturer
Concentration and Formulation as 
Supplied
MEDI0382
MedImmune
2 mg/mL liquid formulation
Placebo
MedImmune
Solution
Note: Diluent (solution manufactured by MedImmune) will be provided to sites for use in the event that a dose 
level requires dilution).
 
 
  
 
 
Investigational product will be supplied to the site as blinded kits each containing 1 vial. 
These kits will each contain a unique identifying number, which will appear on both the vial 
and kit label.
For in-clinic dosing: investigational product kits (ie, containing 1 vial) will be dispensed via 
the IXRS.
For Cohorts 4, 5 and 6 for the in-home dosing: investigational product will be provided to the 
subject in a container with sufficient vials that have 1.3 mL of liquid product in each. The kit 
must be stored in the original container in the refrigerator at all times and must not exceed 
25°C. In addition, sufficient syringes, needles, wipes, gloves and one container for used 
equipment will also be provided.
In the event that a subject is deemed not competent to perform at home dosing, the 
investigational product kit will be stored by the site and utilized there for subject 
administration.


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The unique identifying number on MEDI0382 and matching placebo vial and kit labels will 
be random, to maintain the blind of MEDI0382 and placebo investigational product.
4.5.1.2
Investigational Product Handling
In-clinic Investigational Product Handling
Investigational product should be stored at 2°C to 8°C in the original container. 
Investigational products do not contain preservatives and any unused portion must be 
discarded. Preparation of syringes for dose administration is to be performed aseptically. 
Total in-use storage time from needle puncture of the investigational product vial to start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C. If 
storage time exceeds these limits, a new dose must be prepared from new vials.
At-home Investigational Product Handling
The entire carton of investigational product should be stored in the refrigerator and must not 
exceed 25°C. Subjects should be asked to ensure they have a normal domestic refrigerator at 
home, which should be between 4°C and 8°C.
The subject is to remove from the refrigerator only the 1-vial kit required for their daily dose. 
All other kits are to be kept in the outer carton in the refrigerator until required. The subject 
is to make sure that the temperature does not exceed 25°C. The subject is to avoid the risk of 
freezing the investigational product by carefully placing the investigational product within 
their refrigerator, and is not to use investigational product if it has been frozen. The subject is 
not to administer investigational product if the time outside of the refrigerator has exceeded 1 
day; if storage time exceeds this limit, a new dose must be prepared from a new vial. After 
use, the subject is to retain the vial during the at-home self-administration period for return to 
the site (along with any unused vials) for accountability at the weekly visit. Investigational 
product should be protected from heat and sunlight. The needle should always be removed
and safely discarded after each use.
4.5.1.3
Investigational Product Inspection
Investigational Product Inspection
Each vial selected for dose preparation should be inspected. If there are any defects noted 
with the investigational product, the investigator and site monitor should be notified 
immediately. Refer to the Product Complaint section for further instructions 
(Section 4.5.1.7).


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4.5.1.4
Dose Preparation Steps
In-clinic Dose Preparation Steps
The final delivery volume and concentration for each dose level are described in
Table 4.5.1.4-1 and Table 4.5.1.4-2.
Cohorts 1-3 Dose Preparation Steps
Table 4.5.1.4-1
Cohorts 1–3 MEDI0382 and Placebo Dose Preparation
Dose Level
Formulation Stock Concentration 
(mg/mL)
Volume of Injection 
(mL)
100 μg or placebo
0.2
0.5
150 μg or placebo
0.2
0.75
200 μg or placebo
0.2
1.0
Calculations for dose preparation for Cohorts 1-3 are as follows:
1. Investigational product is supplied in 3 mL glass vials at a nominal concentration of 
2 mg/mL.
2. Determine from Table 4.5.1.4-1 the correct dose level and injection volume.
3. For doses of 100, 150, and 200 μg, a 10-fold diluted stock concentration of 0.2 mg/mL 
will be prepared.
4. To make a 10-fold diluted MEDI0382, it is recommended to take 0.2 mL of MEDI0382 
Drug Product using a needle and 1 mL syringe, add it into a sterile empty vial, followed 
by addition of 1.8 mL of diluent using a needle and 1 mL syringe into the same vial. The 
vial should be mixed by swirling gently to make a homogenous final admixture.
The volume to be delivered will be withdrawn using a 1 mL syringe, and then connected to a 
fresh 30G needle prior to administration.
No incompatibilities between MEDI0382 and plastics tested during the compatibility study 
(ie, polypropylene) syringe, or needle have been observed. (Syringe sizes, vial sizes and 
other consumables may be altered at the discretion of the sponsor, please refer to the 
investigational product manual).


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Cohort 4 Dose Preparation Steps
Table 4.5.1.4-2
Cohort 4 MEDI0382 and Placebo Dose Preparation
Dose Level
Formulation Stock Concentration (mg/mL)
Volume of Injection (mL)/ 
(U)*
Initial Dose; 100 μg or 
placebo
2
0.05 (5)
Titration Dose 1; 
150 μg or placebo
2
0.075 (7.5)
Titration Dose 2; 
200 μg or placebo
2
0.1 (10)
U = units
* The 0.3 mL syringe is marked in “units” where each unit = 0.01 mL, so 0.05 mL = 5 units; 0.075 mL = 
7.5 units; 0.1 mL = 10 units. 
Calculations for dose preparation for Cohort 4 are as follows:
•
Investigational product is supplied in 3 mL glass vials at a nominal concentration of 
2 mg/mL.
•
Determine from Table 4.5.1.4-2 the correct dose level and injection volume.
The volume to be delivered will be withdrawn using a 0.3 mL insulin syringe. Please 
note, dilution of investigational product will not be required for Cohort 4.
Please refer to subject at-home dosing instructions and investigational product manual for 
more information.
Cohort 5 Dose Preparation Steps
Table 4.5.1.4-3
Cohort 5 MEDI0382 and Placebo Dose Preparation
Dose Level
Formulation Stock Concentration (mg/mL)
Volume of Injection (mL)/ 
(U)*
Initial Dose; 100 μg or 
placebo
2
0.05 (5)
Titration Dose 1; 
150 μg or placebo
2
0.075 (7.5)
Titration Dose 2; 
200 μg or placebo
2
0.1 (10)
Titration Dose 3; 
300 μg or placebo
2
0.15 (15)
U = units
* The 0.3 mL syringe is marked in “units” where each unit = 0.01 mL, so 0.05 mL = 5 units; 0.075 mL = 
7.5 units; 0.1 mL = 10; 0.15 mL = 15 units. 


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Calculations for dose preparation for Cohort 5 are as follows:
•
Investigational product is supplied in 3 mL glass vials at a nominal concentration of 
2 mg/mL.
•
Determine from Table 4.5.1.4-3 the correct dose level and injection volume.
The volume to be delivered will be withdrawn using a 0.3 mL insulin syringe. Please note, 
dilution of investigational product will not be required for Cohort 5.
Please refer to subject at-home dosing instructions and investigational product manual for 
more information.
Cohort 6 Dose Preparation Steps
Table 4.5.1.4-4
Cohort 6 MEDI0382 and Placebo Dose Preparation
Dose Level
Formulation Stock Concentration (mg/mL)
Volume of Injection (mL)/ 
(U)*
Initial Dose; 100 μg or 
placebo
2
0.05 (5)
Titration Dose 2; 
200 μg or placebo
2
0.1 (10)
Titration Dose 3; 
300 μg or placebo
2
0.15 (15)
U = units
* The 0.3 mL syringe is marked in “units” where each unit = 0.01 mL, so 0.05 mL = 5 units; 0.075 mL = 
7.5 units; 0.1 mL = 10; 0.15 mL = 15 units.
Calculations for dose preparation for Cohort 6 are as follows:
•
Investigational product is supplied in 3 mL glass vials at a nominal concentration of 
2 mg/mL.
•
Determine from Table 4.5.1.4-4 the correct dose level and injection volume.
The volume to be delivered will be withdrawn using a 0.3 mL insulin syringe. Please note, 
dilution of investigational product will not be required for Cohort 6.
Please refer to subject at-home dosing instructions and investigational product manual for 
more information.


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At-home Dose Preparation Steps
No dilution steps for preparation of investigational product will be performed by the subject 
at home. Specific dose preparation instructions will be provided to subjects on an instruction 
sheet (see Section 4.5.1.5).
4.5.1.5
Treatment Administration
If diluent is required: investigational product should be removed from the refrigerator for at 
least 30 minutes and a maximum of 2 hours for temperature equilibration. If no diluent is 
required, 15 minutes is recommended for temperature equilibration.
In-clinic Treatment Administration
The first day of dosing is considered Day 1. On the day of each dose, following an overnight 
fast for a minimum of 8 hours, investigational product will be administered as soon as is 
practicable after rising. For Cohorts 1-3, investigational product will be administered by SC 
injection in the lower abdomen utilizing a 1 mL syringe and a 30G needle. For Cohorts 4, 5,
and 6 a 0.3 mL insulin syringe will be utilized during the in-clinic treatment period. Please 
refer to the investigational product manual. 
At-home Treatment Administration
Each subject will be provided with an at-home dosing instructions sheet. The sheet will also 
include storage conditions and dose preparation information.
A once-daily dose is to be self-administered by SC injection as soon as practicable upon 
waking each morning prior to breakfast. Refer to Section 4.3.12.3 about training the subject 
for at-home self-administration. For Cohorts 4, 5, and 6 a 0.3 mL insulin syringe will be 
utilized during the at-home treatment period. Please refer to the investigational product 
manual. 
The investigational product is packaged in a carton with sufficient vial kits. Each vial 
contains 1 mL of liquid product with adequate overfill. The carton must be stored in the 
refrigerator.


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4.5.1.6
Monitoring of Dose Administration
Monitoring of In-clinic Dose Administration
As with any exogenous peptide delivered subcutaneously, 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 24-hour post dosing period, vital signs will be 
periodically assessed (see Section 4.3.2.4), and the site of administration will be checked for 
signs of injection site reaction (see Section 4.3.2.2).
Monitoring of At-home Dose Administration
Subjects will be instructed on how and what to record daily for each dose self-administered 
in the Daily Diary (see Section 4.3.12.3).
4.5.1.7
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone: +1-301-398-2105
+1-877-MEDI-411 (+1-877-633-4411)
Fax:
+1-301-398-8800
Mail:
MedImmune, LLC
Attn: Product Complaint Department
One MedImmune Way
Gaithersburg, MD USA 20878


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4.5.2
Additional Study Medications
Subjects should continue to take their metformin therapy at their regular dose prescribed, and 
any other medication prescribed for the treatment of comorbidities associated with T2DM.
Subjects may also continue to take their regular prescribed daily dose of statin during the 
study. MedImmune will not provide metformin or statin.
4.5.3
Labeling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. The label will fulfill GMP
Annex 13 requirements for labeling. Label text will be translated into local languages, as 
required.
4.5.4
Storage
Store investigational product at the clinical site at 2°C to 8°C. Investigational product taken 
home by the subject must be stored in a refrigerator and must not exceed 25°C. Testing of the 
investigational product for photosafety is not applicable because the investigational product 
will not be topically or locally applied, nor does it partition into the skin. Furthermore, the 
investigational product is a peptide comprised of natural amino acids and thus is not expected 
to undergo photodegradation to form toxic metabolites.
4.5.5
Treatment Compliance
Investigational product will be administered by study site personnel, who will monitor 
compliance during the inpatient period. Compliance during the at-home dosing period for 
Cohorts 4, 5, and 6 will be monitored via Daily Diary entries, returned vials, and PK data.
4.5.6
Accountability
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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Accountability for Doses Administered by the Subject during the At-home 
Self-administration Period
Subjects will be instructed to return each used vial and any unused vials to the site along with 
the Daily Diaries containing dosing information when they return for their weekly visits.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IXRS will be used for randomization to a treatment group and assignment of blinded 
investigational product kit numbers. A subject is considered randomized into the study when 
the investigator notifies the IXRS that the subject meets eligibility criteria and the IXRS 
provides the assignment of blinded investigational product kit number to the subject.
For Cohorts 1, 2, and 3, nine subjects in each cohort will be randomized in a 2:1 ratio to 
receive MEDI0382 or placebo. For Cohort 4, approximately 48 subjects will be randomized 
in a 1:1 ratio to receive MEDI0382 or placebo. For Cohorts 5 and 6, 16 subjects in each 
cohort will be randomized in a 3:1 ratio to receive MEDI0382 or placebo. The IXRS will 
assign a unique randomization code and treatment arm for the subject.
4.6.2
Methods for Ensuring Blinding
This is a double-blind study in which MEDI0382 and placebo are identically labeled and 
indistinguishable in appearance. As such, the pharmacist, the subject, and the investigator 
staff who are involved in the treatment or clinical evaluation of the subjects will NOT be 
aware of the treatment received (International Council for Harmonisation [ICH] E9). The 
sponsor will not be blinded to treatment allocation to allow for evaluation of data for dose 
escalation decisions (including safety, PK and PD data) and 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. The medical monitor from the CRO will 
remain blinded throughout the study, and will review blinded AEs and may be asked 
questions around clarification of the information by the site. In the event that treatment 
allocation for a subject becomes known to the investigator or other study staff involved in the 
management of study subjects, the sponsor must be notified immediately. 


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4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IXRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
subject having received investigational product. In the majority of cases, the management of 
a medical emergency would be the same whether or not investigational product was received 
by the subject. If this was the case, the investigational product allocation should not be 
unblinded.
4.7
Restrictions during the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken by the 
subject from the time of screening until the end of the clinical phase of the study (final study 
visit). Any concomitant medication(s), including herbal preparations, taken during the study 
will be recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications described in Section 4.7.2. 
Specifically, subjects should continue to take their metformin therapy at their regular dose 
prescribed, and any other medication prescribed for the treatment of comorbidities associated 
with T2DM. Subjects may also continue to take their regular prescribed dose of statin during 
the study. Statins are allowed in all cohorts. Subjects should receive full supportive care 
during the study in accordance with their institutional guidelines. In the event of nausea or 
vomiting subjects should be encouraged to reduce oral intake of food until symptoms pass. In 
the event that symptoms do not improve, subjects should be offered a centrally acting anti-
emetic such as a 5HT-3 antagonist in the first instance, rather than a prokinetic agent such as 
domperidone or metoclopramide. Hormone replacement therapy and agents for benign 
prostatic hyperplasia are also permitted.
4.7.2
Prohibited Concomitant Medications
Other than the medications described above, use of the following medications are restricted, 
generally speaking, from the time specified in the entry criteria until after the final follow-up 
visit:


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•
Use of other concomitant medications, including over-the-counter medications, herbal 
supplements, multivitamins, and vitamins containing selenium, that are thought to play a 
role in control of body weight or appetite, is prohibited from 1 week prior to Day 1 until 
after the final follow-up visit. Subjects must be instructed not to take any medications, 
including over-the-counter products, without first consulting with the investigator.
•
Use of any other GLP-1 agonist is prohibited.
•
Systemic corticosteroids are prohibited within 28 days prior to screening and throughout 
the study, except if needed to treat a generalized allergic reaction or anaphylaxis as 
defined in Appendix 3. (Inhaled, intranasal, topical, and intra-articular corticosteroids are 
permitted.) Systemic corticosteroid use should first be discussed with and permitted by 
the medical monitor.
•
Use of DPPIV inhibitor, sulphonylurea, or SGLT2 inhibitor is prohibited during the study 
(see inclusion criterion 5b, 5c, and 5d for explanation of washout period). 
•
Compounds known to prolong the QTc interval are prohibited. Refer to 
https://www.crediblemeds.org/healthcare-providers/.
•
Use of antihypertensives, while strongly discouraged, is not strictly prohibited. Stable 
antihypertensive therapy (initiated 2 months before screening) is acceptable; however, 
antihypertensive therapy cannot be initiated during the screening period.
4.8
Statistical Evaluation
4.8.1
General Considerations
Data will be provided in listings and tabular summaries. Categorical data will be summarized 
by the number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics, including mean, standard deviation, median, minimum, 
and maximum. Baseline values will be defined as the last assessment prior to the first 
administration of investigational product. Additional details will be described in the 
statistical analysis plan.
Analysis Populations
The Intent-to-treat (ITT) Population includes all subjects who are randomized and receive
any investigation product analyzed according to the initial randomization.
The As-treated Population includes all subjects who received the actual investigational 
product. All subjects who received investigational product will be analyzed for safety.
The PK Population includes all subjects who received at least 1 dose of investigational 
product and had at least one PK sample taken that is above the lower limit of quantitation.


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The PD Population includes all subjects who participated in at least 1 MMT (ie, gave at least 
1 post-MMT PD blood sample).
4.8.2
Sample Size and Power Calculations
The sample size of 6 subjects in the MEDI0382 group and 3 subjects in the placebo group for 
Cohorts 1, 2, and 3 was empirically determined to obtain adequate safety and tolerability 
evaluation. Under a two-sided 10% significance level, a sample size of 44 evaluable subjects 
(22 per arm) for Cohort 4 will provide 80% power to detect weight loss of 1.5 kg versus 
placebo (assuming a standard deviation of 1.9 kg), and 98% power to detect a 20% relative 
reduction in MMT glucose AUC (up to 240 minutes post-MMT) versus placebo at the end of 
treatment (assuming a coefficient of variation [CV] of 17%). (Internal data from another 
investigational agent for T2DM showed a CV of 17% for 24-hour glucose AUC, and the CV 
for glucose AUC [up to 240 minutes post-MMT] is expected to be similar.) The sample size 
for Cohort 4 is adjusted to 48 subjects (24 per arm) to account for a 10% drop-out rate. For 
Cohorts 5 and 6, under a one-sided 2.5% significance level the combination of 24 subjects in 
the MEDI0382 and 8 subjects in placebo from both cohorts will provide 80% power to rule 
out more than 20% of MEDI0382 subjects having > 5 mm Hg increase from baseline in 
diastolic BP on the seventh day of the 300 μg dose level (Day 22 visit of Cohort 5 and 
Day 17 visit of Cohort 6) relative to that of placebo subjects under the assumption that both 
placebo and MEDI0382 subjects have a true rate of 1% with > 5 mm Hg increase from 
baseline in diastolic BP. Moreover, under a one-sided 2.5% significance level, this sample 
size will provide 88% power to rule out > 20 bpm pulse rate increase from baseline on the 
seventh day of the 300 μg dose level in MEDI0382 subjects relative to that of placebo 
subjects with assumed standard deviation of 15 bpm. The assumed standard deviation is a 
relatively conservative estimation based on a liraglutide publication (Lovshin et al, 2015).
4.8.3
Efficacy
4.8.3.1
Primary Efficacy Analysis
For evaluation of the impact on glucose control and weight after multiple doses of 
MEDI0382 compared to placebo:
The percent change in MMT glucose AUC (up to 240 minutes post-MMT) and change in
weight from baseline to the end of treatment in Cohort 4 will be compared between 
MEDI0382 and placebo groups using an analysis of covariance by adjusting for baseline 
measurement and treatment group. A missing measurement at the end of treatment will be 
replaced with the last available measurement. The comparison will be conducted at a two-


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sided significance level of 0.1. Those analyses will be conducted using the ITT Population in 
Cohort 4.
4.8.3.2
Secondary Efficacy Analysis
Change from baseline in HbA1c and fructosamine, and percent change from baseline (Day -
1) in 24-hour glucose AUC post-MMT through end of treatment in Cohort 4, and percent 
change in MMT glucose AUC (up to 240 minutes post-MMT), and change in weight from 
baseline through end of treatment in all cohorts will be analyzed similarly to the primary
efficacy endpoints.
The 24-hour glucose AUC analyses will include glucose measures from the pre-/post-MMT 
glucose metabolism panel as well as serum chemistry glucose levels and PD glucose 
samples, where those results are from unique time points.
4.8.4
Safety
Safety analyses will be based on the As-treated Population. For each cohort, AEs including 
injection site reactions, clinical chemistry and hematology; and vital signs, ECGs, and ADAs 
(see Section 4.8.5) will be collected. 
Adverse events will be coded using the most updated Medical Dictionary for Regulatory 
Activities (MedDRA) version. The type, incidence, severity and relationship to
investigational product of each AE will be summarized by MedDRA System Organ Class 
and Preferred Term. Specific AEs will be counted once for each subject for calculating 
percentages. In addition, if the same AE occurs multiple times within a particular subject, the 
highest severity and level of relationship observed will be reported.
Electrocardiogram parameters will be assessed using telemetry and 12-lead 
electrocardiography, and the data will be descriptively summarized. Initial safety assessment 
will be based on paper ECG copies at the site.
HR and BP during the at-home self-administration period for Cohorts 4, 5, and 6, as 
measured by the ABPM, will be summarized and listed separately from vital signs data. In 
addition, HR and diastolic BP in Cohorts 5 and 6 will be compared between MEDI0382 and 
placebo groups using an analysis of covariance by adjusting for baseline measurement.
Descriptive statistics for the C-SSRS score will be generated at time points specified in the 
schedules of procedures for Cohort 4.
Other safety endpoints will be summarized descriptively and/or listed as appropriate.


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4.8.5
Pharmacokinetics/Immunogenicity
Pharmacokinetic parameters such as Cmax, Tmax, AUC, elimination half-life, and 
accumulation ratio will be estimated from plasma concentration-time data for MEDI0382 if 
data permit. Descriptive statistics will be generated for PK parameters for the MEDI0382 
group in each cohort. Subjects who have at least one measurable concentration time point of 
investigational product will be used for this analysis.
With respect to metformin PK, changes in metformin levels over time will be evaluated, as 
will any association between baseline metformin dose and change in metformin levels over 
time in the clinical study. In the event that a reduction in metformin levels is seen in Cohorts 
1-3, an exploratory analysis will be performed to examine the relationship between changes 
in metformin level and glucose control over time.
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 cohort. If warranted by the data, the association of ADA positivity with observed 
PK data and safety may be explored.
Data on titers and cross reactivity to GLP-1 and glucagon (if applicable) will be listed.
4.8.6
Pharmacodynamics Analyses
Similar analysis will be used for comparing change in beta cell function and insulin 
sensitivity between MEDI0382 and placebo. Beta cell function will be derived using the 
Homeostasis Model Assessment (HOMA) calculation from fasting glucose and insulin data,
and insulin sensitivity will be derived from MMT data using the HOMA-2 IR algorithm and 
the modified Matsuda index calculation. 
The level of glucose, insulin, pro-insulin, c-peptide, GLP-1, glucagon, and GIP from 
immediately prior to the MMT to 240 minutes and (for glucose only) 24 hours after the
MMT will be collected. Descriptive statistics including mean, standard deviation, median, 
minimum and maximum will be generated for these variables for MEDI0382 in each cohort 
separately and the placebo group, which includes all subjects in the placebo group across 
cohorts.
4.8.7
Subject Diaries and Glucometer Blood Glucose (Cohorts 4, 5, and 6)
Data from Daily Diaries of subjects in Cohorts 4, 5, and 6, as well as blood glucose 
measurements taken by the subject at home with the glucometer during the at-home self-
administration period, will be summarized and/or listed as appropriate.


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4.8.8
Exploratory Analyses
 
 
 
 
Change from baseline to Week 4 in liver fat (%), liver volume (L), visceral 
adipose tissue (L), subcutaneous adipose tissue (L), liver diffusion, sagittal diameter (image 
based), and transversal diameter (image based), as determined by MRI, will be summarized 
descriptively.
4.8.9
Dose Escalation Committee
A DEC will be formed for the purpose of data review and safety monitoring, and for 
decisions on cohort progression as outlined in the DEC Charter. 
The unblinded members of the DEC are the MedImmune medical monitor, sponsor patient 
safety study representative, and the MedImmune PK study representative. The coordinating 
investigator will remain blinded. The committee will meet at the earliest practicable time 
point following availability of PK, safety, and MMT glucose data from each completed 
cohort to determine if dose escalation can proceed. The rules for dose escalation are 
discussed in Section 3.1.3.
For each dose escalation decision, blinded safety data and summary-level (ie, blinded) PK 
and PD data will be reviewed at the first session of the DEC meeting. If a safety signal is 
detected from blinded data review, or if the PK or PD profile warrants evaluation of 
subject-level data, then the MedImmune DEC members will review the unblinded safety data
and/or unblinded PK/PD data in a second separate meeting session. If review of unblinded 
data is not necessary, the second session of the DEC meeting will not occur.
As sponsor of this study, MedImmune will be unblinded to treatment allocation. Appropriate 
measures will be in place to ensure that the coordinating investigator remains blinded to
study treatment during this process (eg, separate dial-in numbers for the meeting sessions, 
distribution of unblinded data to MedImmune DEC members only after a determination that 
it is needed).
4.8.10
Interim Analysis
An interim analysis of the safety and PD data will be conducted after the last subject of 
Cohort 4 has completed dosing. PK data will be analyzed if available at the time of analysis.


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


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•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
Results in persistent or significant disability/incapacity 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
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 AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and collecting additional 
information by the investigator. 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.
Please refer to the Investigator’s Brochure for a discussion of potential risks. The following 
AESIs have been identified specifically for this protocol and are to be reported as described
in Section 5.4 and Section 5.5:
•
Any arrhythmia deemed by the investigator to be clinically significant
•
Any vomiting
Risk mitigation strategies for arrhythmias are built into the study design, ie, extensive time 
points for manual collection of vital signs, ECGs, as well as continuous telemetry during the
inpatient period, and 24-hour ABPM (Cohorts 4, 5, and 6) during the at-home self-
administration period. Subjects with significant vomiting should be monitored for 
electrolytes.
See Section 3.1.4 for a discussion of GI tolerability and other mitigating strategies, eg, 
potential adjustments to planned dose escalations.
Hepatic function abnormality meeting the definition of Hy’s law is also considered an AESI. 
See Section 5.6.2 for the definition and reporting of AESIs of hepatic function abnormality. 


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5.4
Recording of Adverse Events
Adverse events will be recorded on the eCRF using a recognized medical term or diagnosis 
that accurately reflects the event. Adverse events will be assessed by the investigator for 
severity, relationship to the investigational product, possible etiologies, and whether the 
event meets criteria of an SAE and therefore requires immediate notification to the sponsor 
(see Section 5.5). See Section 5.2 for the definition of SAEs. See Appendix 2 for guidelines 
for assessment of severity (grade) 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.
Subcutaneous injection of biological products is commonly associated with injection site 
reactions. The investigator is advised to carefully examine symptoms of adverse reactions 
observed during or shortly after exposure to MEDI0382. Reactions occurring at the time of 
or shortly after subsequent injections of investigational product are to be judged by the 
investigator at his/her own discretion. For the investigator’s convenience and in order to 
facilitate consistency in judgments a copy of the National Institute of Allergy and Infectious 
Diseases and Food Allergy and Anaphylaxis Network guidance for anaphylaxis diagnosis is 
provided in Appendix 3.
5.4.1
Time Period for Collection of Adverse Events
Adverse events will be collected from time of signature of informed consent throughout the 
treatment period and including the follow-up period (28 [± 2] days after the last study dose
for each cohort).
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
MedImmune retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
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 during the course of the study, the investigator or other site personnel will 
inform the appropriate sponsor representative(s) within one day; ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.


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The designated sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor patient safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel will inform 
sponsor representatives of any follow-up information on a previously reported SAE within 
1 calendar day; ie, immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the investigator or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
the SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed.
5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose....................
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the Investigator’s Brochure, 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 with a MedImmune investigational product occurs during the course of the 
study, then the investigator or other site personnel inform appropriate sponsor representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see 
Section 5.5. For other overdoses, reporting must occur within 30 days.


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5.6.2
Hepatic Function Abnormality
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may 
need to be reported as SAEs. Please refer to Appendix 6 for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s law.
5.6.3
Pregnancy..............
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.6.3.1
Maternal Exposure
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational product should be discontinued immediately and the 
pregnancy reported to the sponsor.
5.6.3.2
Paternal Exposure
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product, then the investigator or other site personnel will 
inform the appropriate sponsor representatives within 1 day; ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided 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 the 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.
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review 
and discuss the requirements of the clinical study protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized.


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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 
inconsistency between this clinical study protocol and the Clinical Study Agreement, the 
terms of clinical study protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects, and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail.


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Agreements between MedImmune and the principal investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through the last protocol-specified visit/assessment, regardless of the number of 
doses of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn 
(Section 4.1.5) or the subject was lost to follow-up.
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last subject in the study.
6.4
Data Management 
MedImmune Data Management will be accountable for the data management of this study 
according to the Data Management Plan.
An electronic-based data capture system will be used for data collection and query handling. 
The investigator will ensure that data are recorded on the eCRFs as specified in the study 
protocol and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol, and the principal investigator is not available, the treating physician 


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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
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements.
7.2
Subject Data Protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
Subjects have the option of providing samples for future genetic research and/or future non-
genetic research (refer also to Section 7.4). 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.
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 medical monitor 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.
7.3
Ethics and Regulatory Review
An IRB/IEC should approve the final study protocol, including the final version of the ICF
and any other written information and/or materials to be provided to the subjects. The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff.
The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to MedImmune before enrollment of any subject into the study. 
The IRB/IEC should approve all advertising used to recruit subjects for the study.


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MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrolment of any subject into the study, the final study protocol is approved by the 
national regulatory authority or a notification to the national regulatory authority is done, 
according to local regulations. The ICFs will be approved by the IRB/IEC.
MedImmune will handle the distribution of any of these documents to the national regulatory 
authorities.
MedImmune will provide regulatory authorities, IRB/IEC and principal investigators with 
safety updates/reports according to local requirements, including suspected unexpected 
serious adverse reactions, where relevant.
7.4
Informed Consent
There will be 3 ICFs for this study: a mandatory general ICF, an optional ICF for samples for 
future genetic research, and an optional ICF for samples for future non-genetic research. 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 ICF(s) is/are given to the subject
•
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the informed consent form that is approved by an IRB/IEC
If subjects consent, optional blood samples for future genetic research or future non-genetic 
research (2 additional separate consent forms) will be collected and may be used to study 
disorders of metabolism or related complications. Provision of consent to provide blood 


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samples for future genetic or future non-genetic research is not a requirement to participate in 
the study. 
7.5
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the coordinating
investigator and MedImmune.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each principal investigator(s). For distribution to IRB/IEC see Section 7.3.
If a protocol amendment requires a change to a site’s Informed Consent Form, MedImmune 
and the site’s IRB/IEC are to approve the revised Informed Consent Form before the revised 
form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC.
7.6
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/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 documents, to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, Good Clinical 
Practice, guidelines of ICH, and any applicable regulatory requirements. The investigator 
will contact MedImmune immediately if contacted by a regulatory agency about an 
inspection at the site.


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8
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McQuigg M, Brown JE, Broom J, Laws RA, Reckless JP, Noble PA, et al. The 
Counterweight programme: Prevalence of CVD risk factors by body mass index and the 
impact of 10% weight change. Obes Res Clin Pract. 2008 Mar;2(1):I-II.


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Min SS, Turner JR, Nada A, DiMino TL, Hynie I, Kleiman R, et al. Evaluation of ventricular 
arrhythmias in early clinical pharmacology trials and potential consequences for later 
development. Am Heart J. 2010;159:716-29.
National Institute for Health and Clinical Excellence (2013) Hypertension in adults. NICE 
quality standard 28. Available at: https://www.nice.org.uk/guidance/qs28/chapter/quality-
statement-1-diagnosis-ambulatory-blood-pressure-monitoring.
Olsson M, Schnecke V, Cabrera C, Skrtic S, Lind M. Contemporary risk estimates of three 
HbA1c variables for myocardial infarction in 101,799 patients following diagnosis of type 2 
diabetes. Available at: http://care.diabetesjournals.org/content/early/2015/05/26/dc14-
2351.full.pdf+html.
Pugliese G, Solini A, Bonora E, Orsi E, Zerbini G, Fondelli C, et al; RIACE Study Group. 
Distribution of cardiovascular disease and retinopathy in patients with type 2 diabetes 
according to different classification systems for chronic kidney disease: a cross-sectional 
analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter 
study. Cardiovasc Diabetol. 2014 Mar 13;13:59.
Rajic M, Bogicevic M, Antic S, Ilic S, Vlajkovic M, Avramovic M. et al. The relationship 
between the rates of urinary albumin excretion and glomerular filtration in type 1 diabetes 
mellitus patients. Facta Universitatis Series: Medicine and Biology 2003;10(1):36-40.
Ratziu V, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, et al. 
Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-
controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. 
Gastroenterology. 2008 Jul;135(1):100-10. doi: 10.1053/j.gastro.2008.03.078. Epub 2008 
Apr 8.
Tan TM, Field BCT, McCullough KA, Troke RC, Chambers ES, Salem V, et al. 
Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in 
increased energy expenditure and amelioration of hyperglycemia. Diabetes. 2013;62:1131-8.
Taylor R. Type 2 diabetes: etiology and reversibility. Diabetes Care. 2013;36(4):1047-55.
Victoza (liraglutide) 6 mg/mL for injection in pre-filled pen (Summary of Product 
Characteristics [SPC]). May 2014; Novo Nordisk Limited, West Sussex, United Kingdom. 
Available at: 
https://www.medicines.org.uk/EMC/medicine/21986/SPC/Victoza+6+mg+ml+solution+for+
injection+in+pre-filled+pen


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Wu S, Levenson A, Kharitonenkov A, DeLuca F. Fibroblast growth factor 21 (FGF21) 
inhibits chondrocyte function and growth hormone action directly at the growth plate.J Biol 
Chem. 2012; 287(31):26060-67.
Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, et al. Subcutaneous 
oxyntomodulin reduces body weight in overweight and obese subjects; a double-blind, 
randomized, controlled trial. Diabetes. 2005;54:2390-5.
Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, Bloom SR. Oxyntomodulin 
increases energy expenditure in addition to decreasing energy intake in overweight and obese 
humans: a randomised controlled trial. Int J Obes. 2006;30(12):1729-36.
9
CHANGES TO THE PROTOCOL
All changes described below have been incorporated into the current version of the protocol
9.1
Amendment 8, 23Sep2016
This amendment has been implemented in order to add Part C to the study, including the 
addition of 2 cohorts (Cohorts 5 and 6) to assess the safety and tolerability of the MEDI0382 
300 μg dose and to explore the optimal up-titration. Text revisions resulting from this 
amendment are incorporated in the body of Protocol Amendment 8. Changes to the protocol 
are summarized below:
1. Protocol Synopsis (Study Design and Investigational Product, Dosage, and Mode of 
Administration), Section 3.1.1 (Overview), Section 3.1.2 (Treatment Regimen): Text was 
added to include Part C of the study and to describe the details of Cohorts 5 and 6 in 
terms of number of subjects, treatment duration and dosages, and up-titration schedule.
The study schematic (Figure 3.1.1-1) was updated to include Part C.
2. Section 1.5 (Rationale for Conducting the Study),
 
 
 
3. Protocol Synopsis (Study Endpoints), Section 2.2.2 (Secondary Endpoints), Section 3.1.1 
(Overview), Section 4.3.7 (Pharmacodynamic Evaluation and Methods), Section 4.3.11.1 
(Columbia-Suicide Severity Rating Scale): Text was added to specify that the C-SSRS
score is an endpoint for Cohorts 5 and 6, in addition to Cohort 4; PD endpoints for 
Cohorts 5 and 6 are insulin and glucose only; terminal half-life and accumulation ratio 
are PK endpoints for Cohorts 1 to 3 only.
4. Protocol Synopsis (Study Endpoints), Section 2.2.2 (Secondary Endpoints: “Percent 
change from baseline in MMT glucose AUC (up to 240 minutes post-MMT) to end of 


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treatment” and “Change from baseline in body weight in kg to end of treatment” added as 
secondary endpoints.
5.
 
6. Protocol Synopsis (Study Design), Section 3.1.1 (Overview), Section 4.1.1 (Number of 
Subjects): Number of subjects is increased from 75 to 107 because of the addition of 32 
subjects in Part C.
7. Protocol Synopsis (Study Design), Section 3.1.1 (Overview): Text was added to describe 
the inpatient periods and clinic visits for Cohorts 5 and 6 – subjects will have an initial 
inpatient period ending on Day 3 followed by at-home self-administration of 
investigational product with a clinic visit at each dose up-titration step until initiation of 
the 300 μg dose. Subjects will have a second inpatient period for the initiation of the 
300 μg dose ending on the fourth day at that dose followed by another inpatient period on 
the last day of dosing to collect the final endpoints, with at-home self-administration of 
investigational product in between.
8. Protocol Synopsis (Study Design) and Section 3.1.1 (Overview): Text was added 
concerning the timing of the MMT procedures for Cohorts 5 and 6 - at baseline (Day -1) 
and at the start (Day 16 for Cohort 5 and Day 11 for Cohort 6) and end (Day 22 for 
Cohort 5 and Day 17 for Cohort 6) of the 300 μg dosing schedule.
9. Protocol Synopsis (Study Design), Section 3.1.1 (Overview): Text was added to make 
clear that, for Cohorts 4, 5, and 6, the last PK sample will be collected 24 hours after the 
last dose.
10. Protocol Synopsis (Statistical Analysis Plan) and Section 4.8.2 (Sample Size and Power 
Calculations): Text was added to provide details of the sample size calculation resulting 
in 32 subjects in total in Cohorts 5 and 6.
11. Protocol Synopsis (Statistical Analysis Plan): ‘Cohort 4’ was removed from the 
description of the analysis of efficacy endpoints because, with the addition of 2 secondary 
endpoints, the analysis no longer applies to Cohort 4 only. 
12. Section 3.1.1 (Overview), Section 4.2.1 (Enrollment/Screening Period), Section 5.3 
(Definition of Adverse Events of Special Interest): Text was added to specify 24-hour 
ABPM is applicable to Cohorts 5 and 6, in addition to Cohort 4.
13. Section 3.1.1 (Overview): Text was added to add Cohorts 5 and 6 to the measuring of 
body weight during the outpatient periods, and at the 28-day End of Study Visit.
14. Section 3.1.3 (Cohort Progression), Section 4.6.1 (Methods for Assigning Treatment 
Groups): Text was amended to clarify that the randomization ratio is 3:1 (active: placebo) 
for Cohorts 5 and 6, while remaining unchanged at 2:1 for Cohorts 1 to 3 and at 1:1 for 
Cohort 4.
15. Section 3.1.1 (Cohort Progression): Text was added to describe the sentinel dosing 
approach for Cohorts 5 and 6 that will review 3 subjects in each cohort with 7 days of 
dosing at the 300 μg dose before additional subjects are dosed at this level, and that the 
cohorts will run concurrently.


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16. Section 3.1.3.2 (Cardiac Stopping Criteria): Text was added to the definition of 
hypertension for safety purposes - “or an increase in resting supine diastolic 
BP > 20 mm Hg or above 100 mm Hg and persisting for at least 10 minutes”.
17. Section 3.1.4 (Management of Toxicities and Dose Modification): Text was added to 
include the 5-day up-titration periods for Cohorts 5 and 6, 1 day longer than the 
up-titration periods in Cohorts 2 to 4. In the event of unacceptable nausea and vomiting in 
3 or more subjects, a provision was added to switch remaining Cohort 6 subjects to 
Cohort 5 up-titration schedule after discussion with the medical monitor. 
18. Section 4.1.2 (Inclusion Criteria): Criteria 7, ability to self-administer daily SC injections,
was made applicable to Cohorts 5 and 6, in addition to Cohort 4. Normal saline will be an 
alternative to placebo for the self-injection during the screening period for Cohorts 5 and 
6.
19. Section 4.1.3 (Exclusion Criteria): Criteria 15b text was added to remove the systolic BP 
criteria for subjects aged 60 and over, and to use systolic BP < 90 mm Hg or 
≥140 mm Hg for all subjects in Cohorts 5 and 6.
20. Section 4.1.3 (Exclusion Criteria): Criteria 22b was added for Cohorts 5 and 6, to 
additionally exclude subjects with a history of transient ischemic attack within the 
previous 12 months.
21. Section 4.1.6 (Discontinuation of Investigational Product): Criteria 7 was added for 
safety purposes, because a higher dose of MEDI0382 will be used in Cohorts 5 and 6 -
“Subject develops a resting supine systolic BP of ≥ 180 mm Hg or a resting supine 
diastolic BP of ≥100 mm Hg sustained for more than 10 minutes, or a sustained resting 
tachycardia which is symptomatic and requires urgent medical intervention”.
22. Section 4.2.1 (Enrollment/Screening Period): A row was added to Table 4.2.1-1 to check 
ability to self-administer investigational product for Cohorts 4, 5, and 6.
23. Section 4.2.2 (Randomized Treatment Period): In Table 4.2.2-4 (Cohort 4) the C-SSRS 
assessment on Day 41 was removed because it was not needed. It is being done already 
on the evening of Day 40. There was also a footnote change to remove the 24-hour ECG 
reading on Day 12, because it is already being done on Day 13.
24. Section 4.2.2 (Randomized Treatment Period): In Table 4.2.2-5 (Cohort 4) the 24-hour 
ABPM assessment on Day 40 was moved from ‘Home’ to ‘Clinic’.
25. Section 4.2.2 (Randomized Treatment Period): Table 4.2.2-6, Schedule of Treatment 
Period Procedures for Cohort 5, and Table 4.2.2-7, Schedule of Treatment Period 
Procedures for Cohort 6, were added to provide full details of the assessments for these 
new cohorts. 
26. Section 4.2.3 (Follow-up Period): Table 4.2.3-1 title changed from ‘Cohorts 1 through 4’ 
to ‘All Cohorts’, to add Cohorts 5 and 6.
27. Section 4.2.4 (Early Discontinuation or Unscheduled Study Visit): Pregnancy test made
applicable to Cohorts 5 and 6, in addition to Cohort 4. Also, C-SSRS made applicable to 
Cohorts 5 and 6 as well as Cohort 4.
28. Section 4.3.2.4 (Vital Signs): Ambulatory BP and HR monitoring during the outpatient 
periods made applicable to Cohorts 5 and 6, in addition to Cohort 4.
29. Section 4.3.3 (Clinical Laboratory Tests): Urine drug and alcohol screen prior to 
initiation of the 300 μg dose for Cohorts 5 and 6 added to the urinalysis tests. Magnesium 


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was added to the serum chemistry panel because vomiting may lead to electrolyte 
disturbances, including hypomagnesemia, which may predispose to cardiac arrhythmia. If 
hypomagnesemia were to arise it should be treated and, in the unlikely event of an 
arrhythmia or ECG changes occurring, it would be important to know the serum levels of 
magnesium for root cause analysis of the event.
30. Synopsis (Study Endpoints), Section 4.3.3 (Clinical Laboratory Tests), Section 4.3.10.4 
(Fasting Lipid Profile), Section 4.3.10.5 (Non-alcoholic Steatohepatitis Biomarkers): 
Text was added to make clear that fructosamine, 
 
, 
s are applicable to 
Cohorts 5 and 6 in addition to Cohort 4. To provide more flexibility, beta-
hydroxybutyrate may be done by point-of-care capillary blood ketone testing as per local 
procedures.
31.
32. Section 4.3.3 (Clinical Laboratory Test) and 4.3.7 (Pharmacodynamic Evaluation and 
Methods); Text was added to make clear that only timed glucose and insulin are included 
in the glucose metabolism panel for MMT for Cohorts 5 and 6.
33. Section 4.3.4 (Estimate of Volume of Blood to be Collected): Blood collection volumes 
were added for Cohorts 5 and 6.
34. Section 4.3.8 (Combined PK and PD Blood Sampling Example Schedule): Day 22 
(Cohort 5) and Day 17 (Cohort 6) added to the title of Table 4.3.8-1.
35. Section 4.3.12.1 (Training for Self-Administration and At-Home Preparation of 
Investigational Product): Text was added to make sure that subjects in Cohorts 5 and 6 
are given training to self-administer the investigational product.
36. Section 4.3.12.2 (Training during the Inpatient Period for Using the Standardized 
Glucometers during the Inpatient and Outpatient Periods): Text was added to make blood 
glucose measurements every bedtime for Cohorts 5 and 6.
37. Section 4.3.12.3 (Training for Completing the Daily Diaries during the At-home Self-
administration Period): Text was added to include a Daily Diary for Cohorts 5 and 6.
38. Section 4.3.12.4 (Training for Application and Wearing of ABPM Device): This section 
has been added to make sure that subjects in Cohorts 5 and 6 are given training with the 
ABPM device.
39. Section 4.5.1.1 (Identity of Investigational Products): Text was revised to reflect the 
addition of Cohorts 5 and 6.
40. Section 4.5.1.2 (Investigational Product Handling): Text was added to instruct the subject 
to use their refrigerator, which should be between 4°C and 8°C, and to avoid the risk of 
freezing the investigational product by careful placement within their refrigerator. The 
requirement for the subject to record storage temperatures in the Daily Diary was
removed.
41. Section 4.5.1.4 (Dose Preparation Steps), Section 4.5.1.5 (Treatment Administration): 
Table 4.5.1.4-3 and text were added to describe Cohort 5 MEDI0382 and placebo dose 
preparation. Similarly, Table 4.5.1.4-4 and text were added to describe Cohort 6 
MEDI0382 and placebo dose preparation.
42. Section 4.5.1.5 (Treatment Administration): Text was added to recommend 15 minutes 
for temperature equilibration if no diluent is used. Cohorts 5 and 6 were added.


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43. Section 4.5.5 (Treatment Compliance): Text was added to include Cohorts 5 and 6 in the 
monitoring of at-home doses via Daily Diaries, returned vials, and PK data.
44. Section 4.6.1 (Methods for Assigning Treatment Groups): Cohorts 5 and 6 were added to 
provide number of subjects and randomization ratio.
45. Section 4.8.3.1 (Primary Efficacy Analysis): ‘Day -1’ removed as the definition of 
baseline for change in weight.
46. Section 4.8.3.1 (Secondary Efficacy Analysis): ‘Day-2’ removed as the definition of 
baseline and ‘percent change in MMT glucose AUC (up to 240 minutes post-MMT) and 
change in weight from baseline through end of treatment in all cohorts’ was added to 
state the analysis for these new secondary endpoints.
47. Section 4.8.4 (Safety): Analysis of ABPM measures of HR and BP for Cohorts 5 and 6
added.
48. Section 4.8.7 (Subject Diaries and Glucometer Blood Glucose) and Section 4.8.8 
(Exploratory Analyses): Text added to include Cohorts 5 and 6 in addition to Cohort 4.
49. Section 4.8.10 (Interim Analysis): Text was added to include an interim analysis after the 
last subject in Cohort 4 has completed dosing.
50. Section 8 (References): Details of Davies at al 2015 were added.
9.2
Amendment 7, 25Aug2016
This amendment has been implemented in response to requests made from the Bundesinstitut 
fuer Arzneimittel und Medizinprodukte (BfArM; received 24Aug2016). Revisions have been 
made to two sections of the protocol, as outlined below:
1. Section 4.1.4 (Subject Enrollment and Randomization): Text was reverted to specify that 
subjects may be rescreened only once.
2. Section 4.1.7 (Replacement of Subjects): Text was reverted to state that additional 
subjects may be screened and available to ensure that a sufficient number of subjects are 
randomized into each cohort.
9.3
Amendment 6, 21Jul2016
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 6. Major changes to the protocol are summarized below:
1. Protocol Synopsis (Study Endpoints), Section 2.2.3 (Exploratory Endpoints) and
Section 4.3.3 (Clinical Laboratory Tests):
 
Relevant text was revised to 
reflect this.
2. Protocol Synopsis (Study Design), Section 3.1.1 (Overview): The text was changed from 
“approximately 10 study sites” to “approximately 12 study sites” to reflect current 
projections. Text was changed from “48 subjects” to “approximately 48 subjects”.


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3. Protocol Synopsis (Study Design), Section 3.1.1 (Overview), Figure 3.1.1-1 (Study Flow 
Diagram), Section 3.1.2 (Treatment Regimen),
 
, Section 4.5.4 (Dose Preparation Steps), Table 4.5.1.4-1 
(Cohort 1-3 MEDI0382 and Placebo Dose Preparation): Text was revised to clarify that 
200 μg MEDI0382 is the maximum dose in the study. The study flow diagram and tables 
were updated to align with this.
4. Protocol Synopsis (Study Design), Section 3.1.1 (Overview) and Table 4.2.2-4 (Schedule 
of Treatment Period Procedures: Cohort 4 Overview): Text was revised to widen the 
window for predose MRI scan from Day -2 or Day -1 to anytime between Day -7 to
Day -1 to provide greater flexibility for subject scheduling. Table footnote text was 
updated for consistency and to clarify that the predose MRI may require a separate visit, 
at the subject’s discretion, if not carried out on Day -2 or Day -1.
5. Protocol Synopsis (Study Design), Section 3.1.1 (Overview), Table 4.2.2-4 (Schedule of 
Treatment Period Procedures: Cohort 4 Overview) and Section 4.3.5 (Glucometer Blood 
Glucose Readings during the Inpatient Period): Text was revised and table footnote text 
was updated to clarify that PD glucose will be taken at specified timepoints ±10 minutes 
during Day -1 and the in-clinic dosing period to provide greater flexibility for procedure 
scheduling.
6. Protocol Synopsis (Study Design), Section 2.2.3 (Exploratory Endpoints), Table 4.2.2-4 
(Schedule of Treatment Period Procedures: Cohort 4 Overview), Table 4.2.2-5 (Schedule 
of Treatment Period Procedures: Cohort 4 Self-administration Dosing Period Detail) and 
Section 4.3.10.6 (Magnetic Resonance Imaging of the Liver/Abdomen [Cohort 4]): Text 
was updated to clarify that MRI scans will occur only if MRI is available to the site and
the subject is suitable for and consents to scan. Text in Section 4.3.10.6 was revised to 
clarify that subject suitability to be scanned will be determined against local criteria at the 
scanning site.
7. Protocol Synopsis (Study Design), Section 3.1.1 (Overview), Table 4.2.2-4 (Schedule of 
Treatment Period Procedures: Cohort 4 Overview) and Table 4.2.2-5 (Schedule of 
Treatment Period Procedures: Cohort 4 Self-administration Dosing Period Detail): Text 
was updated to clarify that postdose MRI scan may be done on Day 39, 40, 41, or 42 and 
tables were updated to correct a previous oversight. The text “as determined by site 
feasibility” was removed.
8.
 
9. Section 4.1.3 (Exclusion Criteria): Criterion 11 was updated to clarify glomerular 
filtration rate should be estimated according to Modification in Renal Disease using 
MDRD Study Equation IDMS-traceable (SI units). Criterion 35 was revised to remove 
the text “Cohort 4 only if the site has access to MRI” to correct a previous oversight. 
Criterion 36 was removed as subject suitability for MRI will be determined against local 
criteria at the scanning site (Section 4.3.10.6).
10. Section 4.1.4 (Subject Enrollment and Randomization): Text was revised to clarify that 
subjects may be rescreened more than once based on principal investigator judgment to
aid recruitment.


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11. Section 4.1.7 (Replacement of Subjects) and Section 4.6.1 (Methods for Assigning 
Treatment Groups): Text was revised to clarify that additional subjects can be screened 
and randomized to ensure that a sufficient number of subjects complete each cohort. 
Relevant text was changed from “48 subjects will be randomized” to “approximately 48 
subjects will be randomized” to align with this.
 
13. Table 4.2.2-4 (Schedule of Treatment Period Procedures: Cohort 4 Overview), Table 
4.2.2-5 (Schedule of Treatment Period Procedures: Cohort 4 Self-administration Dosing 
Period Detail): Tables were updated to correct an oversight in Columbia-Suicide Severity 
Rating Scale scheduling and to include a pregnancy test (if applicable) at clinic visits 8, 9, 
10, and 11. Footnote text was revised to change P/MSS completion from “within 30 
minutes” of specified time to “within 30 minutes (+10 minutes)” of specified time to 
provide greater flexibility for procedure scheduling. Footnote text was updated to specify 
that blood samples for the serum chemistry panel should be taken following a minimum 
of 8 hours fasting on Day 1 (V4.1), Day 6 (V5.2), Day 13 (V7), Day 20 (V8), Day 27 
(V9), Day 34 (V10) and Day 42 (V13) to allow for analysis of fasting plasma glucose.
14. Table 4.2.2-5 (Schedule of Treatment Period Procedures: Cohort 4 Self-administration 
Dosing Period Detail): Footnote text was updated to clarify when subjects will be fitted 
with the ambulatory blood pressure monitoring device, the duration of monitoring and 
when the device will be removed. The timeframe for subjects to return the device to the 
clinic was removed to provide greater flexibility for procedure scheduling.
15. Table 4.2.3-1 (Schedule of Follow-up Procedures: Cohorts 1 through 4) and Section 4.2.4 
(Early Discontinuation for Unscheduled Visit): Table was revised to include a pregnancy 
test (if applicable) during the follow-up period and text was revised to add a pregnancy 
test to the list of assessments performed for subjects who prematurely discontinue from 
the study or for subjects who require an unscheduled study visit to correct a previous 
oversight.
16. Section 4.3.3 (Clinical Laboratory Tests): Serum chemistries panel note was updated to 
clarify that bicarbonate may be measured via serum chemistry sample of blood gas 
analyzer per local procedures. 
17. Section 4.3.4 (Estimate of Volume of Blood to Be Collected): The estimated blood 
sample volume for Cohort 4 was increased to 553 mL to reflect the addition of CK18, 
P1NP and ProC3 as serum markers of oxidative stress and liver fibrosis.
18. Section 4.3.11.1 (Columbia-Suicide Severity Rating Scale [Cohort 4]): Text was revised
to clarify that site staff will complete the assessment with the subject in a private, quiet 
place.
19. Section 4.3.12.3 (Training for Completing the Daily Diaries during the At-home 
Self-administration Period): Text was updated to be consistent with device instructions
and to clarify that subjects will be instructed to contact the site in the event of new 
medications, a change in medications or if they experience any symptoms.
20. Section 4.5.1.4 (Dose Preparation Steps), Table 4.5.1.4-1 (Cohort 1 – 3 MEDI0382 and 
Placebo Dose Preparation) and Table 4.5.1.4-2 (Cohort 4 MEDI0382 and Placebo Dose 


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Preparation): Text was updated to provide instructions for Cohort 4. Tables were
updated/inserted to clarify the dose preparation for Cohorts 1-3 and Cohort 4.
21. Section 4.5.1.5 (Treatment Administration): Text was updated to clarify that diluent is 
not required for Cohort 4 and that a 0.3 mL insulin syringe will be utilized during the 
in-clinic and at-home treatment periods.
9.4
Amendment 5, 27Apr2016
This amendment has been implemented in response to requests made from the Bundesinstitut 
fuer Arzneimittel und Medizinprodukte (BfArM; received 13Apr2016). Revisions have been 
made to several sections of the protocol, as outlined below:
1. Protocol Synopsis (Study Design), Section 3.1.1 (Overview): The text was changed from 
“up to 10 study sites” to “approximately 10 study sites” to reflect current projections.
2. Protocol Synopsis (Study Design), Section 3.1.1 (Overview), Section 4.3.2.3 
(Electrocardiograms), Section 4.3.2.3 (Telemetry), Table 4.2.2-3 (Schedule of Treatment 
Period Procedures: Cohort 3), Table 4.2.2-4 (Schedule of Treatment Period Procedures: 
Cohort 4 Overview): The study design was reverted to state that subjects will be admitted 
to and remain in the unit for all doses and all dose levels during the up-titration period as 
requested by the BfArM. Relevant text in Section 4.3.2.3, the telemetry footnote in 
Table 4.2.2-3 (Schedule of Treatment Period Procedures: Cohort 3) and Table 4.2.2-4 
(Schedule of Treatment Period Procedures: Cohort 4 Overview) was modified to reflect 
the reversion in study design. 
3. Protocol Synopsis (Target Subject Population), Section 3.2.2 (Rationale for Study 
Population), Section 4.1 (Subjects), Section 4.1.2 (Inclusion Criteria): The age range for 
inclusion in the study was changed from 18 through ≤ 69 years to 18 through ≤ 65 years, 
as requested by the BfArM, and relevant text was modified to reflect this change.
4. Section 3.2.2 (Rationale for Study Population), Section 4.1.2 (Inclusion Criteria): The 
upper range of screening HbA1c was changed from 9.0% to 8.5%, as requested by the 
BfArM.
5. Section 4.1.3 (Exclusion Criteria): The exclusion criterion of “fasting blood glucose 
≥200 mg/dL (11.11 mmol/L)” was reinstated as requested by the BfArM.
6. Section 4.1.3 (Exclusion Criteria): The upper range of abnormal systolic BP was 
decreased by 10 mm Hg for both age groups (< 60 years old, ≥60 years old), and the 
upper range of abnormal diastolic BP was decreased by 10 mm Hg as requested by the 
BfArM.
9.5
Amendment 4, 18Mar2016
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. Major changes to the protocol are summarized below.


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1.
, Section 1.5 (Rationale for Conducting the 
Study), 
, and Section 3.2.3 (Rationale for Endpoints): 
 
 
In Section 3.2.1, under “Starting Dose and 
Criteria for Dose Escalation”, the median of AUC(0-inf) was updated from 
“152.2 ng•hr/mL” to “155.9 ng•hr/mL” and the range of half-life (hours) was updated 
from “(10.1-13.2)” to “(10.1-18.3)”. 
 
 
 
 
 
2. Protocol Synopsis (Objectives; Target Subject Population), Section 2.1.3 (Exploratory 
Objectives), Section 3.2.3 (Rationale for Endpoints), Section 4.1.2 (Inclusion Criteria), 
Section 4.5.2 (Additional Study Medications), Section 4.7.1 (Permitted Concomitant 
Medications): The inclusion criterion, requiring that subjects in Cohort 4 must be taking 
≥10 mg daily dose of a statin for a period of at least 4 weeks prior to screening, was
removed; text was modified in relevant sections to reflect this change and to clarify that 
statins are permitted (but not required). The requirement for statin therapy in Cohort 4 
was originally introduced to evaluate the possible therapeutic benefit of MEDI0382 on 
lipids when prescribed in addition to statin therapy. The effect of MEDI0382 on lipid 
parameters in addition to statin therapy will now be evaluated later in the clinical 
development program. The removal of this requirement is expected to have no effect on 
the study conduct or the safety profile of MEDI0382 and is implemented to facilitate
study recruitment.  
3. Protocol Synopsis (Objectives; Study Endpoints; Study Design), Section 2.1.3 
(Exploratory Objectives), Section 2.2.3 (Exploratory Endpoints), Section 3.1.1 
(Overview), Section 3.2.3 (Rationale for Endpoints), Table 4.2.2-4 (Schedule of 
Treatment Period Procedures: Cohort 4 Overview), Table 4.2.2-5 (Schedule of Treatment 
Period Procedures: Cohort 4 Self-administration Dosing Period Detail), Section 4.3.10
(Exploratory Endpoints Evaluations and Methods [
 
Magnetic Resonance Imaging]), Section 4.8.8 (Exploratory Analyses): Exploratory 
objectives to explore the effect of MEDI0382 on the volume and fat/water content of the 
liver and on visceral and subcutaneous fat were added. Endpoints of change from 
baseline to Week 4 in liver fat (%), liver volume (L), visceral and subcutaneous adipose 
tissue (L), liver diffusion, and sagittal and transversal diameter (image based) were added 
for Cohort 4; text was added to specify that endpoints are to be measured by MRI of the 
liver/abdomen at sites that have the capacity to perform the procedure. The MRI 
assessment was added to the schedules of treatment procedures for Cohort 4 
(Tables 4.2.2-4 and Table 4.2.2-5) and described in new Section 4.3.10.6 (Magnetic 
Resonance Imaging of the Liver/Abdomen [Cohort 4]). The exploratory 
objectives/endpoints were added as there is potential to see changes in liver, visceral, and 
subcutaneous fat content over the course of the study and will provide information on the 
potential profile of MEDI0382 in treating NASH. The MRI assessment is non-invasive 
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4. Protocol Synopsis (Study Design), Section 3.1.1 (Overview), Section 4.3.2.3 
(Electrocardiograms), Table 4.2.2-3 (Schedule of Treatment Period Procedures: 
Cohort 3), Table 4.2.2-4 (Schedule of Treatment Period Procedures: Cohort 4 Overview): 
The study design was changed to allow subjects in Cohorts 3 and 4 to discontinue 
telemetry and return home (at the discretion of the investigator) after remaining in the 
unit for at least 48 hours after dose initiation and dose uptitration. The telemetry footnote 
in Table 4.2.2-3 (Schedule of Treatment Period Procedures: Cohort 3) and Table 4.2.2-4
(Schedule of Treatment Period Procedures: Cohort 4 Overview) was modified to reflect 
the change in study design. Continuous telemetry measurement is most important during 
treatment initiation and during dose titration. This is because nausea and vomiting may 
impact HR and BP and are most likely to be seen before steady state is 
established/re-established. For MEDI0382, this is predicted to occur within 48 hours post 
dose initiation or uptitration. Given that subjects taking part in this study are extensively 
screened for cardiovascular disease, the risk of significant arrhythmia once steady state is 
achieved is thought to be negligible. For this reason, in the opinion of the sponsor, 
discontinuation of telemetry monitoring outside of these 48-hour periods does not pose an 
increased safety risk and, as such, may be permitted at the investigator’s discretion based 
on tolerability assessments (ie, skin irritation at the site of telemetry electrode placement) 
and/or to allow subjects the option of home visits during the inpatient study period (ie, 
subjects are required to return to the unit for daily dosing and study assessments during 
the inpatient study period in Cohort 3 and the initial inpatient study period in Cohort 4).
5. Protocol Synopsis (Study Design), Section 3.1.1 (Overview), Section 4.1.2 (Inclusion 
Criteria), Table 4.2.1-1 (Schedule of Screening Procedures): The screening window was 
changed from 42 days to 60 days to facilitate study recruitment. Given patients with early 
diabetes are relatively stable with respect to metabolic parameters and co-morbidities, a 
minimal number of subjects are likely to be excluded at Day -1, and the longer screening 
window will allow more time for subjects to plan for the prolonged in-house stay. As 
eligibility is rechecked on Day -1, there is no increased risk to subjects. 
6. Figure 3.1.1-1 (Study Flow Diagram): The figure was updated for clarity and to reflect 
changes in study design.  
7. Section 3.1.3.1 (Progression of Cohorts within this MAD Study): The requirement that 
regulatory approval be obtained “prior to initiating enrollment” in order to proceed with 
Cohort 4 was changed to “prior to initiating dosing” so that screening activities can occur
prior to receiving approval of the Part A (Cohorts 1-3) data submission package. This is 
to allow subjects to plan for both the prolonged inpatient stay associated with Cohort 4
and the subsequent outpatient dosing period by confirming provisional participation as 
soon as possible.  
8. Protocol Synopsis (Target Subject Population), Section 3.2.2 (Rationale for Study 
Population), Section 4.1 (Subjects), Section 4.1.2 (Inclusion Criteria): The age range for
inclusion in the study was changed from 18 through ≤65 years to 18 through ≤69 years, 
and relevant text was modified to reflect this change. The increase in age range from 
65 to 69 years is likely to be associated with only a small increase in prevalent
cardiovascular disease. According to recent UK epidemiology data, prevalence of 
ischemic heart disease in a modern day European population remains at less than 10% up 
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procedures, alteration of the age range is not expected to impact subject safety in this 
clinical study and is implemented to facilitate study recruitment. 
9. Section 3.2.2 (Rationale for Study Population), Section 4.1.2 (Inclusion Criteria): The
lower range of screening HbA1c was changed from 7.0% to 6.5%. As a GLP-1 agonist, 
MEDI0382 is expected to enhance insulin release only in the presence of hyperglycemia
without increasing the risk of hypoglycemia. This change is not expected to impact the 
scientific validity of the study or subject safety and is implemented to facilitate study 
recruitment.
10. Section 3.2.2 (Rationale for Study Population), Section 4.1.2 (Inclusion Criteria): The 
upper range of screening HbA1c was changed from 8.5% to 9.0%. HbA1c is recognized 
as a poor predictor of ischemic cardiovascular disease (see Olsson et al, 2015). As such,
an increase of 0.5% in the upper limit to 9.0% is not expected to impact significantly on 
cardiovascular disease prevalence within the study population or represent any 
incremental safety risk and is implemented to facilitate study recruitment. 
11. Protocol Synopsis (Target Study Population), Section 4.1 (Subjects), Section 4.1.2 
(Inclusion Criteria), and Section 4.7.2 (Prohibited Concomitant Medications): Text was 
added to the inclusion criterion for HbA1c that subjects who are taking sulphonylurea or 
SGLT2 inhibitors may be eligible to enter the study following a 4-week sulphonylurea or 
SGLT2 inhibitor washout period. The study population and prohibited concomitant 
medications were updated to reflect the change in inclusion criteria. Neither 
sulphonylurea or SGLT2 inhibitors are associated with pleotrophic effects on beta cells. 
Hence a 4-week washout period is considered adequate with respect to study entry. The 
dose of sulphonylurea is capped at 50% of the licensed dose to avoid enrolling subjects to 
the study who have limited beta cell reserve.
12. Section 4.1.3 (Exclusion Criteria): The exclusion criterion of “history of cancer, with the
exception of non-melanoma skin cancer” was changed to “history of cancer within the 
last 10 years, with the exception of non-melanoma skin cancer” to facilitate study 
recruitment.
13. Section 4.1.3 (Exclusion Criteria): The exclusion criterion of “fasting blood glucose 
≥200 mg/dL (11.11 mmol/L)” was removed, because the inclusion criterion for HbA1c 
is sufficient to exclude subjects with poor glycemic control.
14. Section 4.1.3 (Exclusion Criteria): The upper range of abnormal systolic BP was 
increased by 10 mm Hg for both age groups. The upper range of abnormal diastolic BP
was increased by 10 mm Hg. Glucagon is mechanistically expected to drive natriuresis, 
and GLP-1 agonism is associated with modest reduction in BP; therefore, at steady state,
GLP-1/glucagon agonists should not lead to hypertension. Data for BP and pulse rate 
changes from Cohort 1 used for the DEC meeting show that MEDI0382 has a benign 
effect on BP and an effect on pulse rate similar to that seen with short-term liraglutide 
use.


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15. Section 4.1.3 (Exclusion Criteria): Text was added to the note for vital signs criteria that 
subjects who fail BP screening at the clinic may be eligible to enter the study based on 
results of 24-hour ABPM to be recommended at the investigator’s discretion. Guidelines 
on BP management recognize the fact that blood pressures measured at the clinic may not 
be predictive of actual BP control. For this reason, ABPM is recommended with respect 
to BP assessment, where available, for subjects entering the study with BP above the 
entry threshold as measured at the clinic in order to rule out “white coat” hypertension 
(see National Institute for Health and Clinical Excellence [2013]).
16. Section 4.1.3 (Exclusion Criteria): A note was added to the exclusion criteria concerning 
QRS duration to allow subjects with QRS duration > 120 msec in the presence of right 
bundle branch block, which is not in the opinion of the investigator associated with 
significant respiratory or cardiovascular disease, to be enrolled in the study. As right 
bundle branch block (in contrast to left bundle branch block) is recognized as a normal 
ECG variant and is not associated with underlying respiratory and cardiovascular disease, 
this should not preclude entry to the study.
17. Section 4.1.3 (Exclusion Criteria): Additional exclusion criteria regarding subject’s use of 
weight loss diets/agents, and conditions where MRI is contraindicated were added for 
Cohort 4 only if the site has access to an MRI scanner. 
 
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18. Tables 4.2.2-1 (Schedule of Treatment Period Procedures: Cohort 1), 4.2.2-2 (Schedule 
of Treatment Period Procedures: Cohort 2), 4.2.2-3 (Schedule of Treatment Period 
Procedures: Cohort 3), 4.2.2-4 (Schedule of Treatment Period Procedures: Cohort 4 
Overview), and Section 4.6.1 (Methods for Assigning Treatment Groups): In table
footnotes pertaining to randomization, the requirement that “dosing must occur within 
10 hours of randomization” was removed; the relevant text in Section 4.6.1 (Methods for 
Assigning Treatment Groups) was deleted. This requirement posed a logistical burden to 
the sites and is deemed unnecessary as randomizations are planned across sites.
19. Section 4.3.2.3 (Electrocardiograms): The printing of paper ECGs was modified from “all
occasions when a digital ECG is sampled” to “at minimum, a single representative ECG 
should be printed and archived in the subject’s file” to reduce the administrative burden 
on sites.
20. Section 4.3.3 (Clinical Laboratory Tests): Clinical laboratory testing for 
anti-drug antibodies, and Ig and subsets (Ig A/E/G/M) were added under “Other Tests” to 
correct an oversight in the original protocol and for consistency with the tables of study 
procedures provided in Section 4.2 (Schedule of Study Procedures).
21. Section 4.5.1.4 (Dose Preparation Steps): Text that syringe sizes, vial sizes and other 
consumables may be altered at the discretion of the sponsor was added so that similar 
changes to consumables will not require an administrative change or an amendment to 
the protocol.
9.6
Administrative Change 1, 05Nov2015
1. Section 4.5.1.4 (Dose Preparation Steps): The specific requirement for 3 cc vials was 
removed, as these are not feasible for use at sites.
1. Section 4.5.1.4 (Dose Preparation Steps): Dilution of MEDI0382 with MEDI0382 
placebo was changed to dilution of MEDI0382 with diluent (solution manufactured by 
MedImmune) to be consistent with the footnote in Table 4.5.1.4-1 (MEDI0382 and 
Placebo Dose Preparation).  
2. Section 4.5.1.4 (Dose Preparation Steps) and Section 4.5.1.5 (Treatment Administration):
The requirement to use a 29G needle for treatment administration was changed to 30G
needle, because 29G needles are not available to the sites.
9.7
Amendment 3, 10Oct2015
This amendment has been implemented in response to requests made from the Bundesinstitut
fuer Arzneimittel und Medizinprodukte (BfArM; received 08Oct2015). Revisions have been 
made to several sections of the protocol, as outlined below:
1. Protocol Synopsis, Section 3.1.2 (Treatment Regimen), Section 3.1.3.1 (Progression of 
Cohorts within this MAD Study), 
, Section 4.5.1.4 (Dose 
Preparation Steps [In-clinic Dose Preparation Steps]) were amended to reflect a reduction 
in the maximum dose to be administered in this study from 400 to 300 μg/day as 
requested by the BfArM. 


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2.
 
3. Section 4.1.3 (Exclusion Criteria), a criterion excluding subjects with a history of lactic 
acidosis or ketoacidosis was added as requested by the BfArM. 
4. Protocol Synopsis, Section 3.1.1 (Overview), Table 4.2.2-1 (Schedule of Treatment 
Period Procedures: Cohort 1), Table 4.2.2-2 (Schedule of Treatment Period Procedures: 
Cohort 2), Table 4.2.2-3 (Schedule of Treatment Period Procedures: Cohort 3), Table 
4.2.2-4 (Schedule of Treatment Period Procedures: Cohort 4 Overview), Section 4.3.5 
(Glucometer Blood Glucose Readings during the Inpatient Period), and Table 4.3.8-1 
(Example Schedule for MEDI0382 PK and for PD Blood Sample Collections on Day 7 
[Cohort 1], Day 11 [Cohort 2], Day 15 [Cohort 3], and Day 41 [Cohort 4]) were amended 
to include collection of finger prick glucose samples 15 minutes prior to and 2 hours after 
breakfast and before going to bed in addition to the measures taken before and after the 
mid-day and evening meals to increase glucose monitoring as requested by the BfArM. 
5. Table 4.2.2-1 (Schedule of Treatment Period Procedures: Cohort 1), Table 4.2.2-2 
(Schedule of Treatment Period Procedures: Cohort 2), and Table 4.2.2-3 (Schedule of 
Treatment Period Procedures: Cohort 3), the footnotes describing the timing of ECG 
capture were corrected to be consistent with the measurements indicated in the tables. 
6. Table 4.5.1.4-1 (MEDI0382 and Placebo Dose Preparation), the volume of injection was 
reduced consistent with the reduction in dose from 400 to 300 μg.
7. Section 4.5.1.4 (Dose Preparation Steps [In-clinic Dose Preparation Steps]) and 
Section 4.5.1.5 (Treatment Administration [In-clinic Treatment Administration]) the 
needle gauge was amended from 27G to 29G to reduce the chance of discomfort for the 
subjects.
9.8
Amendment 2; 14Aug2015
This amendment has been implemented to meet the requirements of the regulatory agency 
whereby data from the SAD study are summarized to support initiation of the MAD study. 
Revisions to several sections of the protocol, as outlined below, reflect changes in the MAD 
study taking into account these SAD data where appropriate.
In addition, the current eligibility criteria are considered unduly restrictive and do not 
accurately represent the expected benefit/risk profile for MEDI0382. These eligibility criteria 
also raise significant concerns around the ability to recruit subjects to the study. The current 
Leipzig (LIFE) Heart Study (courtesy of 
) contains data on 
10,001 men and women, including 337 individuals with T2DM in the 27-65 years age group. 
These data imply that approximately 1% of the current T2DM population in Germany is 
eligible to enter the study with the current inclusion/exclusion criteria. This is further 
supported by data from Vision practices within the United Kingdom Clinical Practice 
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Modification of the eligibility criteria as detailed below is not anticipated to change the 
benefit-risk profile of MEDI0382; specifically the changes with respect to the anticipated 
cardiovascular risk profile of MEDI0382 have been considered. The action of MEDI0382 is 
designed to mimic the action of the naturally occurring peptide hormone oxyntomodulin, a 
peptide with both glucagon and GLP-1 agonist activity. Evidence to support a negative effect 
of glucagon or GLP-1 agonism on blood pressure does not exist. For dual GLP-1 and 
glucagon agonism, as exhibited by oxyntomodulin, no negative effects on pulse or blood 
pressure have been observed. As oxyntomodulin is the prototype naturally occurring model 
for MEDI0382, the benefit-risk profile for MEDI0382 with respect to cardiovascular disease 
is expected to be positive, driven by substantial weight loss against clinically insignificant 
effects on pulse and blood pressure.
Amendments to the eligibility criteria have been made as detailed below; the number of 
clinical sites has also been increased. Text revisions resulting from this amendment are 
incorporated in the body of Protocol Amendment 2. Changes to the protocol are summarized 
below.
 
 
3. Synopsis (Objectives/Endpoints), Section 2.1.1 (Primary Objective), Section 2.2.1 
(Primary Endpoints), and Section 4.8.3.1 (Primary Efficacy Analysis) were changed to 
specify that change from baseline in glucose and body weight will be evaluated rather 
than change from the first dose in an up-titration period, this will more accurately reflect 
the likely clinical use profile of MEDI0382.
4. Synopsis (Objectives), Section 2.1.2 (Secondary Objectives), Section 2.2.2 (Secondary 
Endpoints), and Section 4.8.3.2 (secondary Efficacy Analysis) objective 1 and endpoint 1 
were changed to specify that change from baseline rather than Day 1 will be use evaluate 
glucose control. Given that subjects are admitted 2 days prior to administration of 
investigational product, baseline parameters are considered stable enough to represent a 
subjects’ predose metabolic state accurately. In keeping with the sponsor’s responsibility 
to reduce unnecessary collection of blood samples, collection of these parameters at 
Day 1 has now been rationalized. 
5. Synopsis (Objectives), Section 2.1.3 (Exploratory Objectives), Section 4.1.2 (Inclusion 
Criteria) were clarified to state that subjects should be treated with a daily dose of statin 
at baseline.
6. Synopsis (Endpoints), Section 2.2.2 (Secondary Endpoints), Section 3.1.1 (Overview), 
Section 3.2.2 (Recruitment of Subjects with T2DM on Metformin), Section 3.2.3 
(Rationale for Endpoints Supporting the Secondary Objectives of Safety/Tolerability and 


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PK/Immunogenicity), Table 4.2.2-1 (Schedule of Treatment Period Procedures: 
Cohort 1), Table 4.2.2-2 (Schedule of Treatment Period Procedures: Cohort 2), Table 
4.2.2-3 (Schedule of Treatment Period Procedures: Cohort 3), and Table 4.2.2-4 
(Schedule of Treatment Period Procedures: Cohort 4), Section 4.3.6 (Pharmacokinetic 
Evaluation and Methods) was amended to include measurement of metformin 
concentration. Measurement of metformin concentration at baseline ensures that any 
PK/PD interaction between metformin dosing and MEDI0382 can be adequately explored 
during this intensively monitored, early phase study in a safe, in house environment.
 
 
 
8. Synopsis (Study Design) and Section 3.1.1 (Overview) the number of anticipated clinical
sites anticipated to successfully recruit this study was increased from 8 to 10. In addition, 
the inclusion of overweight as well as obese subjects has been reflected due to the 
increased range for body weight eligibility.
9. Synopsis, Section 3.1.1 (Overview), Figure 3.1.1-1 (Study Flow Diagram), Section 3.1.2 
(Treatment Regimen), were amended to make the language describing the dosing in the 
4 cohorts consistent throughout the protocol and to ensure it more accurately reflects the 
proposed dosing schedule for the MAD study.
10. Synopsis, Section 3.1.1 (Overview) and Table 4.2.1-1 (Screening procedures) were 
amended to lengthen the screening period from 28 days to 42 days to ensure there is 
adequate time for subjects to complete a washout period within the screening period if 
required. 
11. Synopsis, Section 3.1.1 (Overview), Section 4.5.1.1 (Identity of Investigational Product), 
where subjects in Cohort 4 are not considered competent with regards to self-
administration of investigational product, an option for them to continue to receive 
investigational product by a qualified study site professional has been added to ensure 
these subjects are able to continue in the study. 
12. Synopsis and Section 3.1.1 (Overview) were edited to clarify that subjects are admitted to 
the clinic 2 evenings before the receipt of investigational product. 
13. Synopsis, Section 3.1.1 (Overview), Table 4.2.2-1 (Schedule of Treatment Period 
Procedures: Cohort 1), Table 4.2.2-2 (Schedule of Treatment Period Procedures: 
Cohort 2), Table 4.2.2-3 (Schedule of Treatment Period Procedures: Cohort 3), and 
Table 4.2.2-4 (Schedule of Treatment Period Procedures: Cohort 4) the Day 1 assessment 
of MMT and blood samples for glucose metabolism panel were removed from the 
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15. Section 3.1.3.1 (Progression of Cohorts) has been amended to include further details of 
when dose escalation will be stopped and the process leading to a stopping decision.
16. Section 3.1.3.2 (Cardiac Stopping Criteria) has been edited to clarify that pulse rate 
should be measured at 5 timepoints during the 10 minute period. 
17.
 
 
18. Section 3.2.2 (Rationale for Study Population) and Section 4.1.2 (Inclusion Criteria) the 
lower limit of HbA1c for Cohort 4 has been lowered from 7.5% to 7.0%. A different 
lower limit was originally proposed with respect to HbA1c for Cohorts 1-3 vs Cohort 4 to 
facilitate recruitment in the earlier cohorts and maximize the ability to demonstrate a 
reduction in blood glucose for Cohort 4. It has now become apparent that excellence in 
diabetes care within the German T2DM population means that maintaining the lower 
limit of HbA1c at 7.5% will significantly impair recruitment for the proposed study. In 
the opinion of the sponsor the reduction in the HbA1c limit at study entry does not impact 
on patient safety, as GLP-1 agonists when used in monotherapy or in combination with 
metformin are not associated with increased risk of hypoglycemia. 
19. Section 4.1 (Subjects) clarified that the population is to have been treated with a stable 
dose of oral blood glucose lowering therapy for 3 months prior to screening. 
20. Synopsis (Target Subject Population) and Section 4.1.2 (Inclusion Criteria) the 
acceptable BMI range has been changed from 30-35 kg/m2 to 27-40 kg/m2. Section 3.2.2 
(Rationale for Study Population) has also been amended to include the rationale for 
inclusion of subjects in this BMI range. MedImmune considers the current BMI criteria 
(30-35 kg/m2) unduly restrictive. Approximately 44% of the T2DM population have a 
BMI between 30-40 kg/m2 (Daousi et al, 2006) and with regards to cardiovascular 
disease, the greatest increase in prevalence in an unselected primary care population 
occurs at a BMI > 37.5 kg/m2 in men and > 40 kg/m2 in women (McQuigg et al, 2008). 
With the screening procedures in place, including medical history assessment, full 
physical examination, and ECG monitoring throughout the study, MedImmune believes 
that significant ischemic cardiovascular disease can be excluded while allowing for the 
broader BMI range at inclusion.
21. Section 4.1.2 (Inclusion Criteria) the requirement for subjects to be willing and able to 
complete and meet all eligibility requirements for randomization within 42 days after 
signing the informed consent form was added for clarity. 
22. Section 4.1.3 (Exclusion Criteria) the exclusion of subjects with microalbuminuria 
(20-200 mg/L) has been removed from the protocol. MedImmune believes that the 
current exclusion of subjects with microalbuminuria is unnecessarily restrictive. 
Microalbuminuria screening has low accuracy to detect subjects with diabetic 
nephropathy; whereas, deterioration of glomerular filtration rate (GFR) appears at an 
earlier stage in the progression of diabetic nephropathy than albuminuria, and therefore 
represents a more reliable indicator of renal function impairment in diabetic kidney 
disease (exclusion criterion 12; Rajic et al, 2003; Baskar et al, 2006). In addition, 


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multiple parameters of renal function will be closely monitored throughout the study in 
all cohorts, with serial measurements of urinary protein, pH, and specific gravity as well 
as serial measurements of relevant plasma parameters, including creatinine, blood urea 
nitrogen, and electrolytes.
In addition, a change in exclusion criteria to allow subjects with microalbuminuria 
(≤300 mg/L albumin) is likely to have a minimal impact on coronary disease in this 
study population (Pugliese et al, 2014 and data from the CPRD vision practice data 
viewer accessed on 29May2015). Given the multiple screening assessments for 
cardiovascular disease, including medical history, complete physical examination, and 
ECG assessment, MedImmune believes that the change to include subjects with 
microalbuminuria up to 300 mg/L is appropriate and will not impact significantly on the 
cardiovascular risk profile of subjects included in this study.
23. Section 4.1.3 (Exclusion Criteria), criterion 11 was edited to correct an error.
24. Section 4.1.3 (Exclusion Criteria), criterion 14 was deleted to remove redundancy with 
criterion 18.
25. Section 4.1.6 (Discontinuation of Investigational Product) was edited to include both 
mg/dL and mmol/L units for glucose.
26. Section 4.1.7 (Replacement of Subjects) the provision for additional screened subjects to 
be available for randomization was included to ensure that sufficient numbers of subjects 
are randomized into each cohort.
27. Section 4.1.8 (Withdrawal of Informed Consent for Data and Biological Samples) the 
section describing Optional Samples Obtained for Future Genetic Research or Future 
Non-genetic Research was edited to reflect the current practice of the sponsor in handling 
these samples. 
28. Table 4.2.1-1 (Schedule of Screening Procedures) was edited to reduce redundancy and 
the calculation of GFR was added to confirm eligibility.
29. Table 4.2.2-1 (Schedule of Treatment Period Procedures: Cohort 1), Table 4.2.2-2 
(Schedule of Treatment Period Procedures: Cohort 2), Table 4.2.2-3 (Schedule of 
Treatment Period Procedures: Cohort 3), Table 4.2.2-4 (Schedule of Treatment Period 
Procedures: Cohort 4), and Section 4.6.1 Methods for Assigning Treatment Groups, 
randomization was changed to allow for randomization on either Day -1 or Day 1 with 
dosing to occur within 10 hours of randomization to allow adequate time on the day of 
dosing dose preparation. 
30. Table 4.2.2-1 (Schedule of Treatment Period Procedures: Cohort 1), Table 4.2.2-2 
(Schedule of Treatment Period Procedures: Cohort 2), Table 4.2.2-3 (Schedule of 
Treatment Period Procedures: Cohort 3), and Table 4.2.2-4 (Schedule of Treatment 
Period Procedures: Cohort 4) was edited to reduce redundancy, and a predose blood 
sample for evaluation of lactate and screening PD sample for glucose were added. A
MEDI0382 PK dose sample at 48 hours post-final dose for Cohorts 1-3 was also added.
31.
 
 
32. Section 4.2.4 (Early Discontinuation or Unscheduled Visit) was added to the protocol to 
detail the procedures to perform in the event a subject prematurely discontinues from the 
study or requires an unscheduled study visit.


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33. Section 4.3.2.1 (Medical History and Physical Examination) was edited to make it clear 
the assessments to perform for a targeted physical examination (previously termed an 
abbreviated physical examination).
34. Section 4.3.2.2 (Assessment of the Injection Site) was edited to add more detail of the 
types or reactions that may occur.
35. Section 4.3.2.3 (Electrocardiograms) was edited to reflect the practice at clinical sites. 
The process to follow in the case of significant skin irritation was also added. 
36. Section 4.3.4 (Estimate of Blood Volumes) was edited to reflect the changes in blood 
samples taken during the study.
37. Section 4.3.5 (Glucometer Blood Glucose Readings during the Inpatient Period) was 
edited for clarity.
38. Table 4.3.8-1 (Example Schedule for MEDI0382 PK and for PD Blood Sample 
Collections on Day 7 (Cohort 1), Day 11 (Cohort 2), Day 15 (Cohort 3), and Day 41 
(Cohort 4) was edited to clarify that the time of collection is in relation to the MMT only. 
39. Section 4.3.12.3 (Training for Completing the Daily Diaries during the At-home 
Self-administration Period) was edited to reflect the use of electronic diaries.
40. Section 4.5.1.1 (Identity of Investigational Product) was modified to reflect the kit supply 
for at-home dosing.
41. Section 4.5.1.2 (Investigational Product Handling) was edited to remove redundancy. 
42. Section 4.5.1.4 (In-clinic Dose Preparation Steps), Table 4.5.1.4-1 (MEDI0382 and 
Placebo Preparation) were modified to reflect the change in dose selection for this study. 
The calculations for dose preparation were also amended accordingly.
43. Section 4.7.1 (Permitted Concomitant Medications) was amended to specify that 
hormone replacement therapy and agents for benign prostatic hyperplasia are permitted 
during the study.
44. Section 4.8.4 (Safety) was edited to emphasize that safety ECGs will be evaluated based 
on paper ECG copies at site. 
45. Section 5.5 (Reporting of Serious Adverse Events), Section 5.6 (Other Events Requiring 
Immediate Reporting), Section 5.6.1 (Overdose), Section 5.6.2 (Hepatic Function 
Abnormality), and Section 5.6.3 (Pregnancy) have been modified to reflect a change in 
process of SAE reporting by the Sponsor and the implementation of electronic SAE 
reporting. Appendix 6 has been added to provide detail on the reporting of Hy’s law cases 
in line with this updated process.
46. Section 8 (References) has been updated to include additional references included in this 
amendment.
47. Appendix 2 was revised to reflect current sponsor definitions for adverse event severity 
grading. 
9.9
Amendment 1; 26Feb2015
Text revisions resulting from this amendment are incorporated in the body of Protocol 
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requests from the regulatory agency of the country in which the sponsor sought approval to 
conduct the study as well as the central ethics committee. Major changes to the protocol are 
summarized below.
1. Synopsis (under Study Design) and Section 3.1.1 (Overview) the number of anticipated 
study sites was changed from approximately 3 to 5 to “up to 8” to allow for the 
possibility of increasing the number of sites.
 
 
 
 
 
 
 
 
.
3. Section 3.1.3.2 (Progression of Cohorts within this MAD Study): 
a.
The following text was added for subject safety: A sentinel dosing approach is 
planned for Cohorts 1, 2, and 3. Only 2 subjects in a given cohort will be dosed on 
Day 1, and the randomization schedule will ensure that these consist of 1 active and 
1 placebo subject. A time lag of ≥3 days will occur before additional subjects in the 
cohort are dosed. Dosing is proposed to continue based on a lack of significant safety 
findings in the first 2 subjects dosed. The overall randomization schedule will ensure 
a 2:1 randomization (active:placebo) for each cohort.
b. The bolded text in the following phrase was added for clarification: For progression 
from Cohort 1 to Cohort 2, and from Cohort 2 to Cohort 3, the decision whether or 
not to progress will be made by the Dose Escalation Committee. 
c.
Also, the relevant data will be summarized and provided to the appropriate regulatory 
body and central ethics committee.
d. And, approval to proceed with Cohort 4 will be obtained from the appropriate 
regulatory body prior to initiating enrollment.
e.
Under the DEC recommendation options: 
i.
A bullet point was clarified. Expand “dosing” was clarified to say “expand “the 
number of patients dosed” at a particular dose level. 
ii. And, a bullet point (a new option) was added as follows. “Escalate to the next 
cohort but extend the number of dosing days at a particular dose level before dose 
up-titration occurs.”
4. Section 3.1.3.3 (Cardiac Stopping Criteria): The bolded word “or” was added to the 
fourth bullet for clarity, ie, “In a subject receiving MEDI0382: hypertension, defined as 
an increase in resting supine systolic BP > 40 mm mercury (Hg) or above 180 mm Hg 
and persisting for at least 10 minutes.”


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5. Section 3.1.4 (Management of Toxicities and Dose Modification): Significant vomiting 
was clarified as “3 or more episodes of vomiting on a single day or across 2 consecutive 
days, despite adjustment to diet having been made.”
 
 
 
 
 
7. Section 4.1.2 (Inclusion Criteria): A note was added to clarify Inclusion Criterion 9 
(about contraception) reading “Male condom plus spermicide is only considered an 
effective contraceptive measure when used together with another method in
Table 4.1.2-1. None of the methods in Table 4.1.2-1 are intended to be used alone.”
8. Section 4.1.3 (Exclusion Criteria): The exclusion criterion “Concurrent participation in 
another study of any kind is prohibited” was added.
9. Section 4.1.6 (Discontinuation of Investigational Product) was modified to add that an 
individual subject will not receive any further investigational product if that subject has 
more than 2 symptomatic hypoglycemic events (symptoms of hypoglycemia with 
documented finger prick glucose < 2.8 mmol/L); or persistent hyperglycemia 
(> 260 mg/dL measured with 2 laboratory fasting blood glucose samples more than 
3 days apart).
10. Section 4.8.9 (Dose Escalation Committee): In the following sentence, “coordinating” 
investigator replaced “principal” investigator. The CRO medical monitor and the 
coordinating investigator will remain blinded.


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Appendix 1
Signatures
Sponsor Signature(s)
A Phase 1/2, Randomized, Double-blind, Placebo-controlled, Multiple-ascending-dose Study 
to Evaluate the Efficacy, Safety, and Pharmacokinetics of MEDI0382 in Overweight and 
Obese Subjects with a History of Type 2 Diabetes Mellitus
I agree to the terms of this protocol.
Signature and date: 
One MedImmune Way, Gaithersburg MD, 20878, USA 
Telephone number: 






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


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Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product.
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:
•
An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long after, 
administration of the investigational product for it to be considered product-related)
•
A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident)
•
A clearly more likely alternative explanation for the event is present (eg, typical adverse 
reaction to a concomitant drug and/or typical disease-related event)
Individual AE/SAE reports will be considered “related” to use of the investigational product 
if the “not related” criteria are not met. 
“Related” implies that the event is considered to be “associated with the use of the drug” 
meaning that there is “a reasonable possibility” that the event may have been caused by the 
product under investigation (ie, there are facts, evidence, or arguments to suggest possible 
causation).
Relationship to Protocol Procedures
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-
emergent SAEs. A protocol-related SAE may occur as a result of a procedure or intervention 
required during the study (eg, blood collection, washout of an existing medication). The 
following guidelines should be used by investigators to assess the relationship of SAEs to the 
protocol:
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.


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Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record).


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Appendix 3
National Institute of Allergy and Infectious Diseases
and Food Allergy and Anaphylaxis Network Guidance 
for Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis 
Network 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
◦
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, 
hypoxemia)
◦
Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
◦
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula)
◦
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, 
hypoxemia)
◦
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
◦
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
◦
Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP
◦
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline


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Appendix 4
Columbia-Suicide Severity Rating Scale


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Appendix 6
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law. It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) 
criteria are met. HL criteria are met if there is no alternative explanation for the elevations in 
liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the investigational 
product. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting adverse events (AE) and serious adverse events (SAE) according to the outcome of 
the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥ 2 × ULN at any point during the study 
following the start of investigational product irrespective of an increase in alkaline 
phosphatase (ALP).
Hy’s Law (HL)
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, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on 
the same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.


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


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


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



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