Clinical trial NCT03444584
Conditions: Type 2 Diabetes Mellitus
Keywords: 0382 T2DM
Sponsor: MedImmune LLC
Start date: 2018-05-08; Completion date: 2018-12-06
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2 study Comparing the effects on glucose control of MEDI0382 in combination with Dapagliflozin and Metformin compared to placebo in combination with Dapagliflozin and Metformin in overweight/obese participants with Type 2 Diabetes Mellitus (T2DM).

Detailed description:
This is an exploratory randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of MEDI0382 versus placebo in overweight/obese participants with T2DM treated with metformin and dapagliflozin dual therapy. The study will enroll participants with T2DM treated either with metformin monotherapy or with metformin and dapagliflozin dual therapy. After the screening period, participants treated with metformin monotherapy only will enter a 4-week run-in period where participants will be administered oral dapagliflozin 10 mg a day, which will be provided by the sponsor. Enrolled participants that are already treated with metformin and dapagliflozin dual therapy will continue this dual therapy throughout the study and can be randomized after the screening period without entering the run-in period. All participants (ie, on monotherapy and dual therapy) entering the double-blind treatment period will receive dapagliflozin 10 mg a day, which will be provided by the sponsor.

Participants in this study will participate for up to 20 weeks including a screening period of up to 60 days, a 4-week run-in period (for participants on metformin monotherapy only), a 4-week treatment period, and a 4-week follow-up post-treatment period.

Arms: arm 1: Participants will receive subcutaneous dose of MEDI0382 daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 300 μg for 14 days) for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period. arm 2: Participants will receive subcutaneous dose of placebo matched to MEDI0382 daily for 28 days. Participants were on metformin and dapagliflozin background dual therapy during the treatment period
Interventions: intervention 1: MEDI0382 intervention 2: Placebo intervention 3: Dapaglifozin intervention 4: Metformin
Intervention descriptions: intervention 1: Subcutaneous dose of MEDI0382 (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 300 μg for 14 days). intervention 2: Subcutaneous dose of placebo matched to MEDI0382. intervention 3: Oral dose of dapaglifozin 10 mg tablet. intervention 4: Oral dose of metformin tablet (maximum tolerated dose \[MTD\] \> 1 g).

Protocol documents:
Prot_000.pdf: 
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An Exploratory Phase 2a Randomized, Placebo-controlled, 
Double-blind Study to Evaluate the Efficacy and Safety of
MEDI0382 versus Placebo in Overweight/Obese Subjects 
with Type 2 Diabetes Mellitus Treated with Dapagliflozin 
and Metformin 
Sponsor Protocol Number: D5670C00007
Application Number:
2017-002817-78
Investigational Product:
MEDI0382
Sponsor:
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca, Milstein Building, Granta Park, Cambridge, 
CB21 6GH, UK
Medical Monitor:
, MedImmune
Contract Research Organization: Covance Clinical and Periapproval Services Limited 
Osprey House, Westacott Way, Maidenhead, SL6 3QH, 
UK
Protocol History, Date: Original Protocol, 19Sep2017
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from MedImmune.


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PROTOCOL SYNOPSIS
TITLE
An exploratory Phase 2a randomized, placebo-controlled, double-blind study to evaluate the efficacy and 
safety of MEDI0382 versus placebo in overweight/obese subjects with type 2 diabetes mellitus treated with 
dapagliflozin and metformin.
HYPOTHESES
Primary Hypothesis:
•
The administration of MEDI0382 subcutaneously (SC) once daily will improve glycemic control in 
overweight/obese subjects with type 2 diabetes mellitus (T2DM) treated concurrently with dapagliflozin 
and metformin.
•
Secondary Hypotheses: 
•
The administration of MEDI0382 SC will have an acceptable safety profile and be well tolerated when 
coadministrated with dapagliflozin and metformin
•
The pharmacokinetic (PK) profile of MEDI0382 will remain unchanged in the presence of 
coadministered dapagliflozin and metformin.
•
 
•
The administration of MEDI0382 decreases 24-hour glycemic variation when coadministered with 
dapagliflozin and metformin.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To compare the change in glucose area under the 
concentration-time curve (AUC) as measured by a 
standardized mixed meal tolerance test (MMTT) in 
subjects treated with dapagliflozin and metformin 
receiving MEDI0382 or placebo for 28 days
•
Change from baseline (Day -1) to the end of 
28 days of treatment (Day 28) in glucose AUC
from 0 to 4 hours (AUC0-4h) as measured by a 
MMTT
•
Percentage change from baseline (Day -1) to the 
end of 28 days of treatment (Day 28) in glucose 
AUC0-4h as measured by a MMTT
Secondary
To compare the safety and tolerability profile of 
MEDI0382 given SC (titrated up to a dose level of 
300 μg) compared to placebo after 28 days of 
treatment in subjects treated with dapagliflozin and 
metformin
Measures of safety and tolerability include:
•
Incidence of treatment-emergent adverse events 
(TEAEs) and treatment-emergent serious 
adverse events (TESAEs)
•
Clinically important changes in 12-lead 
electrocardiogram (ECG), vital signs (including 
24-hour heart rate and blood pressure), physical 
examination, and clinical laboratory evaluations
To evaluate the PK profile of MEDI0382 and 
dapagliflozin (in subjects treated with dapagliflozin, 
metformin, and MEDI0382) and dapagliflozin (in 
subjects treated with dapagliflozin, metformin, and 
placebo)
PK profile of both MEDI0382 and dapagliflozin 
administered simultaneously and dapagliflozin 
administered with placebo include:
•
Plasma AUC from zero to infinity (AUC0-inf),
from zero to last observation (AUC0-last) and 
over the dosing duration (AUCtau)
•
Maximum-observed serum drug concentration 
(Cmax)


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•
Time to maximum-observed serum drug 
concentration (tmax)
•
Terminal elimination half-life (t1/2)
•
Apparent clearance (Cl/F)
 
 
 
To evaluate 24-hour glucose control as measured by 
continuous glucose monitoring (CGM) in subjects 
treated with dapagliflozin and metformin receiving 
MEDI0382 or placebo for 28 days 
•
Change from baseline to the end of dosing at 
each dose level (Days 7, 14, and 28) in glucose 
AUC at 24 hours (AUC24h) as measured by 
CGM
•
Change from baseline to the end of dosing at 
each dose level (Days 7, 14, and 28) in 24-hour 
mean glucose as measured by CGM
•
Change from baseline to the end of dosing at 
each dose level (Days 7, 14, and 28) in standard 
deviation (SD) of 24-hour glucose readings as 
measured by CGM
•
Change from baseline to Days 7, 14, and 28 in 
the coefficient of variation (CV) (ratio of 
SD:mean over 24 hours) of glucose readings as 
measured by CGM
•
Change from baseline to Days 7, 14, and 28 in 
the mean amplitude of glucose excursion 
(MAGE) of 24-hour glucose readings as 
measured by CGM 
•
Change from baseline to Days 7, 14, and 28 in 
the percentage of 24-hour glucose readings 
obtained from CGM that fall within the 
euglycemic range of ≥ 70 mg/dL (≥3.9 mmol/L) 
and ≤180 mg/dL (≤10.0 mmol/L)
•
Change from baseline to Days 7, 14, and 28 in 
the percentage of 24-hour glucose readings 
obtained from CGM that fall within 
hyperglycemic (high glucose) range of 
> 180 mg/dL (> 10.0 mmol/L)
•
Change from baseline to Days 7, 14, and 28 in 
the percentage of 24-hour glucose readings 
obtained from CGM that fall within the 
hypoglycemic range of < 70 mg/dL 
(< 3.9 mmol/L)
•
Change from baseline to Days 7, 14, and 28 in 
the percentage of 24-hour glucose readings 
obtained from CGM that fall within the 
clinically significant hypoglycemic range of 
< 54 mg/dL (3.0 mmol/L)
Exploratory 
To compare additional measures of glucose control 
(fasting plasma glucose [FPG] and hemoglobin A1c 
[HbA1c]) in subjects treated with dapagliflozin and 
•
Change from baseline (Day -1) to Day 28 in 
FPG


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metformin receiving MEDI0382 or placebo for 
28 days
•
Change from baseline (Day -2) to Day 28 in 
HbA1c
To evaluate pancreatic and incretin hormone AUC 
profiles (ie, active glucagon-like peptide-1 [GLP-1], 
glucagon, insulin, and c-peptide) as measured by 
MMTT in subjects treated with dapagliflozin and 
metformin receiving MEDI0382 or placebo for 
28 days 
•
Change from baseline (Day -1) to Day 28 in 
GLP-1, glucagon, insulin, and c-peptide AUC0-4h
as measured by MMTT
To compare the fasting free fatty acid (FFA) levels 
in subjects treated with dapagliflozin and metformin 
receiving MEDI0382 or placebo for 28 days
•
Change from baseline (Day -1) to Days 7, 14,
and 28 in fasting FFA level
To compare plasma ketone profile 
(β-hydroxybutyrate) in subjects treated with 
dapagliflozin and metformin receiving MEDI0382 or 
placebo for 28 days 
•
β-hydroxybutyrate profile to include AUC0-inf, 
AUC0-last, Cmax, and tmax
To compare the change in body weight after 28 days 
of treatment with MEDI0382 or placebo in subjects 
treated with dapagliflozin and metformin 
•
Change from baseline (Day 1) to Day 29 in body 
weight (kg)
•
Percentage change from baseline (Day 1) to 
Day 29 in body weight (kg)
•
Proportion of subjects achieving ≥5% body 
weight loss from baseline (Day 1) to Day 29
To evaluate 24-hour urinary glucose excretion in
subjects treated with dapagliflozin and metformin 
receiving MEDI0382 or placebo for 28 days
•
Total glucose excreted in urine collected for 
24 hours
STUDY DESIGN
This is an exploratory randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety 
of MEDI0382 versus placebo in overweight/obese subjects with T2DM treated with dapagliflozin and 
metformin. Subjects will participate in the study for up to 20 weeks including a screening period of up to 
60 days, a 4-week run-in period (for subjects on metformin monotherapy only), a 4-week treatment period,
and a 4-week posttreatment follow-up period. There will be 2 inpatient stays.
Four-week run-in period:
Following a screening period of up to 60 days, eligible subjects on metformin monotherapy only will enter a 
4-week run-in period during which time they will receive oral dapagliflozin 10 mg once a day for 28 days 
prior to randomization.
Four-week treatment period:
Subjects will be admitted to the clinical unit on Day -2. Study subjects will undergo initial safety assessments
including but not limited to blood collection for laboratory tests, medical history, abbreviated physical 
examination, vital signs, and training on SC injection administration. At this time, an ambulatory blood 
pressure monitoring (ABPM) device will be fitted on Day -2 and worn for 24 hours. Subjects will be 
expected to conduct daily finger-prick testing for ketone measurements throughout the treatment period. On 
Day -1, after an overnight fast of approximately 10 hours and verification of eligibility criteria, subjects will 
undergo their first MMTT. After the MMTT, subjects will be fitted with a CGM sensor on the contralateral 
arm to the ABPM, which will expire and be replaced every 14 days. Subjects will be expected to wear this 
sensor for the duration of treatment. Other procedures on Day -1 include blood collection for laboratory tests,
dapagliflozin and ketones PK sampling, and training on SC administration. On Day -1, the subject will have 
the option to remain in the unit or return home. Discharged subjects must ensure they undergo an overnight 
fast for approximately 10 hours, and they will return the clinic on Day 1. Subjects can be randomized after 
confirming eligibility at any time from Day -1 to Day 1 (predose) to receive either MEDI0382 or placebo. 
On Day 1, following an overnight fast, dosing will commence after predose safety measures including vital 
signs, an ECG, and blood collection for laboratory tests; blood collection for dapagliflozin PK, ketones PK, 
and ADA; and measurement of weight are performed. Subjects will then receive the following:


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•
MEDI0382 SC once daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and 300 μg for 
14 days) in the morning for 28 days (N = 23) 
•
Placebo SC once daily in the morning for 28 days (N = 23) 
Subjects will be monitored for safety, glucose, and ketones and will be discharged from the unit 
approximately 6 hours postdose. Capillary glucose and ketones monitoring will be done at the site using a 
glucometer. A 24-hour urine collection for glucose excretion will be collected from Day 1 to Day 2. The 
subject will return to the unit on Day 2 for safety monitoring and supervision of investigational product 
administration.
Subjects will then return to the clinical unit at weekly intervals until a maintenance dose of 300 μg is 
achieved. Subjects will return to the unit for outpatient visits on Days 7, 8, 14, 15, and 22 to undergo safety 
assessments including but not limited to an abbreviated physical examination and ECG (Days 7, 14, and 22), 
vital signs (all visits, with ABPM fitted on Day 14 only), urine tests (eg, pregnancy test on Day 14 and 
Day 22), and blood collection for laboratory tests (Days 7, 14, and 22). MEDI0382, dapagliflozin, and 
ketones PK sampling will be performed on Days 7, 8, 14, and 15. Uptitration of SC investigational product 
will occur on Day 8 and Day 15. After uptitration of investigational product, subjects will be monitored for 
safety, glucose, and ketones and will be discharged 6 hours postdose. The CGM device will be replace on 
Day 14. 
Subjects will be expected to return to the unit for final admission on Day 27 to Day 29 to undergo final 
safety assessments including but not limited to an abbreviated physical examination, an ECG, and urine tests 
(eg, pregnancy and drug and alcohol screening) on Day 27 and vital signs (including ABPM) and blood 
collection for laboratory tests on Day 28. On Day 28, following an overnight fast of 10 hours the day before,
subjects will undergo a final MMTT. On Day 28, PK sampling of MEDI0382, dapagliflozin, and ketones 
will be taken relative to time zero of administration of investigational product. A 24-hour urine collection for 
glucose excretion will be collected from Day 28 to Day 29. On Day 29, vital signs, a measurement of weight,
and additional blood collection for ADA and MEDI0383, dapagliflozin, and ketones PK will be performed,
and subjects will be discharged if no safety concerns are identified.
Safety follow-up period:
Once subjects have completed the 4-week combination treatment phase, they will be followed up for safety 
for an additional 4 weeks. Subjects will continue to wear the CGM until approximately 28 days after the last 
dose and will continue to test their ketone level once daily prebreakfast until approximately 14 days after the 
last dose using the testing strips provided.
TARGET SUBJECT POPULATION
Male or female subjects ≥18 years of age with a body mass index ≥25 and ≤40 kg/m2 and a diagnosis of 
T2DM treated with metformin monotherapy or metformin plus dapagliflozin dual therapy with an inadequate 
blood glycemic control (defined by an HbA1c of ≥7.0% to ≤10.0%). Females of childbearing potential must 
not be pregnant and lactating females will be excluded. Females of childbearing potential should be using 
appropriate contraception.
INVESTIGATIONAL PRODUCT, DOSAGE, AND MODE OF ADMINISTRATION
Run-in period:
Eligible subjects on metformin monotherapy will receive oral dapagliflozin 10 mg once a day for 28 days, 
which will be provided by the sponsor.
Treatment period:
Following the run-in period for subjects on metformin monotherapy or screening period for subjects on dual 
therapy, subjects will be randomized as follows:
•
MEDI0382 SC once daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and 300 μg for 
14 days) in the morning for 28 days (N = 23) 
•
Placebo SC once daily in the morning for 28 days (N = 23) 
The dose of MEDI0382 will be titrated up from a starting dose of 100 μg in 100 μg increments to the target 
dose of 300 μg over 2 weeks. Subjects entering the study must have been treated with daily stable oral doses 
of blood glucose-lowering therapy with metformin (maximum tolerated dose ≥1 gram) for at least 8 weeks
prior to screening. The sponsor will provide dapagliflozin to all subjects during the treatment period.


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STATISTICAL ANALYSIS PLAN
Sample size: 
A total of 46 subjects are planned for the study. Each of the 2 treatment groups will be randomized at a 
1:1 ratio to receive (a) MEDI0382 with dapagliflozin and metformin administered simultaneously or (b)
placebo with dapagliflozin and metformin administered simultaneously. A sample size of 23 subjects in each 
treatment group will provide a study power > 95% to detect a difference of 30% between treatment groups in 
the relative change from baseline in glucose AUC0-4h at a two-sided alpha of 5%, assuming a common SD of 
20%. This sample size will also provide a study power > 95% to detect a difference of 225 hr•mg/dL
between treatment groups in absolute change from baseline in glucose AUC0-4h at a two-sided alpha of 5%, 
assuming a common SD of 150 hr•mg/dL.
Statistical analyses:
Efficacy and pharmacodynamics (PD) data will be analyzed based on the Intent-to-Treat population. The 
primary endpoints, change and % change in glucose AUC0-4h as measured by a MMTT from baseline to the
end of 28 days of treatment, will be summarized by treatment group. Statistical comparisons of these 
endpoints between MEDI0382/dapagliflozin/metformin and placebo/dapagliflozin/metformin treatment 
groups will be performed using an analysis of covariance by adjusting baseline and treatment group with 
last-observation-carried-forward (LOCF) approach to handle missing data. Other efficacy and PD endpoints 
including CGM glucose parameters (AUC0-24h, 24-hour mean glucose, SD, CV, MAGE, % of 24-hour 
glucose readings in euglycemic, hyperglycemic, hypoglycemic, and clinically-significant hypoglycemic
ranges), FPG, HbA1c, change from baseline in AUC0-4h of MMTT parameters (GLP-1, glucagon, insulin, 
and c-peptide), fasting FFA level, 24-hour urinary glucose excretion, and body weight will be summarized
and analyzed similarly to the primary endpoints. For the proportion of subjects achieving ≥5% body weight 
loss from baseline after 28 days of treatment, statistical comparisons between 
MEDI0382/dapagliflozin/metformin and placebo/dapagliflozin/metformin treatment groups will be 
performed using a logistic regression by adjusting baseline and treatment group. Descriptive statistics at each 
time point will be provided by treatment group for efficacy and PD endpoints.
Safety analyses:
Safety data including TEAEs, vital signs, safety laboratory, and ECG data will be analyzed based on the 
As-treated population. Treatment-emergent AEs and TESAEs will be summarized according to the Medical 
Dictionary for Regulatory Activities by System Organ Class and Preferred Term for type, incidence, 
severity, and relationship to investigational product. Other safety data such as vital signs (including 24-hour 
ABPM) and clinical laboratory data will be summarized by treatment group at each time point. Additional 
analyses of these data may include the change from baseline to each postbaseline time point where 
appropriate. Electrocardiogram parameters will also be assessed and summarized descriptively.
Pharmacokinetic analyses:
Pharmacokinetic parameters such as, but not limited to, Cmax, tmax, AUC, t1/2, and accumulation ratio will be 
estimated from plasma concentration-time data for MEDI0382 and β-hydroxybutyrate at each dose level 
separately and for 10 mg dapagliflozin. Moreover, if data allow, additional parameters such as Cl/F may be 
derived for MEDI0382 at all dose levels and for 10 mg dapagliflozin. Descriptive statistics will be generated 
for PK parameters for MEDI0382 and dapagliflozin in each cohort. Subjects who have at least one 
measurable concentration time point of investigational product will be used for these analyses.
 
 
Interim analysis:
No interim analysis is planned.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ................................................................................................2
LIST OF ABBREVIATIONS........................................................................................12
1
INTRODUCTION ..............................................................................................14
1.1
Disease Background..................................................................................14
1.2
MEDI0382 Background............................................................................14
1.3
Summary of Nonclinical Experience .........................................................15
1.4
Summary of Clinical Experience...............................................................15
1.5
Rationale for Conducting the Study...........................................................16
1.6
Benefit-risk and Ethical Assessment..........................................................17
1.6.1Nausea and Vomiting ........................................................................17
1.6.2Hypoglycemia ...................................................................................18
1.6.3Volume Depletion .............................................................................18
1.6.4Diabetic Ketoacidosis/Euglycemic Ketoacidosis................................19
1.7
Research Hypotheses ................................................................................21
1.7.1Primary Hypothesis...........................................................................21
1.7.2Secondary Hypotheses.......................................................................21
2
OBJECTIVES AND ENDPOINTS .....................................................................21
2.1
Primary Objective and Associated Endpoints ............................................21
2.2
Secondary Objectives and Associated Endpoints.......................................22
2.3
Exploratory Objectives and Associated Endpoints.....................................23
3
STUDY DESIGN................................................................................................24
3.1
Description of the Study............................................................................24
3.1.1Overview ........................................................................................24
3.1.2Treatment Regimen...........................................................................27
3.1.3Dose Escalation.................................................................................28
3.2
Study Design 
3.2.1Dose Rationale ..................................................................................28
3.2.1.1
Dapagliflozin and Metformin ...........................................28
3.2.1.2
MEDI0382.......................................................................28
3.2.2Rationale for Study Population..........................................................30
3.2.2.1
Recruitment of Subjects with Type 2 Diabetes Mellitus and 
a Body Mass Index 25 to 40 kg/m2.....................30
3.2.2.2
Recruitment of Subjects on Metformin and Dapagliflozin 
Therapy..............................................................30


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3.2.2.3
Selection of Subjects with Type 2 Diabetes Mellitus and 
Stable Glycated Hemoglobin in the Range of 7.0% 
to 10.0% ............................................................31
3.2.3Rationale for Endpoints.....................................................................31
3.2.3.1
Primary Endpoint.............................................................31
3.2.3.2
Secondary Endpoints........................................................31
3.2.3.3
Exploratory endpoints ......................................................33
4
MATERIALS AND METHODS.........................................................................33
4.1
Subjects ....................................................................................................33
4.1.1Number of Subjects...........................................................................33
4.1.2Inclusion Criteria...............................................................................33
4.1.3Exclusion Criteria..............................................................................34
4.1.4Subject Enrollment and Randomization.............................................36
4.1.5Withdrawal from the Study................................................................36
4.1.6Discontinuation of Investigational Product ........................................37
4.1.7Replacement of Subjects ...................................................................38
4.1.8Withdrawal of Informed Consent for Data and Biological Samples ...38
4.2
Schedule of Study Procedures...................................................................38
4.2.1Enrollment/Screening Period.............................................................38
4.2.2Run-in Period....................................................................................39
4.2.3Randomized Treatment Period ..........................................................40
4.2.4Follow-up Period...............................................................................49
4.2.4.1
Early Discontinuation Visit or Unscheduled Study Visit...50
4.3
Description of Study Procedures ...............................................................50
4.3.1Efficacy
........................................................................................50
4.3.1.1
Mixed-meal Tolerance Test..............................................50
4.3.1.2
Body Weight....................................................................51
4.3.2Safety Assessments ...........................................................................51
4.3.2.1
Medical History and Physical Examination ......................51
4.3.2.2
Assessment of the Injection Site.......................................52
4.3.2.3
Vital Signs .......................................................................52
4.3.2.4
Electrocardiograms ..........................................................53
4.3.3Clinical Laboratory Tests ..................................................................53
4.3.4Pharmacokinetic Evaluation and Methods .........................................55
4.3.6Pharmacodynamic Evaluation and Methods.......................................56
4.3.6.1
Training for Application and Wearing of Continuous 
Glucose Monitoring Sensor................................56


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4.3.6.2
Glucometer Measure Capillary Blood Glucose/Ketones 
Reading..............................................................57
4.3.6.3
Training for Application and Wearing of ABPM Device ..57
4.3.7Estimate of Volume of Blood to Be Collected ...................................58
4.4
Study Suspension or Termination..............................................................58
4.5
Investigational Products............................................................................59
4.5.1Identity of Investigational Product(s).................................................59
4.5.1.1
Investigational Product Handling .....................................60
4.5.1.2
Investigational Product Inspection....................................61
4.5.1.3
Treatment Administration ................................................61
4.5.1.4
Monitoring of Dose Administration..................................62
4.5.1.5
Reporting Product Complaints .........................................62
4.5.2Additional Study Medications ...........................................................63
4.5.3Labeling
63
4.5.4Storage
63
4.5.5Treatment Compliance ......................................................................63
4.5.6Accountability...................................................................................64
4.6
Treatment Assignment and Blinding .........................................................64
4.6.1Methods for Assigning Treatment Groups .........................................64
4.6.2Methods for Ensuring Blinding..........................................................64
4.6.3Methods for Unblinding ....................................................................65
4.6.3.1
Unblinding in the Event of a Medical Emergency.............65
4.6.3.2
Unblinding for PK and Immunogenicity Analysis ............65
4.7
Restrictions During the Study and Concomitant Treatment(s) ...................66
4.7.1Permitted Concomitant Medications..................................................66
4.7.2Prohibited Concomitant Medications.................................................66
4.8
Statistical Evaluation.................................................................................67
4.8.1General Considerations .....................................................................67
4.8.1.1
Analysis Population .........................................................67
4.8.2Sample Size and Power Calculations .................................................67
4.8.3Efficacy
68
4.8.3.1
Primary Efficacy Analysis................................................68
4.8.3.2
Secondary Efficacy Analyses ...........................................68
4.8.3.3
Exploratory Analyses.......................................................69
4.8.4Safety
69
4.8.4.1
Analysis of Adverse Events..............................................69
4.8.4.2
Analysis of Safety Data....................................................70
4.8.4.3
Analysis of Clinical Laboratory Parameters......................70


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4.8.5Analysis of
Pharmacokinetics .................................70
4.8.5.1
Pharmacokinetic Analyses................................................70
4.8.6Interim Analysis................................................................................71
5
ASSESSMENT OF SAFETY..............................................................................71
5.1
Definition of Adverse Events ....................................................................71
5.2
Definition of Serious Adverse Events........................................................72
5.3
Definition of Adverse Events of Special Interest .......................................72
5.3.1Hepatic function Abnormalities.........................................................72
5.4
Recording of Adverse Events....................................................................73
5.4.1Time Period for Collection of Adverse Events...................................73
5.4.2Follow up of Unresolved Adverse Events..........................................73
5.5
Reporting of Serious Adverse Events ........................................................73
5.6
Other Events Requiring Immediate Reporting ...........................................74
5.6.1Overdose
........................................................................................74
5.6.2Hepatic Function Abnormality ..........................................................74
5.6.3Pregnancy ........................................................................................75
5.6.3.1
Maternal Exposure ...........................................................75
6
STUDY AND DATA MANAGEMENT .............................................................76
6.1
Training of Study Site Personnel...............................................................76
6.2
Monitoring of the Study............................................................................76
6.2.1Source Data.......................................................................................76
6.2.2Study Agreements .............................................................................77
6.2.3Archiving of Study Documents..........................................................77
6.3
Study Timetable and End of Study............................................................77
6.4
Data Management .....................................................................................77
6.5
Medical Monitor Coverage........................................................................78
7
ETHICAL AND REGULATORY REQUIREMENTS........................................78
7.1
Ethical Conduct of the Study.....................................................................78
7.2
Subject Data Protection.............................................................................78
7.3
Ethics and Regulatory Review...................................................................78
7.4
Informed Consent......................................................................................79
7.5
Changes to the Protocol and Informed Consent Form................................80
7.6
Audits and Inspections ..............................................................................80
8
REFERENCES ...................................................................................................81
9
CHANGES TO THE PROTOCOL......................................................................82
10
APPENDICES ....................................................................................................83
10.1
Appendix 1 - Signatures............................................................................83


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10.2
Appendix 2 - Contraception Guidance.......................................................85
10.3
Appendix 3 - Additional Safety Guidance .................................................86
10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases and Food 
and Allergy Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis.......................................................................................89
10.5
Appendix 5 - Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s law............................................................90
10.6
Appendix 6 - Biological Samples ..............................................................94
LIST OF IN-TEXT TABLES
Table 2.1-1
Primary Objective(s) and Associated Endpoints................................21
Table 2.2-1
Secondary Objectives and Associated Endpoints...............................22
Table 2.3-1
Exploratory Objectives and Associated Endpoints ............................23
Table 3.2.1-1
Proposed Study Doses and Predicted Safety Margins Based on Safety 
Data from the Cynomolgus Monkey .................................................30
Table 4.2.1-1
Schedule of Screening Period Procedures .........................................39
Table 4.2.2-1
Schedule of Run-in Period Procedures..............................................40
Table 4.2.3-1
Schedule of Treatment Period Procedures.........................................42
Table 4.2.4-1
Schedule of Follow-up Procedures....................................................49
Table 4.5.1-1
Identification of Investigational Products..........................................59
LIST OF IN-TEXT FIGURES
Figure 3.1.1-1
Study Flow Diagram.........................................................................27


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ABPM
ambulatory blood pressure monitoring
AE
adverse event
AESI
adverse event of special interest
ALT
alanine transaminase
AST
aspartate transaminase
AUC
area under the concentration-time curve
AUC0-4h
area under the concentration-time curve from zero to 4 hours
AUC24h
area under the concentration-time curve at 24 hours
AUC0-inf
area under the concentration-time curve from zero to infinity 
AUC0-last
area under the concentration-time curve from zero to last observation
AUCtau
area under the concentration-time curve during the dosing period
BMI
body mass index
BP
blood pressure
CGM
continuous glucose monitoring
CI
confidence interval
Cl/F
apparent clearance
Cmax
maximum-observed serum concentration
CSP
clinical study protocol
DKA
diabetes ketoacidosis
ECG
electrocardiogram
EDC
electronic data capture
eCRF
electronic case report form
eDKA
euglycemic diabetes ketoacidosis
eGFR
estimated glomerular filtration rate
FFA
Free fatty acid
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GI
Gastrointestinal
GLP-1
glucagon-like peptide-1
GMP
Good Manufacturing Practice
HbA1c
hemoglobin A1c
HR
heart rate
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee


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Abbreviation or 
Specialized Term
Definition
IFU
instructions for use
ITT
intent-to-treat
LLN
lower limit of normal
LOCF
last observation carried forward
LS
least squares
MAGE
mean amplitude of glucose excursion
MedDRA
Medical Dictionary for Regulatory Activities 
MMTT
mixed meal tolerance test
MDRD
Modification of Diet in Renal Disease
MTD
maximum tolerated dose
NOAEL
no-observed-adverse-effect level
OTC
over-the-counter
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
RR
respiratory rate
SAE
serious adverse event
SC
subcutaneous(ly)
SD
standard deviation
SGLT2
sodium-glucose cotransporter-2
SID
subject identification
T2DM
type 2 diabetes mellitus
t1/2
terminal elimination half-life
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
tmax
time to maximum-observed serum drug concentration
ULN
upper limit of normal


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1
INTRODUCTION
1.1
Disease Background
The rising prevalence of type 2 diabetes mellitus (T2DM) and obesity is a cause of 
substantial health and economic burden worldwide. In many cases of T2DM, significant 
weight loss (typically 5% of body weight or more) can promote improvements in glycemic
control, and it may even slow or reverse disease progression (Petersen et al, 2005). Many 
existing therapies for T2DM focus upon lowering blood glucose; however, there is a major 
unmet need for treatments that improve glycemic control and achieve disease-modifying 
weight loss simultaneously.
Achieving optimal glycemic control early in the course of T2DM is an important goal for 
patients and treating physicians. Early interventions may prevent disease progression and 
decrease the risk of developing long-term T2DM comorbidities. Traditional step-wise 
pharmacotherapy begins with metformin as first-line therapy for the treatment of T2DM; 
however, patients often require combination therapy to achieve and maintain glycemic
control because of the progressive nature of the disease. The combination of dapagliflozin 
and metformin is a common dual oral therapy in T2DM patients who fail treatment with 
monotherapy. The addition of a third noninsulin agent may be considered in patients with 
hemoglobin A1c (HbA1c) above the individualized target after 3 months of treatment with a 
combination of 2 drugs.
Dapagliflozin (Forxiga) is a potent and highly selective inhibitor of sodium-glucose 
cotransporter-2 (SGLT2) and is currently approved for improvement of glycemic control in 
adults with T2DM as monotherapy or as add-on combination therapy with metformin and 
other oral antiglycemic therapies. SGLT2 is localized to the renal proximal tubule where it 
reabsorbs most of the approximately 180 g of glucose normally filtered through the glomeruli 
each day. Inhibition of glucose reabsorption leads to glycosuria and consequently to 
glycemic-lowering effects including decreased levels of fasting plasma glucose (FPG) and 
HbA1c. In addition, the caloric loss associated with the excreted glucose is associated with 
body weight loss. Dapagliflozin has a half-life of approximately 12 hours, thus allowing for 
once daily oral administration. Additional information can be found in Forxiga’s Summary of 
Product Characteristics (Forxiga Summary of Product Characteristics, 2017).
1.2
MEDI0382 Background
MEDI0382 is briefly described below. Refer to the current Investigator’s Brochure (IB) for 
details. MEDI0382 is a synthetic peptide with both glucagon-like peptide-1 (GLP-1) and 


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glucagon-receptor coagonist activity, and it is under development for the treatment of T2DM 
and obesity. GLP-1 receptor agonists are established treatments for T2DM that improve 
glycemic control, delay gastric emptying, and depress appetite, thus leading to modest but 
unsustained weight loss (typically 3% versus baseline at 1 year). Glucagon has similar effects 
to GLP-1 on gastric emptying and appetite and has also been shown to promote increased 
energy expenditure (Lynch et al, 2014; Habegger et al, 2013). Oxyntomodulin, a naturally-
occurring peptide with GLP-1 and glucagon-receptor coagonist activity, has been shown to 
promote weight loss through effects on appetite and energy expenditure (Wynne et al, 2006). 
In addition, coinfusion of GLP-1 and glucagon has synergistic effects on reducing food 
intake and promoting weight loss in human subjects (Bagger et al, 2015).
1.3
Summary of Nonclinical Experience
Refer to the current MEDI0382 IB for a complete summary of nonclinical information. 
Consistent with other GLP-1 receptor agonists, MEDI0382 exposure resulted in the 
anticipated pharmacologic effects on body weight (reduced gain or loss), food consumption 
(sporadic reductions), gastric emptying (delayed in rats), liver (changes indicative of an 
effect on energy homeostasis), pancreas (hypercellularity of the pancreatic islets, acinar 
degranulation), adrenal glands (increased prominence of the zona glomerulosa), and lungs 
(increased macrophage) and rodent-specific effects on the thyroid gland (C-cell 
hyperplasia/adenoma/carcinoma), which had partially or fully reversed (with the exception of 
adenoma/carcinoma) by the end of the treatment-free periods. Increases in heart rate (HR), 
diastolic and mean arterial blood pressure (BP), and nocturnal body temperature noted in 
cynomolgus monkeys were not associated with significant effects on QTc and PR interval, 
QRS duration, systolic BP, or qualitative electrocardiogram (ECG) abnormalities. In general, 
these effects were considered to be consistent with the known effects of licensed GLP-1 
receptor agonists. MEDI0382 was not genotoxic and was not considered to be toxic to 
fertility or embryo-fetal development in the rat and rabbit, with most findings generally being 
associated with maternal stress.
1.4
Summary of Clinical Experience
In prior clinical experience with MEDI0382 (Cohort 4 of Study D5670C00002), 
51 overweight and obese subjects with T2DM were randomized to receive MEDI0382 
titrated up from a starting dose of 100 μg to a dose of 200 μg or placebo for up to 41 days. 
MEDI0382 was shown to have a similar tolerability to marketed GLP-1 receptor agonists, 
with no significant increases in systolic or diastolic BP observed. Following a mixed-meal 
tolerance test (MMTT), a least squares (LS) mean for percent change from baseline in 
glucose area under the concentration-time curve from 0 to 4 hours (AUC0-4h) of -32.78% 


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(90% confidence interval [90% CI] -36.98, -28.57) was observed in MEDI0382-treated 
subjects versus -10.16% (90% CI -14.10, -6.21) in placebo-treated subjects (p < 0.0001). A 
LS mean change from baseline in body weight of -3.84% (90% CI -4.55, -3.12) was observed 
in MEDI0382-treated subjects versus -1.70% (90% CI -2.40, -1.01) in placebo-treated 
subjects (p < 0.001). In the same study (D5670C00002), doses of 300 μg were studied for 
7 days in 2 separate cohorts, each exploring different uptitration schedules to reach this dose. 
The tolerability and efficacy profiles were similar to that observed in previous cohorts.
The combination of MEDI0382 with dual therapy of dapagliflozin and metformin has not 
been studied previously. However, given the commercial availability of dapagliflozin, this 
drug (and other SGLT2 inhibitors) will likely be a concomitant medication in future Phase 3 
clinical studies of MEDI0382. Because the 2 agents exert their glycemic and weight-
lowering effects via different mechanisms, the coadministration of the 2 compounds is 
expected to show improved effects on glycemic control and body weight as well as positive 
effects on BP (due to renal sodium loss driven by both SGLT2 inhibition and glucagon) 
compared to the oral, dual therapy of dapagliflozin and metformin given alone.
Given the likelihood of concomitant administration of MEDI0382 with SGLT2 inhibitors and 
metformin in the ongoing clinical development program, this exploratory study aims to (a) 
explore the efficacy and safety profile associated with the combination of MEDI0382 and
dual therapy of SGLT2 inhibitor (dapagliflozin) and metformin and (b) characterize the 
profile of glycemic and metabolic control following administration of the triple combination 
therapy versus oral, dual-combination therapy.
1.5
Rationale for Conducting the Study
This is an exploratory Phase 2a efficacy study designed to investigate the effects on glycemic
control and the safety profile associated with MEDI0382 titrated up to a dose level of 300 μg 
when coadministered with dapagliflozin and metformin in subjects with T2DM with a body 
mass index (BMI) of ≥25 kg/m2 to ≤40 kg/m2 and a HbA1c of ≥7.0% to ≤10.0%. The 
results of this study will provide additional information about the efficacy, safety, 
tolerability, and pharmacokinetic (PK) profile of MEDI0382 in the likely intended clinical 
T2DM population.
Previous clinical experience with another GLP-1 monoagonist (exenetide) coadministered 
with dapagliflozin demonstrated that the combination resulted in significant reductions in 
HbA1c, FPG, weight, and systolic BP compared to either agent alone on a background of 
metformin (Frías et al, 2016). Therefore, the simultaneous administration of MEDI0382 with 
dapagliflozin is expected to show superior effects on glycemic control, body weight, and BP. 


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SGLT2 inhibitors have emerged as an effective therapy for glucose control and are likely to 
be a concomitant medication for subjects in the ongoing development program for 
MEDI0382. In addition, prior to including such subjects in Phase 3 studies, it is important to 
study the safety profile of MEDI0382 when given in combination with a SGLT2 inhibitor. 
1.6
Benefit-risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonization
(ICH)/Good Clinical Practice (GCP) and applicable regulatory requirements.
MEDI0382 is a GLP-1 and glucagon receptor coagonist that promotes glucose lowering and 
weight loss and is targeted at subjects with T2DM. MEDI0382 has the potential to deliver 
improvements in glycemic control and lipid homeostasis, and it is predicted to be a useful 
therapy for T2DM. 
The study design aims to minimize potential risks to subjects participating in this study based 
on the proposed inclusion/exclusion criteria, safety monitoring, and uptitration dosing 
schedule. Euglycemic diabetic ketoacidosis (eDKA) and hypovolemia are rare potential risks
in subjects taking SGLT2 inhibitors. All subjects will be monitored throughout the study to 
ensure adequate glycemic control, ketones production, and intravascular volume status.
Subjects will be given appropriate training in subcutaneous (SC) injection administration as 
well as use of any devices. Refer to the current MEDI0382 IB and dapagliflozin IB for 
further information on the potential benefits of MEDI0382 and dapagliflozin and an 
assessment of the potential and known risks. Identified risks for this study include nausea and 
vomiting. Potential risks for this study include hypoglycemia, volume depletion, and diabetes 
ketoacidosis (DKA).
1.6.1
Nausea and Vomiting
If a subject experiences nausea and vomiting in relation to the investigational product, in the 
first instance, conservative measures should be advised including reducing meal size and 
maintaining adequate hydration. When necessary, if there is persistent vomiting, a subject 
may be given an antiemetic to control his/her symptoms; a 5HT3 receptor antagonist (eg, 
ondansetron) or cyclizine is preferable in this situation rather than antiemetics, which may 
affect gastric emptying, and in particular dopamine receptor antagonists (eg, metoclopramide 
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1.6.2
Hypoglycemia
A hypoglycemic event is considered severe if associated with severe cognitive impairment 
requiring external assistance for recovery as defined by the American Diabetes Association. 
Spontaneous and clinically significant hypoglycemia defined as blood glucose < 54 mg/dL 
[3.0 mmol/L] with or without symptoms (Skyder et al, 2017) has not been seen in prior 
studies with MEDI0382 (up to a dose of 300 μg) alongside metformin. In addition, no 
episodes of major and minor hypoglycemia were reported in a randomized control study 
evaluating the efficacy and safety of exenatide (a GLP-1 monoagonist) in combination with 
dapagliflozin on a background of metformin (Frías et al, 2016). Furthermore, the mechanism 
of action of dapagliflozin (SGLT2 inhibition) does not interfere with normal endogenous 
glucose production in response to hypoglycemia and does not stimulates insulin release. 
Therefore, the risk of hypoglycemia in this study is considered low. However, all subjects 
will be provided with a diary and a glucometer and will be advised to check their capillary 
blood glucose level if they have symptoms of hypoglycemia (hunger, dizziness, shaking, 
sweating, or irritability) or feel unwell and will be expected to record the blood glucose level 
in their diary and contact the study team immediately. Management of the event should be as 
per standard local protocols. Hypoglycemia episodes should be documented as an adverse 
event (AE). Pharmacological treatments administered for hypoglycemia (eg, 
dextrose/glucose tablets, glucagon) should be recorded in the electronic case report form 
(eCRF) as concomitant medications.
1.6.3
Volume Depletion
MEDI0382 treatment with doses of up to 300 μg has been associated with a reduction in BP 
compared to baseline (-2.26 mmHg for diastolic BP and -8.49 mmHg for systolic BP) as 
estimated by ambulatory blood pressure monitoring (ABPM). 
GLP-1 receptor agonist augment renal sodium excretion (Tonneijck et al, 2016). The 
mechanism by which a GLP-1 receptor agonist increase renal excretion is not well 
understood, but it includes vasodilation and possibly a direct effect on the renal tubule. 
(DeFronzo, 2017).
Dapagliflozin causes glucosuria and a subsequent mild osmotic diuretic effect and decreased 
intravascular volume. Due to its mechanism of action, dapagliflozin increases diuresis 
associated with a modest decrease in BP, which could be more pronounced in patients with 
very high blood glucose concentrations. Refer to the current dapagliflozin IB for more 
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The combined sodium loss and the potential tolerability risk (vomiting) resulting from GLP-
1on a background of dapagliflozin raises a theoretical risk of higher incidence of 
symptomatic hypovolemia in subjects given both products in combination.
During the course of this study, the subject volume status will be closely monitored at each 
visit by assessing vital signs with BP (including lying and standing measurements). In 
addition, an ABPM device will be used during inpatient and outpatient visits. 
Subjects will be advised to maintain adequate fluid intake throughout the study and to contact 
the study team if they experience dizziness or feel unwell. Management of volume depletion 
events should be as per standard local protocols.
Any episodes of symptomatic volume depletion (eg, hypotension, dehydration, or syncope) 
should be recorded as an AE.
1.6.4
Diabetic Ketoacidosis/Euglycemic Ketoacidosis
The glucagon component of MEDI0382 may lead to an increase in ketone production due to 
the potential increased oxidation of free fatty acid (FFA). It is also hypothesized that SGLT2-
induced glycosuria predisposes subjects to increased ketogenesis (Qiu et al, 2017). Therefore, 
the combination of MEDI0382 and dapagliflozin (or any other SGLT2 inhibitor) might 
theoretically increase the risk to ketosis. In MEDI0382 clinical studies to date, there have 
been no cases of ketoacidosis (either hyper- or euglycemic cases).
Diabetes ketoacidosis, sometimes with normal glucose levels (ie, eDKA), has been reported 
very rarely in patients taking SGLT2 inhibitors (canagliflozin, dapagliflozin, or 
empagliflozin) in postmarketing surveillance (Rosenstock and Ferrannini, 2015). The clinical 
risk of developing DKA upon concomitant use of MEDI0382 and dapagliflozin is deemed 
very low. However, adequate monitoring will be implemented as described below to 
minimize the risk to study subjects.
During the course of the study, subjects will test their blood ketone level daily using ketone 
finger-prick testing strips and ketone monitor provided. In addition, subjects will be supplied 
with a paper diary, which will be reviewed by study staff at each visit. Subject will test their 
capillary ketone bodies every day before breakfast. Furthermore, subjects will be advised to 
check their blood for the presence of ketones and check their blood glucose using finger-
prick testing with a glucometer if they experience any of the symptoms listed below and/or 
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Subjects will be instructed to contact the site immediately if the results indicate the presence 
of ketonemia (> 3 mmol/L), and/or elevated glucose levels (> 140 mg/dL [> 7.8 mmol/L]), 
and/or experience the following symptoms:
•
Polyuria or polydipsia
•
Malaise, generalized weakness, or fatigability
•
Nausea and vomiting—may be associated with diffuse abdominal pain, decreased 
appetite, and anorexia
•
Altered consciousness (eg, mild disorientation, confusion)
At the unit, the investigator should assess and determine whether the subject is at risk to 
develop ketoacidosis or is progressing towards ketoacidosis based on the subject’s medical 
history, physical examination, and supportive laboratory results. The investigator should then 
determine whether the subject can be treated at the unit or should be referred to the local 
hospital for further evaluation and treatment of DKA.
The diagnosis of DKA will be made if the following are seen:
•
Plasma glucose > 250 mg/dL (> 13.9 mmol/L)
•
Increased anion gap metabolic acidosis (> 10-12 mEq/l) associated with pH < 7.30 and 
bicarbonate level < 18 mEq/l
•
Elevated plasma ketone levels (> 3.0 mmol/L)
The diagnosis of eDKA will be made if the subject has the following:
•
Increased anion gap metabolic acidosis as outlined above 
•
Elevated plasma ketones with plasma glucose < 250 mg/mL
However, any subject with a pH of < 7.35 associated with ketones > 3.0 mmol/L (regardless 
of glucose levels) may be considered to be progressing towards ketoacidosis. Therefore, such 
subjects should be discontinued from the study (Section 4.1.6) and monitored closely per 
local protocols.
Any event of DKA or eDKA should be managed according to standard local protocols. 
In reporting DKA events, it is important to distinguish ketosis from DKA. Low levels of 
ketosis, in which blood or urine ketone values are elevated, can occur in individuals who 
follow a low-carbohydrate, high-fat diet or after prolonged periods of fasting. Ketosis is a 


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benign condition if symptoms are absent and the blood pH remains within normal limits (ie, 
no acidosis). In contrast, a DKA episode may be confirmed when a subject has potential 
symptoms of DKA as described above, elevated blood/urine ketone values, metabolic 
acidosis (characterized by low arterial blood pH, decreased serum bicarbonate, and an 
increased anion gap), and hyperglycemia (although some individuals may have normal or 
only mildly elevated blood glucose levels).
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
The administration of MEDI0382 SC once daily will improve glycemic control in 
overweight/obese subjects with T2DM treated concurrently with dapagliflozin and
metformin.
1.7.2
Secondary Hypotheses
•
The administration of MEDI0382 SC will have an acceptable safety profile and be well 
tolerated when coadministrated with dapagliflozin and metformin.
•
The PK profile of MEDI0382 will remain unchanged in the presence of coadministered
dapagliflozin and metformin.
•
The immunogenicity profile of MEDI0382 will remain unchanged in the presence of 
coadministered dapagliflozin and metformin. 
•
The administration of MEDI0382 decreases 24-hour glycemic variation when 
coadministrated with dapagliflozin and metformin.
2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoints
Table 2.1-1
Primary Objective(s) and Associated Endpoints
Type
Objective
Endpoints
Efficacy
To compare the change in glucose AUC as 
measured by a standardized MMTT in 
subjects treated with dapagliflozin and 
metformin receiving MEDI0382 or placebo 
for 28 days 
•
Change from baseline (Day-1) to the 
end of 28 days of treatment (Day 28) in 
glucose AUC0-4h as measured by a 
MMTT
•
Percentage change from baseline 
(Day -1) to the end of 28 days of 
treatment (Day 28) in glucose AUC0-4h
as measured by a MMTT
AUC = area under the concentration-time curve; AUC0-4h = area under the concentration-time curve from zero 
to 4 hours; MMTT = mixed meal tolerance test;


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2.2
Secondary Objectives and Associated Endpoints
Table 2.2-1
Secondary Objectives and Associated Endpoints
Type
Objective a
Endpoints
Safety
To compare the safety and tolerability 
profile of MEDI0382 (titrated up to a dose 
level of 300 μg SC) compared to placebo 
after 28 days of treatment in subjects treated 
with dapagliflozin and metformin
Measures of safety and tolerability include:
•
Incidence of TEAEs and TESAEs 
•
Clinically important changes in 12-lead 
ECG, vital signs (including 24-hour HR
and BP), physical examination, and 
clinical laboratory evaluations
PK
To evaluate the PK profile of MEDI0382 
and dapagliflozin (in subjects treated with 
dapagliflozin, metformin, and MEDI0382) 
and dapagliflozin (in subjects treated with 
dapagliflozin, metformin, and placebo)
PK profile of both MEDI0382 and 
dapagliflozin administered simultaneously 
and dapagliflozin administered with placebo 
include:
•
AUC0-inf, AUC0-last, and AUCtau
•
Cmax, tmax, t1/2, and Cl/F
Immunogenicity
To evaluate the immunogenicity profile of 
MEDI0382 (titrated up to a dose level of 
300 μg) in subjects treated with 
dapagliflozin and metformin receiving 
placebo or MEDI0382 for 28 days
•
Immunogenicity as measured by the 
presence of ADA to MEDI0382 (and 
titer if positive) during dosing and 
follow-up periods
Efficacy/PD
To evaluate 24-hour glucose control as 
measured by CGM in subjects treated with 
dapagliflozin and metformin receiving 
MEDI0382 or placebo for 28 days
•
Change from baseline to the end of 
dosing at each dose level (Days 7, 14, 
and 28) in glucose AUC24h as measured 
by CGM
•
Change from baseline to the end of 
dosing at each dose level (Days 7, 14, 
and 28) in 24-hour mean glucose as 
measured by CGM
•
Change from baseline to the end of 
dosing at each dose level (Days 7, 14, 
and 28) in SD of 24-hour glucose 
readings as measured by CGM
•
Change from baseline to Days 7, 14, 
and 28 in the CV (ratio of SD:mean 
over 24 hours) of glucose readings as 
measured by CGM
•
Change from baseline to Days 7, 14, 
and 28 in the MAGE of 24-hour glucose 
readings as measured by CGM 
•
Change from baseline to Days 7, 14, 
and 28 in the percentage of 24-hour
glucose readings obtained from CGM 
that fall within the euglycemic range of 
≥70 mg/dL (≥3.9 mmol/L) and 
≤180 mg/dL (≤10.0 mmol/L)
•
Change from baseline to Days 7, 14, 
and 28 in the percentage of 24-hour 
glucose readings obtained from CGM 
that fall within hyperglycemic (high 
Immunogenicity as measured by the 
g
y
y
presence of ADA to MEDI0382 (and 
p
(
titer if positive) during dosing and 
p
)
follow-up periods
To evaluate the immunogenicity profile of 
g
y p
MEDI0382 (titrated up to a dose level of 
(
p
300 μg) in subjects treated with 
μg)
j
dapagliflozin and metformin receiving
p g
placebo or MEDI0382 for 28 days
Immunogenicity


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Table 2.2-1
Secondary Objectives and Associated Endpoints
Type
Objective a
Endpoints
glucose) range of > 180 mg/dL 
(> 10.0 mmol/L)
•
Change from baseline to Days 7, 14, 
and 28 in the percentage of 24-hour 
glucose readings obtained from CGM 
that fall within the hypoglycemic range 
of < 70 mg/dL (< 3.9 mmol/L)
•
Change from baseline to Days 7, 14, 
and 28 in the percentage of 24-hour 
glucose readings obtained from CGM 
that fall within the clinically significant 
hypoglycemic range of < 54 mg/dL 
(3.0 mmol/L)
AUC24h = area under the concentration-time curve at 24 hours; AUC0-inf = area 
under the concentration-time curve from zero to infinity; AUC0-last = area under the concentration-time curve 
from zero to last observation; AUCtau = area under the concentration-time curve during the dosing period; 
BP = blood pressure; Cl/F = apparent clearance; CGM = continuous glucose monitoring; Cmax = maximum-
observed serum drug concentration; CV = coefficient of variation; ECG = electrocardiogram; HR = heart rate; 
MAGE = mean amplitude of glucose excursion; PD = pharmacodynamics; PK = pharmacokinetics; 
SC = subcutaneous; SD = standard deviation; t1/2 = terminal elimination half-life; TEAEs = treatment-emergent 
adverse events; TESAEs = treatment-emergent serious adverse events; tmax = time to maximum-observed serum 
drug concentration 
a
Secondary efficacy, safety, PK, immunogenicity, and PD endpoints will be evaluated in subjects receiving 
MEDI0382 or placebo coadministered with 10 mg dapagliflozin and metformin.
2.3
Exploratory Objectives and Associated Endpoints
Table 2.3-1
Exploratory Objectives and Associated Endpoints
Type
Objective a
Endpoint
Efficacy
To compare additional measures of glucose 
control (FPG, HbA1c) in subjects treated 
with dapagliflozin and metformin receiving 
MEDI0382 or placebo for 28 days 
•
Change from baseline (Day -1) to 
Day 28 in FPG
•
Change from baseline (Day -2) to 
Day 28 in HbA1c
PD
To evaluate pancreatic and incretin hormone 
AUC profiles (ie, active GLP-1, glucagon, 
insulin, and c-peptide) as measured by 
MMTT in subjects treated with dapagliflozin 
and metformin receiving MEDI0382 or 
placebo for 28 days 
•
Change from baseline (Day -1) to 
Day 28 in GLP-1, glucagon, insulin, and 
c-peptide AUC0-4h as measured by 
MMTT
PD
To compare the fasting FFA levels in 
subjects treated with dapagliflozin and 
metformin receiving MEDI0382 or placebo 
for 28 days 
•
Change from baseline (Day -1) to 
Days 7, 14, and 28 in fasting FFA level
PD
To compare plasma ketone profile 
(β-hydroxybutyrate) in subjects treated with 
dapagliflozin and metformin receiving 
MEDI0382 or placebo for 28 days 
•
β-hydroxybutyrate profile to include 
AUC0-inf, AUC0-last, Cmax, and tmax


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Table 2.3-1
Exploratory Objectives and Associated Endpoints
Type
Objective a
Endpoint
Efficacy
To compare the change in body weight after 
28 days of treatment with MEDI0382 or 
placebo in subjects treated with 
dapagliflozin and metformin
•
Change from baseline (Day 1) to 
Day 29 in body weight (kg)
•
Percentage change from baseline 
(Day 1) to Day 29 in body weight (kg)
•
Proportion of subjects achieving ≥5% 
body weight loss from baseline (Day 1) 
to Day 29
PD
To evaluate 24-hour urinary glucose 
excretion in subjects treated with 
dapagliflozin and metformin receiving 
MEDI0382 or placebo 
•
Total glucose excreted in urine collected 
for 24 hours
AUC = area under the concentration-time curve; AUC0-4h = area under the concentration-time curve from zero 
to 4 hours; AUC0-inf = area under the concentration-time curve from zero to infinity; AUC0-last = area under the 
concentration-time curve from zero to last observation; Cmax = maximum-observed serum drug concentration; 
FFA = free fatty acid; FPG = fasting plasma glucose; GLP-1 = glucagon-like peptide-1; 
HbA1c = hemoglobin A1c; MMTT = mixed meal tolerance test; PD = pharmacodynamics; tmax = time to 
maximum-observed serum drug concentration
a
Exploratory endpoints will be evaluated after 28 days of treatment in subjects receiving MEDI0382 or 
placebo alongside 10 mg dapagliflozin and metformin administered simultaneously as background therapy.
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview
This is an exploratory randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of MEDI0382 versus placebo in overweight/obese subjects with T2DM
treated with dapagliflozin and metformin dual therapy. 
The study will enroll subjects with T2DM treated either with metformin monotherapy or with 
metformin and dapagliflozin dual therapy. After the screening period of up to 60 days, 
subjects treated with metformin monotherapy only will enter a 4-week run-in period where 
subjects will be administered oral dapagliflozin 10 mg a day, which will be provided by the 
sponsor. Enrolled subjects that are already treated with metformin and dapagliflozin dual 
therapy will continue this dual therapy throughout the study and can be randomized after the
screening period without entering the run-in period. All subjects (ie, on monotherapy and 
dual therapy) entering the double-blind treatment period will receive dapagliflozin 10 mg a 
day, which will be provided by the sponsor.
Forty-six subjects are expected to participate in the study for up to 20 weeks including a 
screening period of up to 60 days, a 4-week run-in period (for subjects on metformin 


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monotherapy only), a 4-week treatment period, and a 4-week follow-up posttreatment period. 
There will be a total of 2 inpatient stays with a duration of 2 to 3 days.
Four-week run-in period
After screening, subjects on metformin monotherapy only will begin an open-label, run-in 
period on Day -28 and will receive oral dapagliflozin 10 mg a day for 28 days prior to 
randomization. On Day -14, subjects will return to the clinical unit for an abbreviated
physical examination, vital signs, and blood collection for safety laboratory assessments.
Subjects on dual therapy (metformin plus dapagliflozin) can be randomized after the 
screening period. In addition, all subjects will be given diet and lifestyle advice to follow for 
the duration of the study.
Four-week treatment period
On Day -2, subjects will be admitted to the clinical unit for 1 to 2 nights (ie, subject may 
choose to stay a second night or leave the clinic). Subjects will undergo initial safety 
assessments including but not limited to an abbreviated physical examination, medical 
history, vital signs, blood collection for laboratory tests (eg, lactate, pH, and HbA1c), urine
tests (eg, pregnancy, drug and alcohol screen), and training in SC injection administration.
An ABPM device will be fitted on Day -2 and worn for 24 hours. On Day -1, after an 
overnight fast of approximately 10 hours, subjects will undergo a mixed-meal tolerance test 
(MMTT). Subjects will be asked to drink 1 entire can of Ensure Plus® (a nutritional 
supplement containing the components of fat, carbohydrate, and protein that make up a 
standard MMTT) within 5 minutes. Blood samples will be drawn after consumption of the 
drink for quantification of glucose, active GLP-1, insulin, c-peptide, and glucagon per the 
treatment schedule (Table 4.2.3-1). At this visit, eligibility criteria verification and additional 
training in SC injection administration will be performed. Blood will be collected for 
laboratory tests (eg, FFA, FPG), dapagliflozin PK, and ketone PK sampling. After the 
MMTT on Day -1, the subject will be fitted with a continuous glucose monitoring (CGM) 
device on the contralateral arm to the ABPM, which will expire and be replaced every 
14 days. Subjects will be expected to wear the CGM sensor continuously for the duration of 
treatment (Section 4.2.3 and Table 4.2.3-1 for additional details). Subjects will also be 
expected to conduct daily finger-prick testing for ketone measurements throughout the 
treatment period.
Following completion of the MMTT test and assessments on Day -1, subjects are given the 
option to remain in the unit or return home, but subjects must ensure they undergo an


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overnight fast for approximately 10 hours. Discharged subjects will return to the clinic on 
Day 1. Subjects can be randomized after confirming eligibility at any time from Day -1 to 
Day 1 (predose) to receive either MEDI0382 or placebo. On Day 1, following the overnight 
fast, dosing of MEDI0382 SC or placebo SC will commence after predose safety measures 
including but not limited to vital signs, an ECG, and blood collection for laboratory tests (eg, 
lactate, pH);
dapagliflozin and ketones
PK sampling; and measurement of weight are performed. A 24-hour urinary collection for 
glucose excretion will be collected from Day 1 to Day 2. Subject s will be monitored for 
safety, glucose, and ketones, and will be discharged from the unit approximately 6 hours 
postdose. Capillary glucose and ketones monitoring will be done at the site using a 
glucometer. The subject will return to the unit on Day 2 for safety monitoring and 
supervision of investigational product administration. The subjects will be discharged with 
the same syringe pack of investigational product supplies and will continue to self-administer
investigational product on an outpatient basis.
Subjects will then return to the clinical unit at weekly intervals until a maintenance dose of 
300 μg is achieved. Subjects will return to the unit for outpatient visits on Days 7, 8, 14, 15,
and 22 to undergo safety assessments including but not limited to an abbreviated physical 
examination and ECG (Days 7, 14, and 22), vital signs (all visits with ABPM fitted on 
Day 14 only), urine tests (eg, pregnancy test on Day 14 and Day 22), and blood collection for 
laboratory tests (Days 7, 14, and 22). MEDI0382, dapagliflozin, and ketones PK sampling 
will be performed on Days 7, 8, 14, and 15. Uptitration of SC investigational product will 
occur on Day 8 and Day 15. After uptitration of investigational product, subjects will be 
monitored for safety, capillary glucose and ketones and will be discharged 6 hours postdose. 
A 10-hour overnight fast is required prior to visits on Days 7 and 14, and a standardized 
breakfast meal will be provided 2 hours postdosing on these days. The CGM device will be 
replace on Day 14.
Subjects will return to the unit for admission on Days 27 to 29 (Visit 11) to undergo final 
safety assessments including but not limited to an abbreviated physical examination, an ECG, 
and urine tests (eg, pregnancy and drug and alcohol screening) on Day 27 and vital signs 
(including ABPM) and blood collection for laboratory tests (eg, lactate, pH, HbA1c) on 
Day 28. On Day 28, following an overnight fast of 10 hours, a final MMTT will be 
performed. On Day 28, PK sampling of MEDI0382, dapagliflozin, and ketones will be taken 
relative to time zero of administration of investigational product. A 24-hour urine collection 
for glucose secretion will also be performed from Day 28 to Day 29. On Day 29, vital signs, 
a measurement of weight, and 
MEDI0382, 
dapagliflozin, and ketones PK will be performed. Subjects will be discharged if no safety 


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concerns are identified. Subjects will then enter the 4-week, posttreatment safety follow-up 
period, and they will continue to wear the CGM until approximately 28 days after the last 
dose of investigational product.
Throughout the entire combination treatment period and in the follow-up period, subjects 
will be required to continue wearing the CGM sensor (up to 28 ± 4 days after the last dose of 
investigational product) and to test their ketone level once daily prebreakfast (up to 
14 ± 2 days after the last dose) using the testing strips provided.
Figure 3.1.1-1
Study Flow Diagram
BMI = body mass index; HbA1c = hemoglobin A1c; MTD = maximum-tolerated dose; N = number of subjects; 
QD = once daily; SC = subcutaneous; T2DM = type 2 diabetes mellitus.
*
Run-in period only for subjects on metformin monotherapy only at screening
** Subject on metformin and dapagliflozin dual therapy at screening move directly from screening to double 
blind treatment period
The endpoints to be measured in this study are described in Section 2.
3.1.2
Treatment Regimen
Four-week run-in period
Following screening, subjects previously treated with metformin monotherapy only will enter 
an open-label, run-in period and will receive oral dapagliflozin 10 mg a day for 4 weeks, 
which will be provided by the sponsor.


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Four-week treatment period
Following the run-in period for subjects on metformin monotherapy or the screening period
for subjects on metformin and dapagliflozin dual therapy, subjects will be randomized as 
follows:
•
MEDI0382 SC once daily (titrated up from 100 μg for 7 days to 200 μg for 7 days and to 
300 μg for 14 days) in the morning for 28 days (N = 23) or 
•
Placebo SC once daily in the morning for 28 days (N = 23) 
The sponsor will provide dapagliflozin to all subjects entering the treatment period.
3.1.3
Dose Escalation
Doses of MEDI0382 and placebo will escalate from an initial 100 to 300 μg in 7-day 
intervals during the 4-week combination-treatment phase (Section 3.1.2). 
3.2
Study Design 
3.2.1.1
Dapagliflozin and Metformin
The combination of 10 mg dapagliflozin and metformin (maximum tolerated dose [MTD] of 
≥1 g) as dual therapy has been extensively studied in T2DM subjects and has demonstrated a 
favorable benefit-risk profile. The 10 mg dapagliflozin dose is the most effective approved 
dose and was chosen for this study as it has been extensively studied in previous Phase 3 
studies with a favorable benefit-risk profile (Forxiga Summary of Product Characteristics, 
2017).
3.2.1.2
MEDI0382
To date, the development program for MEDI0382 has studied doses up to 300 μg as part of a 
multiple ascending dose study (D5670C00002). The 300 μg dose has been specifically 
studied for a period of 7 days in 2 separate cohorts, each exploring different uptitration 
schedules to reach this dose. At the 300 μg dose level, the safety and tolerability profile was 
comparable with previous clinical data with lower doses of MEDI0382 and other GLP-1 
mimetics at this stage of development, and there was no increase in systolic or diastolic BP.
In fact, a nonsignificant trend towards reduction of systolic BP was observed (~2-5 mmHg 
reduction across the cohorts after data correction for placebo). Across the 2 cohorts, the LS 
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following a MMTT was -36.73% to -41.65% in MEDI0382-treated subjects versus -8.02%
to -14.54% in placebo-treated subjects. The LS mean for change from baseline in body 
weight was -2.07% to -3.40% in MEDI0382-treated subjects versus -0.68% to -0.86% in 
placebo-treated subjects. Of note, no events of DKA have been observed in the MEDI0382 
development program to date.
The current study intends to minimize the likelihood of observing adverse effects by titrating 
MEDI0382 up to 300 μg (ie, the highest dose previously tested). In addition, this study 
ensures that all doses that are likely to be included in later stages of MEDI0382 development 
(ie, 100 μg through 300 μg) are studied in combination with dapagliflozin. 
Similar studies conducted with exenatide in combination with dapagliflozin showed no 
significant impact on the PK of either drug in the combination arm, despite the delay in 
gastric emptying due to the GLP-1 component of exenatide. Furthermore, given the earlier 
time to maximum-observed serum drug concentration (tmax) of dapagliflozin (~1 hour) 
compared to MEDI0382 (~4 hours), the potential for additional delay in gastric emptying due
to the glucagon component of MEDI0382 is not deemed to be relevant to the absorption 
phase of dapagliflozin. Therefore, it is expected that MEDI0382 and dapagliflozin will retain 
their typical PK profile in the presence or absence of the coadministered drug. 
The no-observed-adverse-effect level (NOAEL) of 90 μg/kg/day was based on findings in a
9-month, daily SC, repeat-dose toxicology study in cynomolgus monkey. These findings 
were consistent with pharmacology-mediated induction of weight loss/lower weight gain, 
reversible changes in the pancreas (acinar degranulation and hypercellularity of the 
pancreatic islets), and changes in energy utilization and associated metabolic stress (minor 
changes in blood chemistry parameters, lower thymus weights). Treatment was also 
associated with changes in the skin (dermal irritation, acanthosis, and hyperkeratosis).
Although the NOAEL determined in a 6-month, daily SC, repeat-dose toxicology study in rat 
(7.5 μg/kg/day) was lower than that in the cynomolgus monkey (90 μg/kg/day), this was 
driven primarily by findings in the thyroid gland (c-cell hyperplasia, adenoma, and 
carcinoma), which were considered adverse in the rat. These findings are a well-known class 
effect of anti-GLP-1 agonists; however, they are considered to be rodent specific and of 
unknown relevance to humans (CDER, 2005). Therefore, cynomolgus monkey and the 
toxicity profile of MEDI0382 in that species is considered to be the most appropriate 
nonclinical species for clinical risk assessment and setting of safety margins.
Table 3.2.1-1 shows the proposed clinical dose levels and estimated safety margins over the 
predicted maximum-observed serum drug concentration (Cmax) and area under the 


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concentration-time curve (AUC) for this human study and the observed Cmax and AUC at the 
NOAEL in the 9-month, repeat-dose toxicity study in cynomolgus monkeys. 
The steady state Cmax- and AUC-based safety margins at the maximum proposed human dose 
of 300 μg (after 4 uptitration steps) based on cynomolgus monkey NOAEL (90 μg/kg/day) 
are 14-fold and 17-fold, respectively, which indicate that the exposure in humans is 
anticipated to be lower than that determined in monkeys at the NOAEL.
Table 3.2.1-1
Proposed Study Doses and Predicted Safety Margins 
Based on Safety Data from the Cynomolgus Monkey
Human Dose (μg)
Predicted median Human Exposure at 
steady state
Safety Margin Over Cynomolgus 
Monkey Exposure at NOAEL a at 
Day 273
AUCtau (ng•h/mL)
Cmax (ng/mL)
AUC
Cmax
100 + 200 + 300
250
16.5
17
25
AUC = area under the concentration-time curve; AUCtau = area under the concentration-time curve where tau 
is the end of a dosing interval; Cmax = maximum observed drug concentration; h = hour; 
NOAEL = no-observed-adverse-effect level.
Note: The information in this table is based on 80 kg human body weight
a
NOAEL = 90 μg/kg/day
3.2.2
Rationale for Study Population
3.2.2.1
Recruitment of Subjects with Type 2 Diabetes Mellitus and a Body Mass 
Index 25 to 40 kg/m2
The mechanisms of action of both MEDI0382 (GLP-1/glucagon coagonism) and 
dapagliflozin (SGLT2 inhibition) result in glucose-lowering effects; therefore, the target 
population for both drugs in combination is subjects with T2DM. In addition, because both 
drugs have demonstrated effects on body weight, subjects who are already overweight or 
obese are most likely to benefit. Although subjects with a BMI > 40 kg/m2 or > 35 kg/m2 plus 
comorbidities may be offered bariatric surgery, those with a BMI in the range of 25 kg/m2
through 40 kg/m2 generally rely upon conservative or medical management for weight 
reduction. The entry criteria with respect to T2DM and a BMI of 25 kg/m2 through40 kg/m2
will provide efficacy, safety, and tolerability data in the likely intended clinical population.
3.2.2.2
Recruitment of Subjects on Metformin and Dapagliflozin Therapy
Metformin is a first-line therapy for T2DM and forms the basis of initial and continuing oral 
therapy for a significant proportion of subjects. Subjects with T2DM taking metformin as 
monotherapy or metformin and dapagliflozin dual therapy have been chosen to provide a 
balance between observing the effect on both safety and efficacy of MEDI0382 when 


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administered alongside with dapagliflozin and metformin. Metformin cotherapy with 
MEDI0382 has been shown to be safe and well tolerated during short-term treatment of up to 
41 days (D5670C00002). Metformin concentrations were measured during this period and 
there were no significant changes in the PK profile of metformin or MEDI0382.
3.2.2.3
Selection of Subjects with Type 2 Diabetes Mellitus and Stable Glycated 
Hemoglobin in the Range of 7.0% to 10.0%
The specified HbA1c range ensures that recruitment to the study is feasible, but also that any 
acute effect of MEDI0382 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 a study for those with an HbA1c > 10.0%. At HbA1c levels < 7.0%, the ability 
to measure clinically significant changes in glucose homeostasis will be limited. In addition, 
the use of multiple antidiabetic medications is generally not clinically indicated at HbA1c 
levels < 7.0%.
3.2.3
Rationale for Endpoints
3.2.3.1
Primary Endpoint
The primary objective of this study is to assess the antihyperglycemic effect of daily 
MEDI0382 treatment (titrated up from 100 μg for 7 days to 200 μg for 7 days and to a final 
dose of 300 μg for 14 days) versus placebo in subjects with T2DM treated with 10 mg 
dapagliflozin and metformin. The change and % change in glucose AUC0-4h from baseline to 
the end-of-treatment period following a MMTT will be evaluated in subjects with T2DM
treated with MEDI0382 or placebo plus dual therapy (ie, dapagliflozin and metformin). On 
the basis of prior evidence, it is known that both MEDI0382 and dapagliflozin given 
individually will result in improved glucose control. However, the extent to which 
MEDI0382 will lower blood glucose when given simultaneously to an add-on, oral dual 
therapy of dapagliflozin and metformin (in a late-stage diabetes population) is unknown. The 
MMTT is well established as a measure of glucose control, and it is used in this study to 
evaluate the effect of MEDI0382 on lowering glucose by measuring changes in glucose AUC 
after consumption of a standardized liquid meal.
3.2.3.2
Secondary Endpoints
Safety and Tolerability
The secondary objective of the study is to evaluate the safety and tolerability profile of 
MEDI0382 versus placebo in combination with a dual therapy of dapagliflozin and 
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In a prior study (D5670C00002), 300 μg of MEDI0382 was administered to 23 obese and 
overweight subjects with T2DM for 7 days after 2 uptitration steps. This dose was shown to 
have an acceptable tolerability and safety profile over this period of dosing. During 
treatment, there was no significant increase in systolic or diastolic BP, but a significant 
increase in HR of 6.6 beats per minute (90% CI 4.1, 9.1) was recorded after 7 days of dosing 
(Cohorts 5 and 6 pooled data; n = 19). In the cohorts that received MEDI0382 uptitrated to 
300 μg, nausea were observed in a maximum of 41.7% (Cohort 6) of subjects, and vomiting 
were observed in a maximum of 27.3% (Cohort 5) of subjects. Safety and tolerability of 
MEDI0382 (uptitrated up to 300 μg) in subjects treated with dual therapy of dapagliflozin 
and metformin will be measured with safety laboratory tests, vital signs including ABPM 
recording of HR and BP, and recording of AEs.
Pharmacokinetics 
Plasma concentrations of MEDI0382 and dapagliflozin will be used to evaluate the PK 
profile: Cmax, tmax, and plasma AUC from zero to infinity (AUC0-inf), from zero to last 
observation (AUC0-last), and during the dosing interval (AUCtau). The expectation is that the 
PK profile of MEDI0382 will not be significantly altered when administered simultaneously
with dapagliflozin and metformin. 
 
 
 
Efficacy
Continuous glucose monitoring is a minimally invasive device applied to the skin in the 
upper arm that provides a measure of interstitial glucose levels every 15 minutes. Exploration 
of the glucose-lowering effect of MEDI0382 in combination with dapagliflozin and 
metformin dual therapy versus the dual therapy alone will be assessed by CGM over a 
24-hour and 7-day periods. Continuous glucose monitoring will allow measurements of 
glucose excursions during different meals and at different times of the day and will allow 
determination of the percentage of time subjects have abnormally high or low blood glucose 
levels. Continuous glucose monitoring will also provide additional safety information such as
glucose measurements any time a subject is in the hypoglycemic range. This data will help
determine whether the glucose-lowering effect is exacerbated by the combination of 
MEDI0382 plus dual therapy compared to the dual therapy alone.


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3.2.3.3
Exploratory endpoints
Further characterization of the additive effects of MEDI0382 in combination with 
dapagliflozin and metformin as dual therapy versus the dual therapy and placebo will be 
assessed by measuring plasma glucagon, insulin, and c-peptide after a MMTT. 
It is hypothesized that the glucagon component of MEDI0382 may lead to increased fatty 
acid oxidation in the liver, thus resulting in increased ketogenesis. This effect alongside the 
dapagliflozin-induced glycosuria may predispose subjects to increase ketogenesis. Changes 
in serum ketones (β-hydroxybutyrate) and FFA profile are used as exploratory endpoints to 
investigate whether or not concomitant treatment of MEDI0382 and SGLT2 inhibitors 
increases the propensity to develop ketosis.
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Enrollment of 46 subjects across sites is planned, with 23 subjects to receive MEDI0382 SC 
and 23 subjects to receive placebo SC once daily in the morning for 28 days.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Male and female subjects aged ≥ 18 years at screening.
2. Provision of signed and dated informed consent form (ICF) prior to any study specific 
procedures.
3. BMI between 25 kg/m2 and 40 kg/m2 (inclusive) at screening.
4. HbA1c range between 7.0% and 10.0% (inclusive) at the time of screening.
5. Diagnosed with T2DM and treated with of metformin monotherapy (MTD > 1 g) at least 
8 weeks prior to screening or treated with stable, oral doses of dapagliflozin 10 mg and 
metformin (MTD > 1 g) for at least 3 months prior screening.
6. Subjects prescribed oral dual therapy with sulphonylurea, glitinide, or dipeptidyl 
peptidase-4 inhibitor (in addition to metformin) may be eligible to enter the study 
following a washout period of these medications totaling at least 28 days before initial 
screening evaluations have been completed.
7. Female subjects of childbearing potential must have a negative pregnancy test at 
screening and randomization and must not be lactating.
8. Females of childbearing potential who are sexually active with a nonsterilized male 
partner must use at least one highly effective method of contraception from screening and 
must agree to continue using such precautions through to the end of the study (see 


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Section 10.2 for accepted methods of contraception). It is strongly recommended for the 
male partner of a female subject to also use male condom plus spermicide throughout this 
period. Cessation of contraception after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. History of, or any existing condition that in the opinion of the investigator would 
interfere with evaluation of the investigational product, put the subject at risk, influence 
the subject’s ability to participate, or affect the interpretation of the results of the study 
and/or any subject unable or unwilling to follow study procedures
2. Any subject who has received another investigational product not included in the protocol 
as part of a clinical trial or a GLP-1 analogue or SGLT2-containing preparation 
(excluding dapagliflozin) within the last 30 days or 5 half-lives of the drug (whichever is 
longest) at the time of screening 
3. Any subject who has received any of the following medications prior to the start of the 
screening period (Visit 1) or prior to the study start period (Visit 4) (see Section 4.7.2 for 
further details):
◦
Concurrent use of any medicinal products, or herbal or over-the-counter (OTC)
preparations licensed for control of body weight or appetite at the time of screening 
(Visit 1)
◦
Concurrent or previous use of drugs approved for weight loss (eg, orlistat, bupropion-
naltrexone, phentermine-topiramate, phentermine, lorcaserin) within the last 30 days 
or 5 half-lives of the drug (whichever is longest) at the time of screening (Visit 1)
◦
Concurrent use of aspirin (acetylsalicylic acid) at a dose greater than 150 mg once 
daily and within the last 72 hours prior to the start of the study (Visit 4) 
◦
Concurrent use of paracetamol (acetaminophen) or paracetamol-containing 
preparations at a total daily dose of greater than 3000 mg and within the last 72 hours 
prior to the start of the study (Visit 4)
◦
Concurrent use of ascorbic acid (vitamin C) supplements at a total daily dose greater 
than 1000 mg and within the last 72 hours prior to the start of the study (Visit 4)
◦
Concurrent use of opiates, domperidone, metoclopramide, or other drugs known to 
alter gastric emptying and within the last 72 hours prior to the start of the study 
(Visit 4)
4. Concurrent participation in another study of any kind and repeat randomization in this 
study is prohibited 
5. Severe allergy/hypersensitivity to any of the proposed study treatments or excipients 
6. Diagnosis of type 1 diabetes mellitus, maturity-onset diabetes of the young, or latent 
autoimmune diabetes of adulthood or presence of anti-glutamic acid decarboxylase, anti-
islet cell, or anti-insulin antibodies


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7. Symptoms of acutely decompensate blood glucose control (eg, thirst, polyuria, weight 
loss) at screening or randomization, a history of DKA, or hyperosmolar nonketotic coma 
or treatment with daily SC insulin within 90 days prior to screening 
8. Fasting hyperglycemia (> 250 mg/dL/ > 13.9 mmol/L) prior to randomization
9. C-peptide level < lower limit of normal (LLN)
10. History of acute or chronic pancreatitis or pancreatectomy 
11. Hypertriglyceridemia (> 400 mg/dL) at screening
12. Significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery 
affecting the upper gastrointestinal (GI) tract (including weight-reducing surgery and 
procedures) which may affect gastric emptying or could affect the interpretation of safety 
and tolerability data 
13. Significant hepatic disease (except for nonalcoholic steatohepatitis or nonalcoholic fatty 
liver disease without portal hypertension or cirrhosis) and/or subjects with any of the 
following results at screening: 
•
Aspartate transaminase (AST) ≥3 × upper limit of normal (ULN)
•
Alanine transaminase (ALT) ≥3 × ULN 
•
Total bilirubin (TBL) ≥2 × ULN 
14. Impaired renal function defined as estimated glomerular filtration rate (eGFR) 
≤60 mL/minute/1.73m2 at screening (eGFR according to Modification of Diet in Renal 
Disease [MDRD] using the isotope dilution mass spectrometry-traceable MDRD Study 
Equation (SI units).
15. Use of loop diuretics within 1 month prior to screening
16. Poorly controlled hypertension as defined below:
!
Systolic BP > 160 mm Hg 
!
Diastolic BP or ≥ 100 mm Hg 
After 10 minutes of supine rest and confirmed by repeated measurement at screening
(Visit 1 for all subjects)
17. Unstable angina pectoris, myocardial infarction, transient ischemic attack, or stroke 
within 3 months prior to screening, or subjects who have undergone percutaneous 
coronary intervention or a coronary artery bypass graft within the past 6 months or who 
are due to undergo these procedures at the time of screening 
18. Severe congestive heart failure (New York Heart Association Class III and IV) 
19. Basal calcitonin level > 50 ng/L at screening or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia 
20. Hemoglobinopathy, hemolytic anemia, or chronic anemia (hemoglobin concentration 
< 11.5 g/dL [115 g/L] for males and < 10.5 g/dL [105 g/L] for females) at screening or 
any other condition known to interfere with interpretation of HbA1c measurement 
21. History of neoplastic disease within 5 years prior to screening, except for adequately 
treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer. 
22. Any positive results for serum hepatitis B surface antigen, hepatitis C antibody, and 
human immunodeficiency virus antibody


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23. Recent viral infection or illness requiring the use of antibiotics in the month prior to 
screening (Visit 1) for subjects on dual therapy or prior to run-in period (Visit 2) for 
subjects on monotherapy
24. History of recurrent (at least 2) urinary tract and/or genital tract infections (including 
mycotic infections such as thrush) within 6 months prior to screening
25. Substance dependence likely to impact subject safety or compliance with study 
procedures 
26. Involvement of any AstraZeneca, MedImmune, contract research organization, or study 
site employees and their close relatives 
Note: Subjects may be rescreened once, if in the opinion of the Investigator there is a reason 
to believe they may be eligible. Subjects should continue to meet all inclusion and none of 
the exclusion criteria to qualify for rescreening. If subject is rescreened, all screening 
procedures including laboratory tests must be repeated. 
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/web response system, interactive 
response technology such as IXRS), and the screening evaluations may begin to assess study 
eligibility (inclusion/exclusion) criteria. The SID number will be used to identify the subject 
during the screening process and throughout study participation if applicable. 
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized) including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not 
be randomized (if applicable) or receive investigational product. There can be no exceptions 
to this rule. Subjects who are enrolled, but subsequently found not to meet all the eligibility 
criteria must not be randomized or initiated on treatment and must be withdrawn from the 
study.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw from the study at any time (investigational product and 
assessments) without prejudice to future treatment (withdrawal of consent). At the time of 
withdrawing consent, subjects will be asked about the reason(s) for withdrawing and the 
presence of any AEs. After consent is withdrawn, no further study visits or data collection 
should take place.


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4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occur in the subject:
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. 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 at the decision of the 
investigator, continuing of investigational product might constitute a safety risk. 
4. Subject noncompliance that in the opinion of the investigator or sponsor warrants 
withdrawal (eg, refusal to adhere to scheduled visits) 
5. Pregnancy in a female subject 
6. Evidence of ketoacidosis or progression to ketoacidosis, ie, blood ketones 
(β-hydroxybutyrate) > 3.0 mmol/l and pH < 7.35 ± serum bicarbonate < 18 mmol/L in 
conjunction with clinical symptoms. The presence of elevated plasma glucose is not 
required as part of this diagnosis. The investigator should consider interrupting
dapagliflozin temporarily if DKA is suspected. The subject should be promptly 
evaluated. If DKA is confirmed, dapagliflozin should be discontinued permanently.
7. Hypoglycemia events: Subjects should discontinue investigational product if they 
experience severe hypoglycemia as define by the American Diabetes Association 
◦
Requiring assistance of another person to actively administer carbohydrates, 
glucagon, or take other corrective actions 
◦
Plasma glucose concentrations may not be available during an event, but neurological 
recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration
8. Kidney disorders as determine by a decrease in renal function that would preclude 
continued treatment with metformin according to local guidance
9. Hepatic disorders: subjects with central laboratory ALT and/or AST > 3 × ULN will be 
scheduled for a follow-up visit within 3 days following the receipt of the results. Subjects 
should be discontinued from receiving investigational product if initial and repeat 
laboratory tests meet any of the following: 
◦
ALT and/or AST are 3 × ULN and TBL > 2 × ULN 
◦
ALT and/or AST are 5 × ULN for 14 consecutive days, at any time after initial 
confirmatory results. 
◦
ALT and/or AST are 8 × ULN
If a subject is required to or chooses to discontinue the investigational product, every 
reasonable effort should be made for the subject to remain in the study for follow up and to 
complete all other study procedures until the scheduled end of the study. It is important that 


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investigators and site staff familiarize themselves with procedures for maintaining such 
subjects in the study to collect their data as scheduled. Subjects who are permanently 
discontinued from receiving investigational product will be followed for protocol-specified 
assessments including follow-up of any AEs unless consent is withdrawn specifically from 
further study participation (Section 4.1.5), the subject is lost to follow-up, the subject starts 
alternative treatment, or the subject is enrolled in another clinical study.
4.1.7
Replacement of Subjects
Subjects who withdraw from the study may be replaced where possible.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of a SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject.  
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed and the action documented. If samples are already analyzed, 
MedImmune is not obliged to destroy the results of this research (Appendix 10.6).
4.2
Schedule of Study Procedures
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, and then 
blood draws. The timing of the first 2 assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the exact nominal time.
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.


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Table 4.2.1-1
Schedule of Screening Period Procedures 
Study Period
Screening
Visit Number
V1
Procedure/Study Day
Day -89 to Day -29
Written informed consent/ assignment of SID number
X
Medical history (including smoking and alcohol history)
X
Concomitant medications
X
Physical examination (full)
X
Body weight, height, and BMI calculations
X
12-lead digital ECG
X
Vital signs (HR, BP, body temperature, and RR)
X
Collect blood for:
Serum chemistry (including eGFR calculation)
X
Hematology
X
Calcitonin
X
HbA1c
X
Coagulation parameters
X
Hepatitis B and hepatitis C serology; HIV-1 and HIV-2 
antibodies
X
Serum pregnancy test (β-hCG, female subjects only)
X
Collect urine for:
Urinalysis (dipstick)
X
Drug and alcohol screen a
X
Check willingness and ability to self-administer IP b
X
Verify eligibility criteria
X
β-hCG = beta human chorionic gonadotropin; BMI = body mass index; BP = blood pressure; 
ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; 
HIV = human immunodeficiency virus; HR = heart rate; IP = investigational product; RR = respiratory rate;
SID = subject identification; V = visit.
a
Breath alcohol testing is acceptable as an alternative to urine testing.
b
Subject’s ability to self-administer investigational product will be verified using normal saline SC 
injections.
4.2.2
Run-in Period
Table 4.2.2-1 shows all procedures to be conducted at the run-in period visits for subjects on 
metformin monotherapy only.


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Table 4.2.2-1
Schedule of Run-in Period Procedures
Study Period
Run-in
Visit Number
V2
V3
Procedure/Study Day
Day -28
Day -14
Verify eligibility criteria
X
Medical history (including smoking and alcohol history)
X
Abbreviated physical examination
X
X
Concomitant medications
X
Body weight
X
12-lead digital ECG
X
Vital signs
X
X
Collect blood for: 
Serum chemistry (predose)a
X
X
Hematology (predose) a
X
X
HbA1C (predose) a
X
Amylase, lipase and lactate (predose) a
X
X
PK for dapagliflozin
X
Collect urine for:
Urinalysis (dipstick)
X
Drug and alcohol screen b
X
β-hCG (pregnancy test)
X
X
Assessment of AEs/SAEs
X
X
Diet and lifestyle counselling
X
X
Discharge from unit
X
X
Subject administration of oral dapagliflozin 10 mg
X
X
Training of subject on glucose and ketone monitoring
X
Subject finger-prick testing of ketones using test strips
X
AE = adverse event; ECG = electrocardiogram; β-hCG = beta human chorionic gonadotropin; 
HbA1c = hemoglobin A1c; PK = pharmacokinetics; SAE = serious adverse event; V = Visit
a
Blood collection is predose on Day -14 only.
b
Breath alcohol testing is acceptable as an alternative to urine testing.
4.2.3
Randomized Treatment Period
Table 4.2.3-1 shows all procedures to be conducted from inpatient Visit 4 (Day -2 to Day 1) 
until the end of the treatment period (inpatient Visit 11, Day 27 to Day 29). Assessments 
should be performed in the order shown in the table.
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, and then 


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blood draws. The timing of the first 2 assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the exact nominal time.


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Table 4.2.3-1
Schedule of Treatment Period Procedures
Study Period
Treatment period
MEDI0382 Dose level
100 μg
200 μg
300 μg
Visit Number
V4
V5
V6
V7
V8
V9
V10
V11
Procedure/
Study Day
-2
-1
1 
2 
7
8
14
15
22
27
28
29
Inpatient or Outpatient 
Inpatient
Outpatient
Outpatient
Outpatient
Outpatient
Outpatient
Outpatient
Inpatient
Verify eligibility criteria a
X
Admit to clinic
X
X
Discharge home b
X
X
X
Medical and disease 
history
X
Physical examination 
(abbreviated)
X
X
X
X
X
Body weight c
X
X
12-lead digital ECG d
X
X
X
X
X
Vital signs e
X
X
X
X
X
X
X
X
X
24-hour ABPM f
X
X
X
Randomization g
X
X
SC injection training h
X
X
Administration of 
dapagliflozin i
------------------------------------------------------------------For the duration of the study-------------------------------------------------
Administration of 
metformin i
------------------------------------------------------------------For the duration of the study-------------------------------------------------


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Table 4.2.3-1
Schedule of Treatment Period Procedures
Study Period
Treatment period
MEDI0382 Dose level
100 μg
200 μg
300 μg
Visit Number
V4
V5
V6
V7
V8
V9
V10
V11
Procedure/
Study Day
-2
-1
1 
2 
7
8
14
15
22
27
28
29
Inpatient or Outpatient 
Inpatient
Outpatient
Outpatient
Outpatient
Outpatient
Outpatient
Outpatient
Inpatient
Administration of SC IP 
(MEDI0382 or placebo) j
X
X
X
X
X
X
X
X
X
Uptitration of SC 
medication
X
X
Capillary glucose and 
ketones monitoring k
X
X
X
Visit requires 10-hour 
overnight fast the day 
before arrival l
X
X
X 
X 
X
Collect Blood samples for:
Serum chemistry (predose 
where applicable) m
X
X
X
X
X
X
Serum amylase and lipase
(predose where applicable)m X
X
X
X
Serum lactate
X
X
X
X
X
X
Serum calcitonin 
X
X
pH
X
X
X
X
X
X
Hematology (predose 
where applicable) m
X
X
X
X
X
X
MEDI0382 PK n
X
X
X
X
X
X


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Table 4.2.3-1
Schedule of Treatment Period Procedures
Study Period
Treatment period
MEDI0382 Dose level
100 μg
200 μg
300 μg
Visit Number
V4
V5
V6
V7
V8
V9
V10
V11
Procedure/
Study Day
-2
-1
1 
2 
7
8
14
15
22
27
28
29
Inpatient or Outpatient 
Inpatient
Outpatient
Outpatient
Outpatient
Outpatient
Outpatient
Outpatient
Inpatient
Dapagliflozin PK n
X
X
X
X
X
X
X
X
Ketones PK o, r
X
X
X
X
X
X
X
X
MMTT sampling for 
glucose, c-peptide, 
glucagon, insulin, active 
GLP-1q
X
X
FFA (fasting)
X
X
X
X
HbA1c 
X
X
FPG
X
X
X
X
Collect urine for:
Urinalysis
X
X
X
X
Pregnancy test
X
X
X
X
24-hour urinary glucose s
X
X


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Table 4.2.3-1
Schedule of Treatment Period Procedures
Study Period
Treatment period
MEDI0382 Dose level
100 μg
200 μg
300 μg
Visit Number
V4
V5
V6
V7
V8
V9
V10
V11
Procedure/
Study Day
-2
-1
1 
2 
7
8
14
15
22
27
28
29
Inpatient or Outpatient 
Inpatient
Outpatient
Outpatient
Outpatient
Outpatient
Outpatient
Outpatient
Inpatient
Drug and alcohol screen t
X
X
Staff review of daily 
ketone testing data
X
X
X
X
X
Subjects finger-prick 
testing of ketones using 
test strips u
-------------------------------------------For the duration of the study until 14 ± 2 days after last dose---------------------------------
CGM v
-------------------------------------------------From Day -1 until 28 ± 4 days after last dose ---------------------------------------------
CGM sensor 
application/change w
X
X
X
Assessment of AEs/SAEs
----------------------------------------------------------For the duration of the study--------------------------------------------------------
Concomitant medications
-----------------------------------------------------------For the duration of the study-------------------------------------------------------
ABPM = ambulatory blood pressure monitoring; 
AEs = adverse events; BP = blood pressure; CGM = continuous glucose 
monitoring; ECG = electrocardiogram; FFA = free fatty acid; FPG = fasting plasma glucose; GLP-1 = Glucagon-like peptide-1; HbA1c = hemoglobin A1c; 
HR = heart rate; IP = investigational product; MMTT = mixed meal tolerance test; PK = pharmacokinetics; RR = respiratory rate; SAEs = serious adverse events; 
SC = subcutaneous(ly); V = visit
a
The eligibility check should be based on all clinical measurements and blood tests taken during the screening visit (V1) with the exception of vital signs, 
urinary illicit drug, and pregnancy tests, which should be rechecked on Day -2. An abbreviated physical examination and repeat medical history should also 
be undertaken on Day -2 to ensure the subject is well enough to commence dosing.
b
On Day -1, following completion of the MMTT test, subjects are given the option to remain in the unit or return home. Discharged subjects must ensure they 
undergo an overnight fast for approximately 10 hours, and they will return to the clinic on Day 1. 


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c
Body weight should be measured in the morning prior to breakfast on Day 1 (predose on Day 1) and on Day 29. The subject should take off their shoes and 
remove bulky clothing. Calibrated scales should be used.
d
A single, digital ECG recording should be performed predose after the subject has rested for 10 minutes on Day 1, 7, 14, 22, and 27. 
e
Vital Signs schedule: Vital signs include BP, HR, RR, and body temperature. On days when ABPM device is due to be checked, a predose set of vital signs 
should be performed only prior to application of the ABPM cuff. BP should be measured once at heart level in the nondominant arm where possible, and 
opposite to the arm where the CGM device is applied. The subject should seat and rest for 10 minutes prior to the measurement. Both lying and standing 
measurements should be taken. 
◦
Day -2, 14, and 28: vital signs to be taken prior to fitting ABPM 
◦
Day 1: vital signs to be taken predose (-15 minutes); immediately after dosing (+ 3 minutes); 15, 30, and 60 minutes (± 5 minutes) postdose; and 2 hours 
(±10 minutes) postdose
◦
Day 15 and 29: vital signs to be taken once ABPM is removed
◦
Day 7, 8, and 22: vital signs to be taken at no specific time point
f
Subjects will be fitted with the ABPM device shortly after they arrive at the clinical unit. Subjects may be involved in practice inflations. On Day -2, 14, and 
28, ABPM should be applied predose. From Day 14 to Day 15, the subject will wear the monitor/cuff for approximately 24 hours (including overnight) and 
will remove the device at home at the end of the 24-hour period. Subjects will return the device to the clinic. On Day -1 and Day 29, the device will be 
removed at the clinic during the inpatient stay.
g
Randomization may occur any time from Day -1 to Day 1 (predose).
h
Normal saline will be used for SC injection administration training.
i
Metformin and dapagliflozin to be administered before investigational product administration. For PK sample collection, dapagliflozin should be 
administered by staff at the clinic on Days -1, 1, 7, 8, 14, 15, and 28 shortly before investigational product.
j
Subjects to dose at home on Day 22 and 27 prior to coming to the clinic. Investigational product will be administered in the clinic on Days 1, 2, 7, 8, 14, 15, 
and 28. Please refer to Investigational Medicinal Product Manual for more details.
k
After investigational product administration (MEDI0382 or placebo) on Day 1 (first dose) and on Days 8 and 15 (uptitration days), subjects will be 
monitored for safety, glucose, and ketones. Capillary blood ketones and glucose monitoring will be done with a glucometer before meal, predose, 2 hours 
postdose, and 4 hours postdose. The subject will be discharge 6 hours postdose.  
l
Outside of fasting times meals/snacks and fluid intake should be standardized across each inpatient stay. 
m
Predose labs not applicable on Day 7, 14, 22, and 28. N-B Serum chemistry will include bicarbonate measurements.
n
PK sampling schedule: Blood samples for PK (MEDI0382 and dapagliflozin) to be drawn as follow:
◦
Dapagliflozin:
▪
Day -1, 7, 14, 28: Predose; 0.5, 1, and 2 hours (± 15 minutes) postdose; and 4, 6, 8, and 12 hours (± 30 minutes) postdose
▪
Day 1, 8, and 15: Predose
▪
Day 29: 24 hours after dosing time on Day 28


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◦
MEDI0382 
▪
Day 7, 14, and 28: Predose; 0.5, 1, and 2 hours (± 15 minutes) postdose; and 4, 6, 8, and 12, (± 30 minutes) postdose
▪
Day 8 and 15: Predose
▪
Day 29: 24 hours after dosing time on Day 28
o
Ketone blood sampling schedule:
◦
Blood samples for ketone (β-hydroxybutyrate) PK to be drawn following an overnight fast of at least 10 hours at the following times:
▪
Day -1, 7, 14, and 28: Predose; 0.5, 1, and 2 hours (± 15 minutes) postdose; and 4, 6, 8, and 12, (± 30 minutes) postdose. A standardized breakfast 
meal will be provided 2-hour post dose on Day 7 and 14 (see footnote “r”)
◦
Additional blood samples for ketone PK to be drawn as follow: 
▪
Day 1, 8, and 15: Predose 
▪
Day 29: 24 hours after dosing time on Day 28 (± 30 minutes)
q
MMTT schedule: The MMTT is conducted on Day -1 and Day 28 following a minimum 10-hour fast the day before. On Day -1, the MMTT starts 2 hours 
after dapagliflozin administration. On Day 28, the MMTT starts 2 hours after investigational product (MEDI0382 or placebo) and dapagliflozin 
administration. A blood sample for glucose metabolism panel (glucose, insulin, c-peptide, glucagon, and active GLP-1) will be taken immediately prior to 
the subject drinking one entire can of Ensure Plus as a standardized meal (ie, “0 minutes”). In addition, blood samples for glucose metabolism panel will be 
drawn at 15, 30, 45, 60, 90, 120, 180, and 240 minutes (±5 minutes) after consumption of the standardized meal. Additional sampling for glucagon, insulin, 
c-peptide, and glucose to be taken at 6, 8, 12, and 24 hour after time 0 (± 30 minutes) of the standardized meal administration on Days -1 and Day 28.
r
Standardized breakfast meal: On Day 7 and 14, a standardized breakfast meal will be provided approximately 2 hours after dapagliflozin and 
investigational product administration. The meal will have approximately 450 kilocalories and will consist of 1 egg, 2 slices of white bread, 1 slide of Swiss 
cheese and 1 cup (240 ml) of orange juice (approximately 30% fat, 15% protein and 55% carbohydrates).
s
Twenty-four-hour urinary collection for measurements of glucose excretion to start first thing in the morning soon after waking on Day 1 and Day 28. 
Instruct the subject to pass urine soon after waking and flush down the toilet. Note the exact time this was done. The collection of urine will start from this 
time. Proceed to collect every drop of urine day and night for 24 hours and finish by passing urine the next morning at exactly the same time collection was 
started the day before. This urine should also be added to the bottle. 
t
Breath alcohol testing is acceptable as an alternative to urine testing.
u
Subjects will be provided with a ketones monitor and strips for capillary blood ketone testing and will be instructed to test once a day (prebreakfast) and to 
do additional tests including glucose if they feel unwell. Subjects will be asked to record ketone values in a paper diary, which will be provided and checked 
by study staff.
v
CGM device to be fitted and worn continuously throughout the study. The sensor should be applied to the arm, taking into account which side the subject 
sleeps on and also which side the ABPM device will be applied. The sensor applied to the skin is single use and may not be reattached once removed. 


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w
CGM sensors last 14 days and should be changed at 14-day intervals at the same time of day (± 20 minutes) as originally applied on Day -1. For example, if 
the sensor is applied at 6:00 am on Day -1, it should also be applied at 6:00 am (± 20 minutes) predose on Day 14 and 28. If the sensor fails, or needs to be 
replaced, it should be reapplied as soon as possible.


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4.2.4
Follow-up Period
Table 4.2.4-1 shows all procedures to be conducted during the follow-up period. 
After the end of the follow-up period, subjects will return to the care of their own physicians 
according to local requirements and local standards.
Table 4.2.4-1
Schedule of Follow-up Procedures 
Study Period
Follow-up Period
Visit Number
V12
End-of-Study Visit
V13
Procedure/Study Day
14 days post last dose (±2 days)
28 days post last dose (±4 days)
Physical examination 
(abbreviated)
X
X
Body weight
X
ECG
X
Vital signs (HR, BP, RR, 
temperature)
X
X
Serum chemistry 
X
Calcitonin
X
Hematology
X
Urinalysis
X
Assessment of AEs/SAEs
X
X
Concomitant medications
X
X
Staff review of daily finger-prick 
ketone testing data
X
CGM sensor change
X
Remove CGM sensor
X
AE = adverse event; BP = blood pressure CGM = continuous glucose monitoring; 
ECG = electrocardiogram; EOS = end of study visit; HR = heart rate; RR = respiratory rate; SAE = serious 
adverse event; V = visit
 
 


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4.2.4.1
Early Discontinuation Visit or Unscheduled Study Visit
The following study procedures should be conducted for subjects who prematurely 
discontinue from the study or for subjects who require an unscheduled study visit. 
Assessments should be performed in the order shown below:
•
Abbreviated physical examination 
•
ECG
•
Vital signs
•
Body weight
•
MEDI0382 and dapagliflozin PK
•
Blood tests: chemistry and hematology panel
•
Assessment of AEs/ serious adverse events (SAEs)
•
Concomitant medications
•
Pregnancy test (if applicable)
4.3
Description of Study Procedures
4.3.1
Efficacy
4.3.1.1
Mixed-meal Tolerance Test
Subjects will be admitted to the unit on Day -2 and on Day 27. On Day -1 and on Day 28, 
following a minimum 10-hour fast, a blood sample for glucose metabolism panel (glucose, 
insulin, c-peptide, glucagon, and active GLP-1) will be taken immediately prior to the subject 
drinking a standardized mixed meal (t = “0 minutes”). The subject will then consume a can 
of Ensure Plus, which is a nutritional supplement containing the components of fat, 
carbohydrate, and protein that make up a standard MMTT. After the meal, timed, serial blood 
samples will be obtained for measurement of glucose and parameters related to glucose 
metabolism (with no additional food intake during this time). The MMTT will be performed 
on Day -1 and Day 28 as specified in the schedule of procedures.
Blood samples for the glucose metabolism panel will be drawn at t = “0 minutes” (before 
meal) and at 15, 30, 45, 60, 90, 120, 180, and 240 minutes (± 5 minutes) after consumption 
of the standardized meal. Additional sampling for glucagon, insulin, c-peptide, and glucose 
will be taken at 6, 8, 12, and 24 hours (± 30 minutes) postadministration (t = “0 minutes”) of
the standardized meal on Day -1 and 28.


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The change and % change from baseline (Day-1) to the end of the 28 days of treatment 
(Day 28) in glucose AUC0-4h will be determined as measured by the MMTT. In addition, the 
change from baseline (Day -1) to Day 28 in active GLP-1, glucagon, insulin, and c-peptide 
AUC0-4h will also be measured by MMTT.
4.3.1.2
Body Weight
Body weight will be measured during the screening period, at the start of the run-in period 
(Day -28), and prior to breakfast on Day 1 (predose) and Day 29. The subject should take off 
their shoes and remove bulky clothing. Calibrated scales should be used.
The change and % change in body weight from baseline (Day 1) to Day 29 (kg) will be 
determined. The proportion of subjects achieving ≥5% body weight loss from baseline 
(Day 1) to Day 29 will also be determined.
4.3.2
Safety Assessments
4.3.2.1
Medical History and Physical Examination 
Complete medical history will include history and current medical conditions; past or present 
cardiovascular disorders; respiratory, GI, renal, hepatic, neurological, endocrine, lymphatic, 
hematologic, immunologic, dermatological, psychiatric, genitourinary, drug, and surgical 
history; and any other diseases or disorders.
Physical examinations will be performed by a physician or qualified designee and will 
include examination of the following body systems: immunologic/allergy; head, ears, eyes, 
nose, and throat; respiratory; cardiovascular; GI; musculoskeletal; neurological (structured 
neurological examination to encompass mental status, cranial nerves, nystagmus, motor 
system/muscle strength, sensory system/sensation, bowel and bladder function, deep tendon 
reflexes, gait, station, coordination, fundoscopy, and cerebellar function); psychiatric (to the 
extent of determining whether or not the subject is willing and able to cooperate with the 
required study procedures in the investigator’s judgment); dermatological, 
hematologic/lymphatic; and endocrine.
Any focal deficit identified at baseline should be documented in the eCRF.
A full physical examination including structured neurological examination will be conducted 
during the screening period (Day -89 to Day -29, Visit 1), and abbreviated physical 
examinations (evaluation of selective body systems at the judgment of the physician or 
qualified designee based on subject presentation) will be conducted on Day -28, -14, -2, 7, 


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14, 22, and 27. Abbreviated physical examinations will also be performed during the follow-
up period.
Clinically significant abnormal findings will be recorded. Physical examinations will be 
performed at the time points specified in the schedules of procedures. Height will be 
measured at screening.
4.3.2.2
Assessment of the Injection Site
Site staff will check the injection site for injection-site reactions during study visits as 
required. Injection-site reactions may include (but are not limited to) local erythema, pain, 
tenderness, induration, swelling, pruritus, ulceration, and pigmentation.
4.3.2.3
Vital Signs
Vital sign measurements (BP, HR, body temperature, and respiratory rate [RR]) will be 
obtained after the subject has rested in the supine position at the time points specified in the 
schedules of procedures for at least 10 minutes. For any time points where ECG recording 
precedes vital signs measurements, the 10-minute rest prior to the ECG suffices for the rest 
prior to vital sign measurement). Route of body temperature measurement will be according 
to local protocols.
For ambulatory BP checks, subjects will be fitted with the ABPM device shortly after they 
arrive at the clinical unit; subjects may practice inflations at this point. The ABPM device 
should be applied predose on Days -2, 14, and 28. The ABPM device should be applied on 
the arm opposite to where the CGM device is applied. The subject will then wear the 
monitor/cuff for approximately 24 hours (including overnight) and will remove the device at 
home at the end of the 24-hour period. Subjects will return the device to the clinic.
On days when the ABPM device is due to be checked, a predose set of vital signs (BP, HR, 
RR, and temperature) should be performed only prior to application of the ABPM cuff. 
Blood pressure should be measured once at heart level in the nondominant arm where 
possible and opposite to the arm where the CGM device is applied. The subject should sit 
and rest for 10 minutes prior to the measurement. Both lying and standing measurements 
should be taken. The vital sign schedule will be conducted as follows:
•
Day -2, 14, and 28: vital signs to be taken prior to fitting ABPM 
•
Day 1: vital signs to be taken predose (-15 minutes); immediately after dosing 
(+ 3 minutes); 15, 30, and 60 minutes (± 5 minutes) postdose; and 2 hours (±10 minutes) 
postdose


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•
Day 15, and 29: vital signs to be taken once ABPM is removed
•
Day 7, 8, and 22: vital signs to be taken at no specific time point
4.3.2.4
Electrocardiograms
A single, digital ECG recording should be performed during the screening, treatment, and 
follow-up periods at the visits specified in schedule of procedures (Table 4.2.1-1, 
Table 4.2.3-1, and Table 4.2.4-1). A single ECG recording should be conducted predose after 
the subject has rested for 10 minutes on Days 1, 7, 14, 22, and 27. The ECG recording can be 
taken at no specific time point for other days.
The same recorder will be used for each subject at each time point, if possible. Date and time 
settings should be checked at the start of each study day and aligned with an official 
timekeeper for all machines used in the study.
Skin preparation should be thorough and electrode positions should be according to standard 
12-lead ECG placement. 
In this study, lead V2 will be analyzed and reported as primary. For all visits, lead V5 will be 
analyzed as backup for any subject where analysis in lead V2 is not deemed possible predose,
for significant parts of whole visits, or for whole visits.
The following variables will be reported: HR, RR, PR, QRS, and QT intervals from the 
primary lead of the digital 12-lead ECG. The investigator may add extra 12-lead ECG safety 
assessments if there are any abnormal findings or if the investigator considers it is required 
for any other safety reason.
4.3.3
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. 
Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed, central or local clinical laboratory. Any abnormal laboratory results should be 
repeated as soon as possible (preferably within 24 to 48 hours). 
Clinical laboratory tests will be performed on the days specified on the schedule of 
procedures (Table 4.2.1-1, Table 4.2.3-1, and Table 4.2.4-1). 
The following clinical laboratory tests will be performed as specified in the schedule:


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Serum Chemistry
•
Bicarbonate *
•
ALT
•
Glucose
•
TBL
•
Calcium
•
Creatinine
•
Chloride
•
Blood urea
•
Potassium
•
Albumin
•
Sodium
•
Magnesium
•
Bilirubin
•
ALP
•
AST
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; FFA = free fatty 
acids; TBL = total bilirubin
Notes: 
Liver function tests = AST, ALT, ALP, TBL, and albumin 
Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed concurrently. 
* May be measured via serum chemistry sample of blood gas analyzer per local procedures.
Hematology
•
White blood cell count with differential
•
Platelet count
•
Red blood cell count
•
Mean corpuscular volume
•
Hematocrit
•
Mean corpuscular hemoglobin concentration
•
Hemoglobin
•
Coagulation panel PT, PTT, INR
INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time
Urinalysis
•
Glucose
•
Drug and alcohol screen 
•
Protein
•
Ketones
•
Blood
Note: Urinalysis for protein, glucose, ketones, and blood may be performed at the site using a licensed test 
(dipstick).
Pregnancy Test (females of childbearing potential only)
•
urine human chorionic gonadotropin (hCG)
•
serum β-hCG (at screening only)
β-hCG = beta human chorionic gonadotropin; hCG = human chorionic gonadotropin
Other Tests
•
Calcitonin
•
Fasting FFA 
•
Lactate
•
Pancreatic amylase, lipase
•
pH
•
Glucose metabolism panel for MMTT: timed 
glucose, insulin, active and total GLP-1, and 
glucagon
•
fasting plasma glucose


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•
HbA1c
•
HIV-1 and HIV-2 antibodies (at screening)
•
c-peptide
•
HBsAg, hepatitis C antibody (at screening)
•
24- hour urine collection for glucose excretion
•
Plasma ketone profile (β-hydroxybutyrate)
FFA = free fatty acid; GLP-1 = glucagon-like peptide-1; 
HbA1c = hemoglobin A1c; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; 
MMTT = mixed-meal tolerance test
Notes:
•
Tests for pancreatic and incretin hormone profiles: active GLP-1, glucagon, insulin, and c-peptide
•
Test for additional measures of glucose control: fasting plasma glucose, HbA1c
4.3.4
Pharmacokinetic Evaluation and Methods
Blood will be collected to evaluate PK of MEDI0382 and dapagliflozin in plasma (see
Table 4.2.3-1 for collection time points). The PK of MEDI0382 and dapagliflozin in serum 
will be measured utilizing a validated immunoassay method. 
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. Pharmacokinetics
samples should be taken at the specified times and prior to administration of investigational 
product where indicated, and before meals or other assessments.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
 
 
 
 
 
 
 
 
 
 
 
 


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4.3.6
Pharmacodynamic Evaluation and Methods
4.3.6.1
Training for Application and Wearing of Continuous Glucose Monitoring 
Sensor
A Freestyle Libre® Pro CGM device will be used to measure interstitial glucose levels during 
the study. The Freestyle Libre® Pro CGM device measures interstitial glucose levels every 
15 minutes continuously for 2 weeks and does not require any calibration or periodic 
near-field/bluetooth connections with the device to perform this function. The Freestyle 
Libre® Pro CGM device does not permit flash glucose measurements. Study-site staff and 
investigators should avoid periodic reviews of interstitial glucose levels during the study to 
avoid the risk of unblinding. However, should a subject experience an AE or SAE, and the 
investigator deems information acquired by CGM to be useful in the subject’s ongoing 
management, interstitial glucose readings may be reviewed by the investigator as described 
in the manual, but they should avoid review of baseline readings taken on Day -1. The CGM 
sensor, which is a small plastic circular device of 35 mm diameter and 5 mm depth, should 
be applied to the arm, taking into account which side the subject sleeps on and also which 
side the ABPM device will be applied. The selected site should be shaved where necessary, 
and a sterile alcohol wipe (supplied with the kit) should be used to clean the site prior to 
application. Study-site staff should refer to the training materials and manual for application 
of the CGM sensor. Subjects will be expected to wear the CGM sensor continuously up until 
the time of a sensor change, which should occur within 14 days. Moreover, subjects are to be 
advised that they may bathe, shower, or swim (up to 3 m depth for up to 30 minutes) while 
wearing the CGM sensor. The CGM sensor should be removed at the specified times in the 
schedule of assessments (CGM sensor change). At this time, the site should be inspected and 
cleaned, and a new CGM sensor may be reapplied. Ideally, the new sensor should be applied 
close to the original site but taking into account the subject’s preference on site. The CGM 
sensor should be changed at the same time of day (± 20 minutes) as originally applied on 
Day -1. CGM sensors are single use and cannot be reapplied once removed. CGM sensors 
may only be applied to the upper arm and not to any other site in the body. It should be noted 
that monitors should remain at the study site and not be provided to subjects to take home.


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If a subject is unable to tolerate wearing the CGM sensor for the entire duration of the study, 
the sensor should be removed; but the subject should remain in the study with or without 
continued CGM.
4.3.6.2
Glucometer Measure Capillary Blood Glucose/Ketones Reading
At the start of the study, each subject in both cohorts will be issued with a standardized 
glucometer, testing strips for glucose and ketones, and a diary. For the duration of the study,
subjects will be encouraged to perform finger-prick tests if they feel unwell and in particular 
if they feel the symptoms may be due to hypoglycemia, but they will not be required to test
routinely. If the investigator or site staff feel that a subject could be experiencing hypo- or 
hyperglycemia, capillary blood glucose should be tested with a standardized glucometer. 
Capillary blood glucose levels of < 3 mmol/L (54 mg/dL) should be recorded as an AE 
regardless of whether the subject has symptoms or not.
During the course of the study, subjects will test their blood ketone level daily (prebreakfast) 
using the ketone finger-prick testing strips and ketone monitor provided. Furthermore, 
subjects will be advised to check their blood for the presence of ketones and check their 
blood glucose using finger-prick testing with a glucometer if they experience any of the 
symptoms described in Section 1.6.4 and/or during acute illness. Subjects will be instructed 
to contact the site immediately if the results indicate the presence of ketonemia
(> 3 mmol/L), and/or elevated glucose levels (> 140 mg/dL [> 7.8 mmol/L]), and/or present 
the symptoms described in Section 1.6.4. Subjects will be asked to record ketone values in a 
paper diary, which will be provided and checked by study staff during the outpatient visits
(ie, when subjects bring the paper diary back in house). The clinic staff will provide training 
on how to use the ketones monitor.
4.3.6.3
Training for Application and Wearing of ABPM Device
Subjects will be given training at their local study site on 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,
the device will be fitted to the nondominant arm of the subject (with the bladder placed over 
the artery), and an initial test reading will be performed. The subjects will be advised that the 
device will inflate to a pressure of 180 mm Hg for the first reading; thereafter, the device will 
adapt to inflate to a pressure just above the last recorded BP. The subject will be advised to 
undergo normal daily activities while wearing the cuff, and he/she will be advised to avoid 
any strenuous form of activity, bathing, or showering while wearing the cuff. The subject 
will be advised to remain still during a measurement with the arm relaxed at heart level. The 
subject will also be given advice on (a) how to wear the device during the day and at night 


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while sleeping, and (b) what to expect in terms of frequency of readings during the day 
(every 15 minutes) and overnight (every 30 minutes). During ABPM, systolic and diastolic 
BP, HR pressure, HR, and mean arterial pressure readings will be recorded over a period of 
24 hours.
Subjects will be fitted with the ABPM device shortly after they arrive at the clinical unit on 
Day -2. On Days 14 and 28, ABPM should be applied predose. The ABPM device should be 
applied on the opposite arm to the arm where the CGM device is applied. On Days 14 to 15,
the subject will wear the monitor/cuff for approximately 24 hours (including overnight) and 
will remove the device at home at the end of the 24-hour period. Subjects will return the 
device to the clinic. On Day -1 and Day 29, the device will be removed at the clinical during 
the inpatient stay.
4.3.7
Estimate of Volume of Blood to Be Collected
The total blood drawn during the study is 670 mL, but no more than 440 mL will be drawn in 
a 4-week period.
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include but are not limited 
to the following: 
•
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects (eg, drug-related SAEs, anaphylactic reaction, hepatic enzyme 
alterations meeting Hy’s law, signs of renal toxicity, QT interval prolongation).
•
Subject enrollment is unsatisfactory
•
Noncompliance that might significantly jeopardize the validity or integrity of the study
•
Sponsor decision to terminate development
•
Sponsor decided to terminate the study
If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.


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If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Independent Ethics Committee (IEC) promptly and provide the reason(s) for the 
suspension/termination. If the study is suspended for safety reasons and it is deemed 
appropriate by the sponsor to resume the study, approval from the relevant regulatory 
authorities (and IECs when applicable) will be obtained prior to resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
MedImmune will provide the investigator(s) with investigational product (Table 4.5.1-1) 
using designated distribution centers. 
Table 4.5.1-1
Identification of Investigational Products 
Investigational Product
Manufacturer
Concentration and Formulation as 
Supplied
MEDI0382
MedImmune
Solution for injection in 1.0 mL
prefilled syringe, 100 μg per
dose, 1 dose
MEDI0382
MedImmune
Solution for injection in 1.0 mL
prefilled syringe, 200 μg per
dose, 1 dose
MEDI0382
MedImmune
Solution for injection in 1.0 mL
prefilled syringe, 300 μg per
dose, 1 dose
Placebo
MedImmune
Solution for injection in 1.0 mL prefilled 
syringe, 1 dose
Dapagliflozin
Bristol-Myers Squibb
10 mg green, plain, diamond shaped, film-
coated tablet
MEDI0382 is provided as a sterile liquid drug product (nominal concentration of 0.5 mg/mL) 
in 50 mM sodium phosphate buffer, propylene glycol 1.85 % w/v, (pH 7.8), and it is intended 
for SC administration.
Placebo is provided as a sterile solution of 50 mM sodium phosphate buffer, propylene 
glycol 1.85 % w/v, (pH 7.8), and it is intended for SC administration.
MEDI0382 and placebo will be supplied to the site in blinded kits each containing 8 prefilled 
syringes. Each kit has a unique number that is printed on all labels within the kit (ie, the outer 


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carton label and the label of the prefilled syringe within the carton). When supplying the 
investigational product for at-home dosing, each subject will receive sufficient quantity of 
drug to last until the next visit, and the kits containing 8 prefilled syringes will be supplied in 
an additional take-home carton.
Dapagliflozin tablets will be provided in open label bottles containing 70 tablets. The tablets 
may contain lactose.
4.5.1.1
Investigational Product Handling
In-clinic Investigational Product Handling
The investigational product manager or study personnel who receives, inspects, and stores
the investigational product will be unblinded. The MEDI0382 or placebo kits must be stored 
at 2°C to 8°C in their original container. Subjects should be instructed to refer to the 
Instructions for Use (IFU) of investigational product.
The staff at the clinic should refer to the IFU of the investigational product for additional 
information.
At-home Investigational Product Handling
Subjects will be given training in self-administration of investigational product, disposal of 
used prefilled syringes, and other investigational product handling steps, and will be provided 
with an IFU booklet detailing instructions for at-home administration. An IFU booklet must 
be provided to each subject on each occasion investigational product is dispensed for 
at-home use. Subjects will also be asked to return used investigational product kit boxes 
along with sharps bins and unused prefilled syringes to the investigational site.
The entire kit of investigational product (MEDI0382 or placebo) should be stored in the 
refrigerator. Subjects should be asked to ensure they have a normal domestic refrigerator at 
home, which should be between 2°C and 8°C.
The subject is to remove from the refrigerator only the prefilled syringe required for their 
daily dose. All other syringes are to be kept in the refrigerator until required. The subject is to 
avoid the risk of freezing the investigational product (MEDI0382 or placebo) by carefully 
placing the investigational product (MEDI0382 or placebo) within their refrigerator, and they 
should not use investigational product (MEDI0382 or placebo) if it has been frozen. The 
prefilled syringe should always be safely discarded after use. The subject will return any 
unused prefilled syringes to the site for accountability at the outpatient/inpatient visit. 


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Investigational product should be protected from heat and light. Subjects should be instructed 
to refer to the IFU of investigational product.
4.5.1.2
Investigational Product Inspection
MEDI0382 is supplied as a sterile liquid solution in a prefilled syringe for single use. Each 
syringe selected for in-clinic treatment administration should be inspected by the unblinded 
investigational product manager or unblinded study personnel prior to injection. MEDI0382 
is supplied at a concentration of 0.5 mg/mL. The solution should not be cloudy, discolored, 
or contain any visible particles.
Subjects should be instructed to refer to the IFU of investigational product.
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 4.5.1.5) for 
further instructions.
4.5.1.3
Treatment Administration
In-clinic Treatment Administration
MEDI0382 or placebo should be stored at 2°C to 8°C in the original container. The dose to 
be administered should be allowed to warm up at room temperature for about 30 minutes 
before injection. The first day of dosing with MEDI0382 or placebo is considered Day 1. On 
the day of each dose, investigational product (MEDI0382 or placebo) will be administered 
according to the schedule of procedures. On study days where fasting is required for an 
additional assessment, the investigational product (MEDI0382 or placebo) should be taken 
approximately 2.5 hours prior to the applicable assessment. Investigational product 
(MEDI0382 or placebo) will be administered by SC injection in the lower abdomen.
Subjects should be instructed to take a whole tablet of dapagliflozin with a half glass of 
water.
At-home Treatment Administration
Investigational product (MEDI0382 or placebo) should be removed from the refrigerator for 
at about 30 minutes for temperature equilibration. The subject is not to administer 
investigational product (MEDI0382 or placebo) if the time outside of the refrigerator has 
exceeded 8 hours. If the storage time exceeds this limit, a new prefilled syringe should be 
used. After injection, the subject is to place the used prefilled syringe in the supplied sharps 
bin. A once-daily dose is to be self-administered by SC injection using the prefilled syringe 


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as soon as practicable upon waking each morning prior to breakfast. Each prefilled syringe 
contains only a single dose, and cannot be reused. The subject should be instructed not to 
reuse the prefilled syringe after administration of the single-dose administration. Subjects 
should refer to the IFU document for at-home administration details.
If a dose of MEDI0382 or placebo is missed, subjects should take the dose as soon as it is 
remembered unless it is almost time for the next dose, in which case subjects should skip the 
missed dose and take the study drug at the next regularly scheduled time. 
Subjects should take dapagliflozin (10 mg oral) once daily from the run-in period (for 
eligible subjects on metformin monotherapy) or randomization (for eligible subjects on dual 
therapy) until Day 29. Subjects should be instructed to take a whole tablet of dapagliflozin
with a half glass of water. If a dose of dapagliflozin is missed, subjects should take the dose 
as soon as it is remembered unless it is almost time for the next dose, in which case subjects 
should skip the missed dose and take the study drug at the next regularly scheduled time.
4.5.1.4
Monitoring of Dose Administration
As with any exogenous peptide, allergic reactions to dose administration are possible.
In prior experience with MEDI0382, there has been 1 injection-site reaction and no 
anaphylactic reactions. During visits to the clinical unit, the site of administration will be
checked for signs of injection-site reaction as required (Section 4.3.2.2).
4.5.1.5
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 
Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labelled conditions unless otherwise instructed.
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


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Mail:
MedImmune, LLC
Attn: Product Complaint Department
One MedImmune Way,
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
Subjects entering the study must have been treated either with daily, stable doses of oral, 
blood glucose-lowering therapy with metformin (MTD > 1 gram) monotherapy for at least 
8 weeks or stable doses of metformin (MTD >1gram) plus oral dapagliflozin 10 mg once 
daily dual therapy for at least 3 months prior to screening. Metformin is not provided by the 
study sponsor. 
After screening, eligible subjects on metformin monotherapy will begin an open-label, run-in 
period on Day -28 and will receive oral dapagliflozin 10 mg per day for 28 days prior to 
randomization until Day 29. Eligible subjects on dual therapy will receive oral dapagliflozin 
10 mg per day from randomization until Day 29.
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 fulfil GMP 
Annex 13 requirements for labeling. Label text will be translated into local languages, as 
required.
4.5.4
Storage
All investigational product should be kept in a secure place under appropriate storage 
conditions. The label on the investigational product kit specifies the appropriate storage. 
4.5.5
Treatment Compliance
In-clinic administration
At the clinic, investigational product (MEDI0382 or placebo) is administered by study-site 
personnel, who will monitor compliance.
At-home administration
Compliance during the at-home dosing period to be monitored via daily diary entries, 
returned prefilled syringes, and bottles of dapagliflozin. The distribution of investigational 
product for self-administration should be recorded in the appropriate sections of the eCRF.


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4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records and will account for all 
investigational product dispensed to and returned by the subject. Study-site staff, if 
applicable, or the site monitor delegated to investigational product management will account 
for all investigational product received at the site, unused investigational product, and for 
appropriate disposition of investigational product in accordance to local procedures. Upon 
completion of the study, copies of investigational product accountability records will be 
returned to MedImmune. All unused investigational product will be returned to a 
MedImmune-authorized depot or disposed of upon authorization by MedImmune.
In the case of a malfunctioning prefilled syringe, the designated investigational product 
manager (pharmacist/study nurse) should contact the site monitor delegated to investigational 
product management to initiate a product complaint process according to Section 4.5.1.5.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IXRS will be used for assignment of dapagliflozin tablet bottles (where required), 
randomization to a treatment group and assignment of blinded MEDI0382 or placebo 
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 investigational product kit number to the subject.
Eligible subjects will be randomized at a 1:1 ratio following screening to receive either 
MEDI0382 SC or placebo SC. The IXRS will assign a unique randomization code and 
treatment group to the subject at each randomization. Subjects who withdraw from the study 
may be replaced, if deemed necessary by the medical monitor, to ensure that safety data are 
collected on a sufficient number of subjects.
4.6.2
Methods for Ensuring Blinding
This is a double-blind study in which MEDI0382 and placebo are not identical in the 
prefilled syringe titration volumes. Neither the subject nor any of the investigator or sponsor 
staff who are involved in the treatment or clinical evaluation of the subjects will be aware of 
the treatment received (ICH E9).
The different fill volumes of investigational product (MEDI0382 and placebo) and the 
relative position of the plunger rods will be visually distinct during administration. To 


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maintain the blind, investigational product (MEDI0382 and placebo) prefilled syringes will 
be handled by an unblinded investigational product manager or unblinded study personnel 
that will not be involved in the treatment or clinical evaluation of subjects. An unblinded 
qualified designee may administer investigational product to subjects during in-clinic visits. 
An independent investigational product monitor will also be unblinded to perform 
investigational product accountability. In the event that the 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. If the treatment allocation for a subject 
needs to be known to treat an individual subject for an AE, the investigator must notify the 
sponsor immediately. The site will maintain a written plan detailing which staff members are 
blinded/unblinded and the process of investigational product administration used to maintain 
the blind.
4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency 
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IXRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
subject having received investigational product. In the majority of cases, the management of 
a medical emergency would be the same whether or not investigational product was received 
by the subject. If this was the case, the investigational product allocation should not be 
unblinded. 
MedImmune retains the right to unblind the treatment allocation for SAEs that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. 
If a subject’s investigational product allocation is unblinded, the subject should be 
discontinued from investigational product.
4.6.3.2
Unblinding for PK 
Analysis
A small number of clinical bioanalytical personnel, who will not be involved in the treatment 
or clinical evaluation of subjects, will be unblinded to subject treatment allocation to analyze 
PK and immunogenicity samples. Local SOPs will govern maintenance of the blind and 
information on treatment allocation will not be communicated outside of these clinical 
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4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the study (end-of-study visit). Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care, except for those medications identified as “excluded” and
listed in Section 4.7.2. Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, 
antiemetics, antidiarrheals, analgesics, and other care as deemed appropriate and in 
accordance with their institutional guidelines.
4.7.2
Prohibited Concomitant Medications
Other than the medications described above, use of concomitant medications including OTC 
medications, herbal supplements, vitamins, etc at the times specified in the list below is not 
permitted. Subjects must be instructed not to take any medications including OTC products 
without first consulting with the investigator.
Use of the following concomitant medications is not permitted:
•
Concurrent use of SGLT2 inhibitors (except for dapagliflozin), GLP-1-analogue-
containing preparation or any other glucose-lowering agent other than metformin within 
the last 30 days or 5 half-lives of the drug (whichever is longer) at the time of screening 
(Visit 1)
•
Concurrent use of any medicinal products, or herbal or OTC preparations licensed for 
control of body weight or appetite at the time of screening (Visit 1)
•
Concurrent or previous use of drugs approved for weight loss (eg, orlistat, bupropion-
naltrexone, phentermine-topiramate, phentermine, lorcaserin) within the last 30 days or 
5 half-lives of the drug, whichever is longest, at the time of screening. (Visit 1)
•
Any other investigational agent not included in the protocol within last 30 days or 5 half-
lives (whichever is longer) from screening (Visit 1)
•
Concurrent use of Aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily 
and within the last 72 hours prior to the start of the study (Visit 4) 
•
Concurrent use of paracetamol (acetaminophen) or paracetamol-containing preparations 
at a total daily dose of greater than 3000 mg once daily and within the last 72 hours prior 
to the start of the study (Visit 4)


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•
Concurrent use of ascorbic acid (vitamin C) supplements at a total daily dose of >than 
1000 mg and within the last 72 hours prior to the start of the study (Visit 4)
•
Concurrent use of opiates, domperidone, metoclopramide, or other drugs known to alter 
gastric emptying and within the last 72 hours prior to the start of the study (Visit 4)
•
Loop diuretics within one month prior to screening (Visit 1) and during the study
4.8
Statistical Evaluation
4.8.1
General Considerations
Data will be provided in listings sorted by treatment group and subject number. Tabular 
summaries will be presented by treatment group. Categorical data will be summarized by the 
number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics, including mean, standard deviation (SD), median, 
minimum, and maximum. Baseline values will be defined as the last valid assessment prior to 
the first administration of investigational product unless otherwise specified. Details of 
endpoint analyses will be described in the statistical analysis plan.
4.8.1.1
Analysis Population
Efficacy Population: The Intent-to-treat (ITT) population includes all subjects who are 
randomized and receive any investigation product analyzed according to their randomized 
treatment group.
Safety Population: The As-treated population includes all subjects who receive any 
investigation product analyzed according to the treatment they actually receive.
PK Population: The PK population includes all subjects who received at least 1 dose of 
investigational product and had at least one PK sample taken that is above the lower limit of 
quantitation.
 
 
4.8.2
Sample Size and Power Calculations
A total of 46 subjects are planned for the study. Each of the 2 treatment groups will be 
randomized at a 1:1 ratio to receive (a) MEDI0382 with dapagliflozin and metformin 
administered simultaneously or (b) placebo with dapagliflozin and metformin administered 
simultaneously. A sample size of 23 subjects in each treatment group will provide a study 


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power > 95% to detect a difference of 30% between treatment groups in relative change from 
baseline in glucose AUC0-4h at a two-sided alpha of 5%, assuming a common SD of 20%. 
This sample size will also provide a study power > 95% to detect a difference of 
225 hr•mg/dL between treatment groups in absolute change from baseline in glucose AUC0-
4h at a two-sided alpha of 5%, assuming a common SD of 150 hr•mg/dL. The SD
assumptions are based the result of 300 μg cohorts in a prior study (D5670C00002).
4.8.3
Efficacy
4.8.3.1
Primary Efficacy Analysis
The primary efficacy analysis will be based on the ITT population. The primary endpoints, 
change and % change from baseline to the end of 28 days of treatment in glucose AUC0-4h as 
measured by a MMTT, will be summarized by treatment group. Statistical comparisons of 
these endpoints between MEDI0382/dapagliflozin/metformin and 
placebo/dapagliflozin/metformin treatment groups will be performed using an analysis of 
covariance by adjusting baseline and treatment group with last-observation-carried-forward 
(LOCF) approach to handle missing data.
Descriptive statistics at each time point will be provided by treatment group.
4.8.3.2
Secondary Efficacy Analyses
Secondary efficacy and pharmacodynamics (PD) analysis will be based on the ITT 
population. The following endpoints will be summarized by treatment group and analyzed
similarly to the analysis of primary efficacy endpoints.
•
Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in 
glucose AUC at 24 hours as measured by CGM
•
Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in 
24-hour mean glucose as measured by CGM 
•
Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in SD 
of 24-hour glucose readings as measured by CGM 
•
Change from baseline to Days 7, 14, and 28 in coefficient of variation (ratio of SD:mean 
over 24 hours) of glucose readings as measured by CGM
•
Change from baseline to Days 7, 14, and 28 in the mean amplitude of glucose excursion
of 24-hour glucose readings as measured by CGM 
•
Change from baseline to Days 7, 14, and 28 in the % of 24-hour glucose readings 
obtained from CGM that fall within the euglycemic range of ≥70 mg/dL (≥3.9 mmol/L) 
and ≤180 mg/dL (≤10.0 mmol/L)


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•
Change from baseline to Days 7, 14, and 28 in the % of 24-hour glucose readings 
obtained from CGM that fall within the hyperglycemic range of > 180 mg/dL 
(> 10 mmol/L)
•
Change from baseline to Days 7, 14, and 28 in the % of 24-hour glucose readings 
obtained from CGM that fall within the hypoglycemic range of < 70 mg/dL 
(< 3.9 mmol/L)
•
Change from baseline to Days 7, 14, and 28 in the % of 24-hour glucose readings 
obtained from CGM that fall within the clinically significant hypoglycemic range of 
< 54 mg/dL (< 3.0 mmol/L)
Descriptive statistics at each time point will be provided by treatment group.
4.8.3.3
Exploratory Analyses 
Exploratory efficacy and PD analysis will be based on the ITT population. The following 
endpoints will be summarized by treatment group and analyzed similarly to the analysis of 
primary efficacy endpoints.
•
Change from baseline (Day -1) to Day 28 in FPG
•
Change from baseline (Day -2) to Day 28 in HbA1c
•
Change from baseline (Day -1) to Day 28 in active GLP-1, glucagon, insulin, c-peptide 
AUC0-4h as measured by MMTT
•
Change from baseline (Day -1) to Day 7, 14, and 28 in fasting FFA level
•
Change from baseline (Day 1) to Day 29 in body weight (kg)
•
Percentage change from baseline (Day 1) to Day 29 in body weight (kg)
•
Total glucose excreted in urine collected for 24 hours
For the proportion of subjects achieving ≥5% body weight loss from baseline after 28 days
treatment, pairwise statistical comparisons between MEDI0382/dapagliflozin/metformin and 
placebo/dapagliflozin/metformin treatment groups will be made using a logistic regression by 
adjusting baseline and treatment group with an LOCF approach to handle missing data. 
Descriptive statistics at each time point will be provided by treatment group.
4.8.4
Safety
4.8.4.1
Analysis of Adverse Events
Safety analysis will be based on the As-treated population. Adverse event collection begins 
after the subject signs the ICF and lasts until the end of the study. Treatment-emergent AEs 


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(TEAEs) and treatment-emergent SAEs (TESAEs) will be coded by the most updated version 
of the Medical Dictionary for Regulatory Activities (MedDRA), and the type, incidence, 
severity and relationship to investigational product will be summarized by MedDRA’s
System Organ Class, Preferred Term, and by treatment group. Treatment-emergent AEs
leading to discontinuation, TEAEs leading to death, and deaths will also be summarized. 
Specific TEAEs will be counted once for each subject for the calculation of percentages. In 
addition, if the same TEAE occurs multiple times within a particular subject, the highest 
severity and level of relationship observed will be reported. 
4.8.4.2
Analysis of Safety Data
Safety data such as vital signs (including 24-hour ABPM) will be summarized by treatment 
group at each time point. Change from baseline to each postbaseline time point in these data 
will also be summarized, where appropriate. Electrocardiogram parameters will also be 
assessed and summarized descriptively by treatment group.
4.8.4.3
Analysis of Clinical Laboratory Parameters
Clinical laboratory data will be summarized by treatment group at each time point. Change 
from baseline to each postbaseline time point in these data will also be summarized, where 
appropriate. 
4.8.5
Analysis of 
Pharmacokinetics 
4.8.5.1
Pharmacokinetic Analyses
If data allow, PK parameters such as Cmax, tmax, AUC, and terminal elimination half-life will 
be estimated from plasma concentration-time data for MEDI0382 and β-hydroxybutyrate at 
each dose level separately and for 10 mg dapagliflozin. Moreover, if data allow, additional 
parameters such as apparent clearance may be derived for MEDI0382 at all dose levels and 
for 10 mg dapagliflozin. 
Descriptive statistics will be generated for PK parameters for the MEDI0382 and 
dapagliflozin group in each cohort. Subjects who have at least one measurable concentration 
time point of investigational product will be used for this analysis.
 
 
 


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4.8.6
Interim Analysis
No interim analysis is planned.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for GCP E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s pre-
existing condition. 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-TEAE 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 preexisting condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.


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5.2
Definition of Serious Adverse Events
An SAE is any AE that:
•
Results in death
•
Is immediately life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
Results in persistent or significant disability/incapacity 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations or development of drug dependency or drug 
abuse.
5.3
Definition of Adverse Events of Special Interest
An adverse event of special interest (AESI) is an AE of scientific and medical interest 
specific to understanding of the investigational product and may require close monitoring and 
collecting additional information by the investigator for the sponsor. 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.
All AESIs should be recorded in the eCRF within 24 hours. In addition, AESIs that are also 
SAEs should be reported to MedImmune Patient Safety within 24 hours. Instructions to the 
site on how to record (in the eCRF) and report AESI is provided in Section 5.4 and
Appendix 10.5, respectively. The AESI for this study is defined below.
5.3.1
Hepatic function Abnormalities
Refer to Section 5.6.2 and Appendix 10.5 for the definition and follow up for liver 
abnormalities. There are no other AESIs in this study.


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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. Treatment-emergent AEs will be assessed by the 
investigator for severity, relationship to the investigational product, possible etiologies, and 
whether the event meets criteria of an SAE and therefore requires immediate notification to 
the sponsor (Section 5.5). See Section 5.2 for the definition of SAEs and Appendix 10.3 for 
guidelines for assessment of severity and relationship. If a TEAE evolves into a condition 
that meets the regulatory definition of “serious,” it will be reported in the eCRF.
5.4.1
Time Period for Collection of Adverse Events
All AEs and SAEs will be collected from the time of admission to the clinical unit (Day -2) 
throughout the treatment period and including the follow-up period (28 ±4 days after the last 
dose of investigational product (inpatient Visit 13).
5.4.2
Follow up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
MedImmune retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. Updates regarding SAEs that were 
ongoing at the time of the subject’s completion of study participation should be submitted to 
the study representative using a paper SAE follow-up form.
5.5
Reporting of Serious Adverse Events
Serious adverse events have to be reported whether or not they are considered casually 
related to the investigational product or to the study procedure(s). All SAEs will be recorded 
in the CRF. 
If any SAE occurs during the course of the study, the investigator or other site personnel will 
inform the appropriate sponsor representative(s) within 1 day, ie, immediately but no later 
than 24 hours of when he/she becomes aware of the event. The designated sponsor 
representative works with the investigator to ensure that all the necessary information is 
provided to the sponsor’s patient safety data entry site within 1 calendar day of initial receipt 
for fatal and life threatening events and within 5 calendar days of initial receipt for all other 
SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow up is undertaken immediately. Investigators or other site personnel will inform 


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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/she becomes aware of 
the event.
Once the investigator or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated e-mail alert is sent to 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 in this study is defined as a subject receiving a dose of investigational product
that is greater than the dose that was intended to be given:
•
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
•
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose with a MedImmune investigational product occurs during the course of the 
study, then the investigator or other site personnel inform appropriate sponsor representatives 
immediately but no later than 24 hours of when he/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.
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 TBL ≥2 × ULN may need to be 
reported as SAEs. Please refer to Appendix 10.5 for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s law.


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5.6.3
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor.
5.6.3.1
Maternal Exposure
Women of childbearing potential in this study who are sexually active with a nonsterilized
male partner are required to use 2 forms of contraception (with at least 1 highly effective 
method) as described in the inclusion criteria (Section 4.1.2 and Appendix 10.2). Pregnancy 
should be avoided for at least 28 days after receiving investigational product or until the 
subject completes participation in the study, whichever is longer. If a subject becomes 
pregnant during the course of the study, investigational product should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed 
up and documented even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate sponsor representatives within 1 day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided within 1 to 5 calendar days for SAEs (Section 5.5) and within 
30 days for all other pregnancies.
The same timelines apply when outcome information is available.
Any subject who becomes pregnant during the course of the study will be followed so that 
pregnancy outcome can be determined and reported to the sponsor and the regulatory 
authorities.


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6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review 
and discuss the requirements of the Clinical Study Protocol (CSP) and related documents 
with the investigational staff and also train them in any study-specific procedures and 
system(s) utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study
(medical, nursing, and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site 
including visits to do the following:
•
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.


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6.2.2
Study Agreements
The Principal Investigator at each/the 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 CSP and the Clinical Study Agreement, the terms of CSP
shall prevail with respect to the conduct of the study and the treatment of subjects. In all 
other matters not relating to study conduct or treatment of subjects, the terms of the Clinical 
Study Agreement shall prevail.
Agreements between MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place or subjects are enrolled.
6.2.3
Archiving of Study Documents
The Investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through the last protocol-specified visit or assessment (including telephone contact)
or assessed for the primary end point of the study, regardless of the number of doses of 
investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow up (Section 4.1.5 and Section 4.1.6).
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit or assessment (including telephone contact) for the last subject in the study. 
6.4
Data Management 
Data management will be performed by MedImmune Data Management staff or other party 
according to the Data Management Plan.
A web-based data capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.


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6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the Principal Investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician with 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 CSP
and the principal investigator is not available, the treating physician or health care provider 
can contact a medical monitor through this system, which is managed by a third party 
vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
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/GCP, and applicable regulatory 
requirements.
7.2
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc will only be collected with the subject’s informed consent. The ICF will 
incorporate or, in some cases, be accompanied by a separate document incorporating wording 
that describes how subject data will be collected, used, and distributed in compliance with 
relevant data protection and privacy legislation.
 
 
7.3
Ethics and Regulatory Review
The IEC responsible for each site must review and approve the final CSP including the final 
version of the ICF and any other written information and/or materials to be provided to the 
subjects. The IEC must also approve all advertising used to recruit subjects for the study. The 


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investigator or representative is responsible for submitting these documents to the applicable 
IEC and distributing them to the study-site staff.
The opinion of the IEC should be given in writing. The investigator should submit the written 
approval to MedImmune before enrollment of any subject into the study. 
The IEC should approve all advertising used to recruit subjects for the study.
MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be reapproved by the IEC annually.
Before enrollment of any subject into the study, the final CSP including the final version of 
the ICF is approved by the national regulatory authority or a notification to the national 
regulatory authority is done, according to local regulations. MedImmune will handle the 
distribution of any of these documents to the national regulatory authorities.
MedImmune will provide Regulatory Authorities, IEC and Principal Investigators with safety 
updates/reports according to local requirements including suspected unexpected serious 
adverse reactions, where relevant.
Each Principal Investigator is responsible for providing the IEC with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with the 
investigational product. MedImmune will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
7.4
Informed Consent
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 each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
•
Ensure each subject provides signed and dated ICF before conducting any procedure 
specifically for the study
•
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File
•
Ensure a copy of the signed ICF is given to the subject


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•
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IEC
7.5
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
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 in a new version of the study protocol,
where required.
The amendment is to be approved by the relevant 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 IEC see Section 7.3.
If a protocol amendment requires a change to a site’s ICF, MedImmune and the site’s IEC 
are to approve the revised ICF before the revised form is used. The IEC must also approve 
advertising and any other written information and/or materials resulting from the change to 
the protocol.
If local regulations require, any administrative change will be communicated to or approved 
by each IEC.
7.6
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IEC may perform 
audits or inspections at the center including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents; to determine whether these activities were conducted; and to confirm that data 
were recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines 
of the ICH, and any applicable regulatory requirements. The investigator will contact 
MedImmune immediately if contacted by a regulatory agency about an inspection at the site.


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8
REFERENCES
Bagger et al, 2015
Bagger JI, Holst JJ, Hartmann B, Andersen B, Knop FK, Vilsbøll T. Effect of 
oxyntomodulin, glucagon, GLP-1, and combined glucagon +GLP-1 infusion on food intake, 
appetite, and resting energy expenditure. J Clin Endocrinol Metab. 2015;100(12):4541-52.
CDER, 2005
Center for Drug Evaluation and Research. Byetta Pharmacology Review. 2005.9.
DeFronzo, 2017
DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. 
Diabetes Obes Metab. 2017 Apr 22. [epub ahead of print].
Forxiga Summary of Product Characteristics, 2017
Forxiga [Summary of Product Characteristics on the Internet]. Södertälje (Sweden): 
AstraZeneca AB, 2017 [revised 2017 May 02; cited 2017 Aug 10]. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002322/WC500136026.pdf.
Frías et al, 2016
Frías JP, Guja C, Hardy E, Ahmed A, Dong F, Öhman P, et al. Exenatide once weekly plus 
dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 
diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, 
multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 
2016 Dec;4(12):1004-16.
Habegger et al, 2013
Habegger KM, Stemmer K, Cheng C, Müller TD, Heppner KM, Ottaway N, et al. Fibroblast 
growth factor 21 mediates specific glucagon actions. Diabetes. 2013;62(5):1453-63.
Lynch et al, 2014
Lynch AM, Pathak N, Pathak V, O'Harte FP, Flatt PR, Irwin N, et al. A novel DPP IV-
resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-
protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor 
activation. Diabetologia. 2014;57(9):1927-36.


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Petersen et al, 2005
Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of non-
alcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight 
reduction in patients with type 2 diabetes. Diabetes. 2005 Mar;54(3):603-8.
Rosenstock and Ferrannini, 2015
Rosenstock J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, 
and Preventable Safety Concern with SGLT2 Inhibitors. Diabetes Care. 2015
Sep;38(9):1638-42.
Qiu et al, 2017
Qiu H, Novikov A, Vallon V. Ketosis and diabetic ketoacidosis in response to SGLT2 
inhibitors: basic mechanisms and therapeutic perspectives. Diabetes Metab Res Rev. 2017 
Jul;33(5).
Skyder et al, 2017
Skyder JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et al. Differentiation of 
diabetes by pathophysiology, natural history, and prognosis. Diabetes. 2017 Feb;66(2):241-
55.
Tonneijck et al, 2016
Tonneijck L, Smits MM, Muskiet MH, Hoekstra T, Kramer MH, Danser AH, et al. Acute 
renal effects of the GLP-1 receptor agonistexenatide in overweight type 2 diabetes patients: a 
randomised, double-blind placebo-controlled trial. Diabetologia. 2016 Jul;59(7):1412-21.
Wynne et al, 2006
Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, et al. Oxyntomodulin 
increases energy expenditure in addition to decreasing energy intake in overweight and obese 
humans: a randomised controlled trial. Int J Obes. 2006;30(12):1729-36.
9
CHANGES TO THE PROTOCOL 
Not applicable; this is an original protocol.


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10 APPENDICES
10.1
Appendix 1 - Signatures
Sponsor Signature(s)
An exploratory Phase 2a randomized, placebo-controlled, double-blind study to evaluate the 
efficacy and safety of MEDI0382 versus placebo in overweight/obese subjects with type 2 
diabetes mellitus inadequately controlled with dapagliflozin and metformin 
I agree to the terms of this protocol.
Signature and date: 
Electronic Signature Attached
Boaz Hirshberg, MD
Clinical Therapeutic Area Head
One MedImmune Way, Gaithersburg MD, 20878, USA 
Telephone number: 1-301-398-0645


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Signature of Principal Investigator
An exploratory Phase 2a randomized, placebo-controlled, double-blind study to evaluate the 
efficacy and safety of MEDI0382 versus placebo in overweight/obese subjects with type 2 
diabetes mellitus inadequately controlled with dapagliflozin and metformin 
I, the undersigned, have reviewed this protocol, and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Conference on Harmonization guidelines on Good 
Clinical Practice, any applicable laws and requirements, and any conditions required by a 
regulatory authority and/or /Independent Ethics Committee (IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and IEC, 
and must be approved by the IEC prior to implementation except when necessary to 
eliminate immediate hazards to the subjects or when the change(s), as deemed by the 
sponsor, involves only logistical or administrative changes. Documentation of IEC approval 
must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:  
Address including postal code: 
  
Telephone number: 
Site/Center Number (if available)
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in
this protocol may be subject to change and revision.


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


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


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


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


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10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases
and Food and Allergy Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
The National Institute of Allergy and Infectious Diseases and the Food and Allergy 
Anaphylaxis Network define anaphylaxis as a serious allergic reaction that is rapid in onset 
and may cause death (Error! Reference source not found.). 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, 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
b. Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
c.
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. Persistent GI symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline
Reference:
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, Brown SG, et 
al. Second symposium on the definition and management of anaphylaxis: summary report—Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. J Allergy Clin Immunol. 2006 Feb;117(2):391-7.


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10.5
Appendix 5 - Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law (HL). 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 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 AEs and SAEs 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 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 CSP.
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
References:
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’:http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
nces/UCM174090.pdf


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10.6
Appendix 6 - Biological Samples
Storage, Reuse and Destruction of Biological Samples
Biological samples will be stored for a maximum of 15 years from the date of the Last 
Subject’s Last Visit, after which they will be destroyed. 
The results of biomarker research will be reported either in the Clinical Study Report itself or 
as an addendum, or separately in a scientific report or publication. The results of this 
biomarker research may be pooled with biomarker data from other studies with the study 
drug to generate hypotheses to be tested in future research. Antidrug antibody samples will 
be stored for up to 2 years after marketing approval.
Labelling and Shipment of Biological Samples
The principal investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A 
criteria).
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with MedImmune and appropriate 
labelling, shipment and containment provisions are approved.
Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The principal investigator at each study site keeps full traceability of collected biological 
samples from the subjects while in storage at the study site until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival. The sample receiver keeps full 
traceability of the samples while in storage and during use until used or disposed of or until 
further shipment and keeps documentation of receipt of arrival.
MedImmune keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the Translational Sciences Biorepository 
during the entire life cycle.


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Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
Signed By 
Meaning of Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.  
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MedImmune 
Statistical Analysis Plan for Protocol D5670C00007 
MEDI0382 
 
03JUL2018; Final version 0.1 
CONFIDENTIAL AND PROPRIETARY 
1 of 17 
SAP template version 3.0 
Statistical Analysis Plan 
An Exploratory Phase 2a Randomized, Placebo-controlled, 
Double-blind Study to Evaluate the Efficacy and Safety of 
MEDI0382 versus Placebo in Overweight/Obese Subjects 
with Type 2 Diabetes Mellitus Treated with Dapagliflozin 
and Metformin 
 
Protocol Number: D5670C00007 


MedImmune 
Statistical Analysis Plan for Protocol D5670C00007 
MEDI0382 
 
03JUL2018; Final version 0.1 
CONFIDENTIAL AND PROPRIETARY 
2 of 17 
SAP template version 3.0 
TABLE OF CONTENTS 
1 
INTRODUCTION ...........................................................................................................6 
2 
STUDY OVERVIEW .....................................................................................................6 
2.1 
Study Objectives ...................................................................................................6 
2.1.1Primary Study Objective(s) ..........................................................................6 
2.1.2Secondary Study Objectives .........................................................................6 
2.1.3Exploratory Study Objectives .......................................................................6 
2.2 
Study Design .........................................................................................................7 
2.3 
Treatment Assignment and Blinding ....................................................................8 
2.4 
Sample Size...........................................................................................................9 
3 
STATISTICAL METHODS ...........................................................................................9 
3.1 
General Considerations .........................................................................................9 
3.2 
Analysis Populations...........................................................................................10 
3.3 
Study Subjects.....................................................................................................11 
3.3.1Subject Disposition and Completion Status ...............................................11 
3.3.2Demographics and Baseline Characteristics ...............................................11 
3.3.3Study Drug Exposure ..................................................................................11 
3.3.4Concomitant Medications ...........................................................................11 
3.4 
Efficacy Analyses ...............................................................................................11 
3.4.1Primary Efficacy Endpoint(s) and Analyses ...............................................11 
3.4.1.1 
Primary Efficacy Endpoint(s) ...................................................11 
3.4.1.2 
Handling of Dropouts and Missing Data ..................................12 
3.4.1.3 
Primary Efficacy Analysis ........................................................12 
3.4.2Secondary Efficacy Endpoint(s) and Analyses ...........................................12 
3.4.2.1 
Secondary Efficacy Endpoint(s) ...............................................12 
3.4.2.2 
Handling of Dropouts and Missing Data ..................................13 
3.4.2.3 
Secondary Efficacy Analyses ...................................................13 
3.4.3Exploratory Efficacy Endpoint(s) and Analyses ........................................13 
3.4.3.1 
Exploratory Efficacy Endpoint(s) .............................................13 
3.4.3.2 
Exploratory Efficacy Analyses .................................................13 
3.5 
Pharmacodynamic Exploratory Endpoint(s) and Analyses ................................13 
3.5.1.1 
Pharmacodynamic Endpoint(s) .................................................13 
3.5.1.2 
Analysis of Pharmacodynamic Endpoint(s) .............................14 
3.6 
Safety Analyses...................................................................................................14 
3.6.1Adverse Events and Serious Adverse Events .............................................14 
3.6.2Adverse Events of Special Interest .............................................................14 
3.6.3Deaths and Treatment Discontinuations due to Adverse Events ................14 


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3.6.4Clinical Laboratory Evaluation ...................................................................15 
3.6.5Other Safety Evaluations ............................................................................15 
3.6.5.1 
Vital Signs .................................................................................15 
3.6.5.2 
Electrocardiogram .....................................................................15 
 
 
3.8 
Pharmacokinetics ................................................................................................16 
4 
INTERIM ANALYSIS..................................................................................................17 
5 
VERSION HISTORY ...................................................................................................17 
 
LIST OF TABLES 
Table 3.2-1 
Analysis Populations ............................................................................10 
 
 


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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ABPM 
Ambulatory blood pressure monitoring 
 
 
AE 
Adverse event 
AUC 
Area under the concentration-time curve 
CGM 
Continuous glucose monitoring 
Cmax 
Maximum observed concentration 
ECG 
Electrocardiogram 
FFA 
Free fatty acids 
FPG 
Fasting plasma glucose 
GLP-1 
Glucagon-like peptide-1 
HbA1c 
Hemoglobin A1c 
ITT 
Intent-to-Treat 
IXRS 
Interactive voice/web response system 
LOCF 
Last observation carried forward 
MAGE 
Mean amplitude of glucose excursion 
MMTT 
Mixed-meal tolerance test 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
SPP 
Statistical Programming Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
T2DM 
Type 2 diabetes mellitus 


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Abbreviation or 
Specialized Term 
Definition 
tmax 
Time to maximum-observed concentration 
ULN 
Upper limit of normal range 


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1 
INTRODUCTION 
This document describes the statistical analysis methodology for protocol D5670C00007, a 
Phase 2a exploratory randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of MEDI0382 versus placebo in overweight/obese subjects with type 2 
diabetes mellitus (T2DM) treated with dapagliflozin and metformin. This document details 
the statistical summaries relating to each study objective and describes the general 
conventions and definitions that will be used. In addition, a set of table templates and 
specifications will be included in a statistical programming plan (SPP) to complement this 
document. 
2 
STUDY OVERVIEW 
2.1 
Study Objectives 
2.1.1 
Primary Study Objective(s) 
To compare the change in glucose area under the concentration-time curve (AUC) as 
measured by a standardized mixed meal tolerance test (MMTT) in subjects treated with 
dapagliflozin and metformin receiving MEDI0382 or placebo for 28 days 
2.1.2 
Secondary Study Objectives 
 To compare the safety and tolerability profile of MEDI0382 (titrated up to a dose 
level of 300 μg subcutaneous [SC]) compared to placebo after 28 days of treatment in 
subjects treated with dapagliflozin and metformin 
 To evaluate the pharmacokinetics (PK) profile of MEDI0382 and dapagliflozin (in 
subjects treated with dapagliflozin, metformin, and MEDI0382) and dapagliflozin (in 
subjects treated with dapagliflozin, metformin, and placebo) 
 
 
 
 
 To evaluate 24-hour glucose control as measured by continuous glucose monitoring 
(CGM) in subjects treated with dapagliflozin and metformin receiving MEDI0382 or 
placebo for 28 days 
2.1.3 
Exploratory Study Objectives 
 To compare additional measures of glucose control (fasting plasma glucose [FPG] 
and hemoglobin A1c [HbA1c]) in subjects treated with dapagliflozin and metformin 
receiving MEDI0382 or placebo for 28 days 


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 To evaluate pancreatic and incretin hormone AUC profiles (ie, active glucagon-like 
peptide-1 [GLP-1], glucagon, insulin, and c-peptide) as measured by MMTT in 
subjects treated with dapagliflozin and metformin receiving MEDI0382 or placebo 
for 28 days 
 To compare the fasting free fatty acid (FFA) levels in subjects treated with 
dapagliflozin and metformin receiving MEDI0382 or placebo for 28 days 
 To compare plasma ketone profile (β-hydroxybutyrate) in subjects treated with 
dapagliflozin and metformin receiving MEDI0382 or placebo for 28 days 
 To compare the change in body weight after 28 days of treatment with MEDI0382 or 
placebo in subjects treated with dapagliflozin and metformin 
 To evaluate 24-hour urinary glucose excretion in subjects treated with dapagliflozin 
and metformin receiving MEDI0382 or placebo 
2.2 
Study Design 
This is an exploratory randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of MEDI0382 versus placebo in overweight/obese subjects with T2DM 
treated with dapagliflozin and metformin dual therapy. Subjects will participate in the study 
for up to 20 weeks, including a screening period of up to 60 days, a 4-week run-in period (for 
subjects on metformin monotherapy only), a 4-week treatment period, and a 4-week 
post-treatment follow-up period. 
The study will enroll subjects with T2DM treated either with metformin monotherapy or with 
metformin and dapagliflozin dual therapy. After the screening period of up to 60 days, 
subjects previously treated with metformin monotherapy only will enter an open-label, run-in 
period where subjects will be administered oral dapagliflozin 10 mg a day for 4 weeks. 
Enrolled subjects who are already treated with metformin and dapagliflozin dual therapy will 
continue this dual therapy throughout the study and can be randomized after the screening 
period without entering the run-in period. All subjects (ie, on monotherapy and dual therapy) 
entering the double-blind treatment period will receive dapagliflozin 10 mg a day. (Figure 
2.2-1) 
Figure 2.2-1 Study Flow Diagram 


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2.3 
Treatment Assignment and Blinding 
An Interactive voice/web response system (IXRS) will be used for assignment of 
dapagliflozin tablet bottles (where required), randomization to a treatment group, and 
assignment of blinded MEDI0382 or placebo 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 IXRX provides the assignment of investigational 
product kit number to the subject. 
Eligible subjects will be randomized at a 1:1 ratio following screening to receive either 
MEDI0382 SC or placebo SC. The IXRS will assign a unique randomization code and 
treatment group to the subject at each randomization. Subjects who withdraw from the study 
may be replaced, if deemed necessary by the medical monitor, to ensure that safety data are 
collected on a sufficient number of subjects. 
This is a double-blind study in which MEDI0382 and placebo are not identical in the 
prefilled syringe titration volumes. Neither the subject nor any of the investigator or sponsor 
staff who are involved in the treatment or clinical evaluation of the subjects will be aware of 
the treatment received (ICH E9). 


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The different fill volumes of investigational product (MEDI0382 and placebo) and the 
relative position of the plunger rods will be visually distinct during administration. To 
maintain the blind, investigational product (MEDI0382 and placebo) prefilled syringes will 
be handled by an unblinded investigational product manager or unblinded study personnel 
that will not be involved in the treatment or clinical evaluation of subjects. An unblinded 
qualified designee may administer investigational product to subjects during in-clinic visits. 
An independent investigational product monitor will also be unblinded to perform 
investigational product accountability. In the event that a 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. If the treatment allocation for a subject 
needs to be known to treat an individual subject for an adverse event (AE), the investigator 
must notify the sponsor immediately. The site will maintain a written plan detailing which 
staff members are blinded/unblinded and the process of investigational product 
administration used to maintain the blind. 
2.4 
Sample Size 
A total of 46 subjects are planned for the study. Each of the 2 treatment groups will be 
randomized at a 1:1 ratio to receive (a) MEDI0382 with dapagliflozin and metformin 
administered simultaneously or (b) placebo with dapagliflozin and metformin administered 
simultaneously. A sample size of 23 subjects in each treatment group will provide a study 
power > 95% to detect a difference of 30% between treatment groups in relative change from 
baseline in glucose AUC0-4h at a two-sided alpha of 5%, assuming a common standard 
deviation (SD) of 20%. This sample size will also provide a study power > 95% to detect a 
difference of 225 hr•mg/dL between treatment groups in absolute change from baseline in 
glucose AUC0-4h at a two-sided alpha of 5%, assuming a common SD of 150 hr•mg/dL. The 
SD assumptions are based the result of 300 μg cohorts in a prior study (D5670C00002). 
3 
STATISTICAL METHODS 
3.1 
General Considerations 
Data will be presented in data listings sorted by treatment group, subject number, and date 
collected, where appropriate. Tabular summaries will be presented. Categorical data will be 
summarized by the number and percentage of subjects within each category. In general, 
continuous variables will be summarized by descriptive statistics including mean, standard 
deviation, median, minimum, and maximum. For some variables, the geometric mean and 
95% CI will be presented. 
All available data will be included in the analyses and missing data will not be imputed, 
except in a last observation carried forward (LOCF) analysis and as specified in the 


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calculation of the AUC values. When LOCF is used to impute for missing post-baseline data, 
only post-baseline data will be carried forward (eg, baseline data will not be carried forward). 
Unless otherwise specified, baseline values will be defined as the last valid assessment prior 
to the first administration of study medication (MEDI0382 or placebo). 
All statistical tests will be 2-sided at an alpha level of 5% unless stated otherwise. There will 
be no adjustment for multiplicity. 
Data analyses will be performed using SAS
® version 9.3 or higher (SAS Institute Inc., Cary, 
NC). The analytical results generated from SAS programs will follow MedImmune SAS 
programming standards and will be validated according to MedImmune SAS validation 
procedures. 
3.2 
Analysis Populations 
The analysis populations are defined in Table 3.2-1. 
Table 3.2-1 
Analysis Populations 
Population 
Description 
Intent-to-treat (ITT) 
Population 
Randomized subjects who receive any investigational product 
(MEDI0382 or placebo) analyzed according to their randomized 
treatment group. 
As-treated 
Population 
Subjects who receive any investigation product (MEDI0382 or 
placebo) analyzed according to the treatment they actually receive. 
MEDI0382 PK 
Population 
Subjects who receive at least 1 dose of investigational product 
(MEDI0382 or placebo) and have at least 1 MEDI0382 PK sample 
taken that is above the lower limit of quantitation. 
Dapagliflozin PK 
Population 
Subjects who receive at least 1 dose of investigational product 
(dapagliflozin or placebo) and have at least 1 dapagliflozin PK sample 
for dapagliflozin taken that is above the lower limit of quantitation. 
Ketone PK 
Population 
Subjects who receive at least 1 dose of investigational product 
(MEDI0382 or dapagliflozin or placebo) and have at least 1 ketone PK 
sample taken that is above the lower limit of quantitation. 
 
 
 
 


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3.3 
Study Subjects 
3.3.1 
Subject Disposition and Completion Status 
A summary of subject eligibility and randomization as well as treatment group received 
(including a summary of subjects randomized but not treated) will be provided. In addition, 
disposition of subjects throughout the study with respect to completion of treatment and end 
of study will be provided. 
3.3.2 
Demographics and Baseline Characteristics 
Demographic information related to sex, age, race, weight, height, and body mass index 
(BMI) will be presented by treatment group and for all subjects combined. A summary of 
baseline disease characteristics may include, but not be limited to duration of T2DM, 
diabetes complications, HbA1c, fasting plasma glucose, eGFR, background therapy for 
diabetes (eg, metformin monotherapy or metformin + dapagliflozin). 
3.3.3 
Study Drug Exposure 
The duration of exposure (number of days dosed) of MEDI0382 and dapagliflozin will be 
summarized by treatment group with descriptive statistics and by frequency. 
3.3.4 
Concomitant Medications 
Concomitant medications will be coded using current World Health Organization Drug 
Dictionary. The number and percentage of subjects who took concomitant medications will 
be summarized by the highest anatomical therapeutic chemical class and preferred term by 
treatment group for the As-treated Population. The summary of concomitant medications will 
include all concomitant medications taken on or after the date of first dose of study 
medication or any concomitant medication started prior to first dose study medication that 
continued beyond the date of first dose of study medication. 
3.4 
Efficacy Analyses 
3.4.1 
Primary Efficacy Endpoint(s) and Analyses 
3.4.1.1 
Primary Efficacy Endpoint(s) 
 Change from baseline (Day -1) to the end of 28 days of treatment (Day 28) in glucose 
AUC from 0 to 4 hours (AUC0-4h) as measured by a MMTT 
 Percentage change from baseline (Day -1) to the end of 28 days of treatment (Day 28) 
in glucose AUC0-4h as measured by a MMTT 


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3.4.1.2 
Handling of Dropouts and Missing Data 
No missing data imputation will be used for the primary efficacy analysis since there is only 
one post-baseline data collected for the primary efficacy endpoint. If any glucose values used 
in the calculation of the glucose AUC are missing, the AUC will be calculated as described 
in the SPP. 
3.4.1.3 
Primary Efficacy Analysis 
The primary efficacy analysis will be based on the ITT population. The primary endpoints, 
change and % change from baseline to the end of 28 days of treatment in glucose AUC0-4h as 
measured by a MMTT, will be summarized by treatment group. Statistical comparisons of 
these endpoints between MEDI0382 and placebo treatment groups will be performed using 
an analysis of covariance by adjusting baseline value and treatment group. 
3.4.2 
Secondary Efficacy Endpoint(s) and Analyses 
3.4.2.1 
Secondary Efficacy Endpoint(s) 
 Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in 
glucose AUC at 24 hours (AUC24h) as measured by CGM 
 Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in 24-
hour mean glucose as measured by CGM 
 Change from baseline to the end of dosing at each dose level (Days 7, 14, and 28) in SD 
of 24-hour glucose readings as measured by CGM 
 Change from baseline to Days 7, 14, and 28 in the coefficient of variation (CV) (ratio of 
SD:mean over 24 hours) of glucose readings as measured by CGM 
 Change from baseline to Days 7, 14, and 28 in the mean amplitude of glucose excursion 
(MAGE) of 24-hour glucose readings as measured by CGM 
 Change from baseline to Days 7, 14, and 28 in the percentage of 24-hour glucose 
readings obtained from CGM that fall within the euglycemic range of ≥ 70 mg/dL 
(≥ 3.9 mmol/L) and ≤ 180 mg/dL (≤ 10.0 mmol/L) 
 Change from baseline to Days 7, 14, and 28 in the percentage of 24-hour glucose 
readings obtained from CGM that fall within hyperglycemic (high glucose) range of 
> 180 mg/dL (> 10.0 mmol/L) 
 Change from baseline to Days 7, 14, and 28 in the percentage of 24-hour glucose 
readings obtained from CGM that fall within the hypoglycemic range of < 70 mg/dL (< 
3.9 mmol/L) 
 Change from baseline to Days 7, 14, and 28 in the percentage of 24-hour glucose 
readings obtained from CGM that fall within the clinically significant hypoglycemic 
range of < 54 mg/dL (3.0 mmol/L) 


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3.4.2.2 
Handling of Dropouts and Missing Data 
LOCF approach will be used to handle missing data for all secondary efficacy and 
pharmacodynamics (PD) analyses. If any values used in the calculation of the AUC are 
missing, the AUC will be calculated as described in the SPP. 
3.4.2.3 
Secondary Efficacy Analyses 
Secondary efficacy analysis will be based on the ITT population. The secondary efficacy 
endpoints will be summarized by treatment group at each time point and analyzed similarly 
to the analysis of primary efficacy endpoint with LOCF approach to handle missing data. 
3.4.3 
Exploratory Efficacy Endpoint(s) and Analyses 
3.4.3.1 
Exploratory Efficacy Endpoint(s) 
 Change from baseline (Day -1) to Day 28 in FPG 
 Change from baseline (Day -2) to Day 28 in HbA1c 
 Change from baseline (Day 1) to Day 29 in body weight (kg) 
 Percentage change from baseline (Day 1) to Day 29 in body weight (kg) 
 Proportion of subjects achieving ≥ 5% body weight loss from baseline (Day 1) to Day 29 
3.4.3.2 
Exploratory Efficacy Analyses 
Exploratory efficacy analyses will be based on the ITT population. The change from baseline 
endpoints will be summarized by treatment group at each time point and the final treatment 
evaluation time analyzed similar to the analysis of primary efficacy endpoint with LOCF 
approach to handle missing data. 
The proportion of subjects achieving ≥ 5% body weight loss from baseline (Day 1) to Day 29 
will be analyzed using a logistic regression by adjusting baseline value and treatment group. 
3.5 
Pharmacodynamic Exploratory Endpoint(s) and Analyses 
3.5.1.1 
Pharmacodynamic Endpoint(s) 
 Change from baseline (Day -1) to Day 28 in GLP-1, glucagon, insulin, and c-peptide 
AUC0-4h as measured by MMTT 
 Change from baseline (Day -1) to Days 7, 14, and 28 in fasting FFA level 
 β-hydroxybutyrate profile to include AUC0-inf, AUC0-last, Cmax, and tmax  
 Total glucose excreted in urine collected for 24 hours on Days 1 and 28 


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3.5.1.2 
Analysis of Pharmacodynamic Endpoint(s) 
PD analysis will be based on the ITT population. The change from baseline endpoints for 
GLP-1, glucagon, insulin, and c-peptide AUC0-4h and for fasting FFA levels will be 
summarized by treatment group at each time point and the final treatment evaluation time 
analyzed similar to the analysis of primary efficacy endpoint with LOCF approach to handle 
missing data. 
Descriptive statistics will be provided for β-hydroxybutyrate parameters: AUC0-inf, AUC0-last, 
Cmax, and tmax at each time point and total glucose urinary excretion (Days 1 and 28). The β-
hydroxybutyrate parameters will be calculated by the Pharmacokinetics group following the 
calculations provided below in the Pharmacokinetics Section. 
3.6 
Safety Analyses 
3.6.1 
Adverse Events and Serious Adverse Events 
Adverse events (AE) will be coded by MedDRA version 20.0 or higher. Analysis of adverse 
events will include the type, incidence, severity and relationship to study investigational 
product (MEDI0382 or dapagliflozin) summarized by MedDRA System Organ Class (SOC) 
and Preferred Term by treatment group as well as for overall treatments. The AEs summaries 
will include only treatment-emergent AEs; ie, those occurring after initial receipt of 
investigational product. Subjects will be counted once for specific PT or MedDRA SOC 
when calculating incidence. If the same AE Preferred Term occurs multiple times within a 
subject, the highest severity and level of relationship observed will be reported. Non-
treatment-emergent AEs/serious adverse events will be presented in the listings. 
3.6.2 
Adverse Events of Special Interest 
Hepatic function abnormality meeting the definition of Hy’s law is considered an adverse 
event of special interest. Number and proportion of subjects who meet Hy’s law criteria: 
aspartate transaminase or alanine transaminase ≥ 3 × upper limit of normal range (ULN) 
together with total bilirubin ≥ 2 × ULN will be summarized by treatment. 
3.6.3 
Deaths and Treatment Discontinuations due to Adverse Events 
Death and AEs resulting in permanent discontinuation from the study drug will be 
summarized by treatment. The summary includes overall, categorized by MedDRA system 
organ class, and preferred term. 


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3.6.4 
Clinical Laboratory Evaluation 
Hematology, serum chemistry, and urinalysis laboratory evaluations will be performed 
during the study. The hematology and serum chemistry (including amylase, lipase, lactate, 
and calcitonin) parameters as well as their changes from baseline will be summarized with 
descriptive statistics (number of subjects, mean, and standard deviation, median, minimum 
and maximum) by treatment group at each time point. The urinalysis results will be listed. 
The hematology and serum chemistry results will also be classified as low, normal, or high. 
The urinalysis results will be classified as normal or abnormal. The shift from baseline 
hematology, serum chemistry, and urinalysis results will be summarized by treatment group 
at each time point. 
3.6.5 
Other Safety Evaluations 
3.6.5.1 
Vital Signs 
Vital signs including pulse rate (beats/min), blood pressure (mm Hg), temperature (oC), and 
respiratory rate (breaths/min), as well as the change from baseline for each of those 
parameters will be descriptively summarized by treatment group at each time point. 
The 24-hour average ambulatory blood pressure monitoring (ABPM) pulse rate (beats/min) and 
systolic and diastolic blood pressure (mm Hg) from the ABPM will be summarized by treatment 
group at each time point. The change from baseline (Day -2) for the 24-hour average pulse rate 
and systolic and diastolic blood pressure at each post-baseline visit will be analyzed with an 
analysis of covariance with an effect for treatment and the baseline value as the covariate. The 
above summary and analyses will also be conducted for pulse rate, systolic blood pressure, and 
diastolic blood pressure during asleep and awake periods. 
3.6.5.2 
Electrocardiogram 
Electrocardiogram parameters will be assessed using standard 12-lead electrocardiography. 
The following Electrocardiogram (ECG) parameters as well as the change from baseline for 
each of those parameters will be reported and descriptively summarized by treatment group 
at each of the specified time points: Heart rate (beats/min), RR (msec), PR (msec), QRS 
(msec), and QT (msec) intervals and the QT corrected interval.  
The normality/abnormality of the ECG evaluation will be summarized using frequency tables 
of the number of subjects with a normal/abnormal ECG evaluation at each scheduled visit.  
 
 
 
 


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3.8 
Pharmacokinetics 
For MEDI0382, Dapagliflozin and β-hydroxybutyrate, actual time of sampling, rather than 
nominal (planned) sampling time, will be used to derive PK parameters. Nominal sampling 
time will be used for the summary of PK concentrations and will be utilized in the descriptive 
summaries in mean plots. Missing PK parameters will not be imputed. 
For subjects in each treatment group the following pharmacokinetic parameters will be 
determined from the plasma concentration-time data for MEDI0382, dapagliflozin and β-
hydroxybutyrate if data allow. The pharmacokinetic parameters will be calculated by 
standard non-compartmental analysis according to current working practices and using 
Phoenix WinNonlin 6.3 or equivalent: 
1. Cmax: The first occurrence of the maximum observed plasma concentration 
determined directly from the raw concentration-time data 


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2. tmax: The first time at which Cmax is observed will be determined directly from the raw 
concentration-time data. 
3. C: trough concentrations from the plasma concentration-time data at the end of the 
dosing interval (i.e. 24 hours). 
4. AUCτ: Area under the plasma concentration time curve at the end of the dosage 
interval τ. 
5. Ro: observed accumulation ratio will be calculated using both the AUC and Ctrough 
methods, where data allows, as follows: Ro = AUCdayi/AUCday1 and Ro = 
Cdayi/Cday1. 
If data allows additional parameters may be derived for MEDI0382 and Dapagliflozin such 
as t half: the apparent terminal elimination half-life (t1/2) obtained as the ratio of ln2/z, 
where z is the terminal phase rate constant estimated by linear regression analysis of the log 
transformed concentration-time data; and Cl/F: the apparent clearance calculated as 
CL/F=Dose/AUC(0-∞). 
All the derived parameters described above will be listed. For each of these parameters, 
except for tmax, the following summary statistics will be calculated for each active treatment 
group: median, maximum, minimum, arithmetic mean, standard deviation, CV, geometric 
mean. For tmax, the following summary statistics will be calculated for each active treatment 
group:  median, maximum, minimum, arithmetic mean.  
Individual Ctrough will be listed by treatment and day and will be summarized as maximum, 
minimum, arithmetic mean and geometric mean. 
Subjects who have at least one measurable concentration time point of investigational 
product will be used for this analysis. 
4 
INTERIM ANALYSIS 
No interim analysis is planned. 
5 
VERSION HISTORY 
Version 
Date 
Summary of Changes 
Reason for Change 
1.0 
03JUL2018 
Initial document 
Initial document 
 


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Sent: 7/6/2018 2:32:29 PM
Viewed: 7/6/2018 2:39:39 PM 
Signed: 7/6/2018 6:32:20 PM
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Security Level: Email, Account Authentication 
(None)
Using IP Address: 104.129.194.127
Sent: 7/6/2018 2:32:29 PM
Viewed: 7/6/2018 3:28:16 PM 
Signed: 7/6/2018 3:28:35 PM
Electronic Record and Signature Disclosure: 
      Accepted: 7/6/2018 3:28:16 PM
      ID: 1d2851a7-0b74-4af4-857c-4991781b941b
AstraZeneca
Security Level: Email, Account Authentication 
(None)
Using IP Address: 104.129.194.134
Sent: 7/6/2018 2:32:30 PM
Viewed: 7/6/2018 2:32:41 PM 
Signed: 7/6/2018 2:32:47 PM
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
 
(None)
Using IP Address: 104.129.194.70
Sent: 7/6/2018 2:32:30 PM
Viewed: 7/10/2018 6:12:31 PM 
Signed: 7/10/2018 6:12:42 PM
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp


Agent Delivery Events
Status
Timestamp
Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
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Timestamp
Carbon Copy Events
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Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
7/6/2018 2:32:31 PM
Certified Delivered
Security Checked
7/10/2018 6:12:32 PM
Signing Complete
Security Checked
7/10/2018 6:12:42 PM
Completed
Security Checked
7/10/2018 6:12:42 PM
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE 
From time to time, AstraZeneca (we, us or Company) may be required by law to provide to you
certain written notices or disclosures. Described below are the terms and conditions for
providing to you such notices and disclosures electronically through your DocuSign, Inc.
(DocuSign) Express user account. Please read the information below carefully and thoroughly,
and if you can access this information electronically to your satisfaction and agree to these terms
and conditions, please confirm your agreement by clicking the 'I agree' button at the bottom of
this document. 
Getting paper copies 
At any time, you may request from us a paper copy of any record provided or made available
electronically to you by us. For such copies, as long as you are an authorized user of the
DocuSign system you will have the ability to download and print any documents we send to you
through your DocuSign user account for a limited period of time (usually 30 days) after such
documents are first sent to you. After such time, if you wish for us to send you paper copies of
any such documents from our office to you, you will be charged a $0.00 per-page fee. You may
request delivery of such paper copies from us by following the procedure described below. 
Withdrawing your consent 
If you decide to receive notices and disclosures from us electronically, you may at any time
change your mind and tell us that thereafter you want to receive required notices and disclosures
only in paper format. How you must inform us of your decision to receive future notices and
disclosure in paper format and withdraw your consent to receive notices and disclosures
electronically is described below. 
Consequences of changing your mind 
If you elect to receive required notices and disclosures only in paper format, it will slow the
speed at which we can complete certain steps in transactions with you and delivering services to
you because we will need first to send the required notices or disclosures to you in paper format,
and then wait until we receive back from you your acknowledgment of your receipt of such
paper notices or disclosures. To indicate to us that you are changing your mind, you must
withdraw your consent using the DocuSign 'Withdraw Consent' form on the signing page of your
DocuSign account. This will indicate to us that you have withdrawn your consent to receive
required notices and disclosures electronically from us and you will no longer be able to use your
DocuSign Express user account to receive required notices and consents electronically from us
or to sign electronically documents from us. 
All notices and disclosures will be sent to you electronically 
Unless you tell us otherwise in accordance with the procedures described herein, we will provide
electronically to you through your DocuSign user account all required notices, disclosures,
authorizations, acknowledgements, and other documents that are required to be provided or
made available to you during the course of our relationship with you. To reduce the chance of
you inadvertently not receiving any notice or disclosure, we prefer to provide all of the required
notices and disclosures to you by the same method and to the same address that you have given
us. Thus, you can receive all the disclosures and notices electronically or in paper format through
the paper mail delivery system. If you do not agree with this process, please let us know as
described below. Please also see the paragraph immediately above that describes the
consequences of your electing not to receive delivery of the notices and disclosures
electronically from us. 
Electronic Record and Signature Disclosure created on: 8/28/2017 4:41:22 PM
Parties agreed to: Flor, Armando


How to contact AstraZeneca: 
You may contact us to let us know of your changes as to how we may contact you electronically,
to request paper copies of certain information from us, and to withdraw your prior consent to
receive notices and disclosures electronically as follows:
 To contact us by email send messages to: 
 
To advise AstraZeneca of your new e-mail address 
To let us know of a change in your e-mail address where we should send notices and disclosures
electronically to you, you must send an email message to us at
and in the body of such request you must
state: your previous e-mail address, your new e-mail address.  We do not require any other
information from you to change your email address..  
In addition, you must notify DocuSign, Inc to arrange for your new email address to be reflected
in your DocuSign account by following the process for changing e-mail in DocuSign. 
To request paper copies from AstraZeneca 
To request delivery from us of paper copies of the notices and disclosures previously provided
by us to you electronically, you must send us an e-mail to
 and in the body of such request you must state
your e-mail address, full name, US Postal address, and telephone number. We will bill you for
any fees at that time, if any. 
To withdraw your consent with AstraZeneca 
To inform us that you no longer want to receive future notices and disclosures in electronic
format you may:
i. decline to sign a document from within your DocuSign account, and on the subsequent
page, select the check-box indicating you wish to withdraw your consent, or you may;
ii. send us an e-mail to 
and in the body
of such request you must state your e-mail, full name, IS Postal Address, telephone
number, and account number. We do not need any other information from you to withdraw
consent..  The consequences of your withdrawing consent for online documents will be
that transactions may take a longer time to process.. 
Required hardware and software 
Operating Systems: 
Windows2000? or WindowsXP? 
Browsers (for SENDERS): 
Internet Explorer 6.0? or above 
Browsers (for SIGNERS): 
Internet Explorer 6.0?, Mozilla FireFox 1.0,
NetScape 7.2 (or above) 
Email: 
Access to a valid email account 
Screen Resolution: 
800 x 600 minimum 
Enabled Security Settings: 
•Allow per session cookies
 
•Users accessing the internet behind a Proxy
Server must enable HTTP 1.1 settings via
proxy connection 
** These minimum requirements are subject to change. If these requirements change, we will
provide you with an email message at the email address we have on file for you at that time


providing you with the revised hardware and software requirements, at which time you will
have the right to withdraw your consent. 
Acknowledging your access and consent to receive materials electronically 
To confirm to us that you can access this information electronically, which will be similar to
other electronic notices and disclosures that we will provide to you, please verify that you
were able to read this electronic disclosure and that you also were able to print on paper or
electronically save this page for your future reference and access or that you were able to
e-mail this disclosure and consent to an address where you will be able to print on paper or
save it for your future reference and access. Further, if you consent to receiving notices and
disclosures exclusively in electronic format on the terms and conditions described above,
please let us know by clicking the 'I agree' button below. 
By checking the 'I Agree' box, I confirm that: 
•
I can access and read this Electronic CONSENT TO ELECTRONIC RECEIPT OF
ELECTRONIC RECORD AND SIGNATURE DISCLOSURES document; and
 
•
I can print on paper the disclosure or save or send the disclosure to a place where I can
print it, for future reference and access; and
 
•
Until or unless I notify AstraZeneca as described above, I consent to receive from
exclusively through electronic means all notices, disclosures, authorizations,
acknowledgements, and other documents that are required to be provided or made
available to me by  AstraZeneca during the course of my relationship with you.