Clinical trial NCT03645421
Conditions: Type 2 Diabetes
Keywords: Diabetes MEDI0382 D5674C00001 T2DM Type 2 Diabetes
Sponsor: AstraZeneca
Start date: 2018-08-10; Completion date: 2019-01-17
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2a study designed to assess the safety and tolerability of MEDI0382 titrated up to a dose level of 100, 200 or 300 µg from 50 µg vs Placebo across 48 days in Japanese subjects.

The study D5674C00001 can be conducted with a reasonable expectation of safety and tolerability in Japanese T2DM patients. The design of this study has taken into account the known benefits and risks of GLP-1 receptor agonists and glucagon receptor agonists as well as the translatable effects observed in nonclinical studies of MEDI0382.

Detailed description:
This is a randomized, parallel-group, placebo-controlled, double-blind, multicenter Phase Ⅱa study to evaluate the safety, efficacy, and pharmacokinetics of MEDI0382 in Japanese preobese and obese subjects with type 2 diabetes who have inadequate glycemic control with diet and exercise. Subject fulfilling all of the inclusion criteria and none of the exclusion criteria will be randomised in a 1:1:1:1 ratio to four treatment arms. This is a Phase IIa study designed to evaluate the dose range for MEDI0382 to explore the safety profile, as well as blood glucose control and weight loss effects of MEDI0382 in Japanese patients with T2DM. The design of this study has taken into account the known benefits and risks of GLP-1 receptor agonists and glucagon receptor agonists as well as the translatable effects observed in nonclinical studies of MEDI0382, such that benefit-risk balance for the Japanese preobese and obese patients with T2DM in this study is considered favourable. A treatment period of 48 days is required to properly evaluate the dose range and safety and tolerability in three different doses. Inclusion of placebo in the study allows appropriate basis of AEs, glycaemic control, and weight loss. Benefits related to participation in this trial include close follow-up of a subject's diabetes and treatment with anti-diabetes agents. Although one of possible treatments is placebo, appropriate rescue therapy for worsening glycaemic control will be implemented if required.

Arms: arm 1: Placebo per day,SC injection on 48 days. arm 2: 50 μg/day,SC injection on the first 5 days and 100 μg/day,SC injection on 43 days arm 3: 50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days and 200 μg/day,SC injection on 36 days. arm 4: 50 μg/day,SC injection on the first 5 days, 100 μg/day,SC injection on 7 days, 200 μg/day,SC injection on 7 days and 300 μg/day,SC injection on 29 days
Interventions: intervention 1: MEDI0382 100 μg intervention 2: MEDI0382 200 μg intervention 3: MEDI0382 300 μg intervention 4: PlaceboA intervention 5: MEDI0382 50 ug intervention 6: PlaceboB
Intervention descriptions: intervention 1: Solution for injection in 1.0 mL pre-filled syringe, 100 μg per dose, 1 dose intervention 2: Solution for injection in 1.0 mL pre filled syringe 200 μg per dose, 1 dose intervention 3: Solution for injection in 1.0 mL pre filled syringe, 300 μg per dose, 1 dose intervention 4: 1.0 mL liquid formulation per Vial intervention 5: Solution for injection, 1.0 mL per vial, 50 ug intervention 6: Solution for injection in 1.0 mL pre-filled syringe.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol -8.0 
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Clinical Study Protocol 
 
Drug Substance 
MEDI0382 
 
Study Code 
D5674C00001 
 
Version 
8.0 
 
Date 
12 June 2019 
 
 
A Phase IIa, Randomised, Parallel, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Efficacy, and Pharmacokinetics of MEDI0382 in 
Japanese Preobese or Obese Subjects with Type 2 Diabetes Who Have 
Inadequate Glycemic Control with Diet and Exercise 
 
Sponsor:  
Astrazeneca K.K. 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan 
 


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VERSION HISTORY 
Version 1.0, 18 May 2018 
Initial creation 
Version 2.0, 18 June 2018 
2.2 Background: Findings from Study D5670C00011 was added. 
4.3 Justification for dose: Findings from completed clinical studies was added. 
6.1.2 Medical devices: A typo was corrected. 
6.5.2 Other concomitant treatment: Reporting process of adverse events due to self-injection was 
added. 
6.5.3 Rescue medication: Monitoring process for significant vomiting was added. 
8.1.4 Continuous glucose monitoring (CGM): Data handling and reporting process were clarified. 
8.2.1 Clinical safety laboratory assessments: Duplications were corrected. 
8.2.5.1 Ambulatory Blood Pressure Monitoring: Data handling and reporting process were clarified.
8.2.5.2 Daily Diaries: Any other events was added. 
8.4.2.1 Maternal exposure: Reporting process was clarified. 
8.4.4.3 Reporting of medical device incidents to sponsor: Reporting process was clarified. 
Appendix G: Created new. 
Version 3.0, 17 July 2018 
1.1 Schedule of Activities (SoA) Table2 Note i: A typo was corrected. 
6.3.1 Methods for ensuring blinding: Blinding process was clarified. 
6.5.3 Rescue medication Rescue process was clarified. 
Appendix G: Order was arranged. 
Appendix H: Order was arranged. 
Version 4.0, 8 August 2018 
1.1 Schedule of Activities (SoA) Table2: Withdrawal test was added and clarified. 
1.1 Schedule of Activities (SoA) Table2: Note i Withdrawal test was clarified. 
1.1 Schedule of Activities (SoA) Table2: Note o Created new. 
1.2 Synopsis Study Period: Estimated date of last patient completed was extended. 
6.3.1 Methods for ensuring blinding: Blinding process was clarified. 
7.1.1 Procedures for discontinuation of study treatment: Discontinuation treatment was clarified. 
Version 5.0, 4 September 2018 
1.1 Schedule of Activities (SoA) Table1: Laboratory assessment was added. 
1.1 Schedule of Activities (SoA) Table2: Change in measurement item from glycoalbumin to 
fructosamine. This change does not affect the efficacy evaluation and makes  the measurement more 
convenient. 
1.2 Synopsis: Change in measurement item from glycoalbumin to fructosamine. This change does 
not affect the efficacy evaluation and makes  the measurement more convenient. 


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3 OBJECTIVES AND ENDPOINTS: Change in measurement item from glycoalbumin to 
fructosamine. This change does not affect the efficacy evaluation and makes  the measurement more 
convenient. 
4.2.2.2 Rationale for Secondary Endpoints: Change in measurement item from glycoalbumin to 
fructosamine. This change does not affect the efficacy evaluation and makes the measurement more 
convenient. 
6.3.1 Methods for ensuring blinding: Change in measurement item from glycoalbumin to 
fructosamine. This change does not affect the efficacy evaluation and makes the measurement more 
convenient. Blinding process was clarified.  
8 STUDY ASSESSMENTS AND PROCEDURES: Change the amount of blood and description 
was clarified. 
8.1.3 HbA1c, Fasting plasma glucose and fructosamine : Change in measurement item from 
glycoalbumin to fructosamine. This change does not affect the efficacy evaluation and makes the 
measurement more convenient. 
8.2.1 Clinical safety laboratory assessments:S-ketone to beta-hydroxybutyrate due to change of 
measurement item. Change in measurement item from glycoalbumin to fructosamine. This change 
does not affect the efficacy evaluation and makes the measurement more convenient. Laboratory 
assessment item was clarified. 
8.7.1 Collection of samples: Description was clarified. 
Appendix H: Delete GA. 
Version 6.0, 18 October 2018 
1.2 Synopsis Objectives and Endpoints/Secondary Objectives/Endpoint/variable: Correction of typo 
in the evaluation schedule of CGM. 
1.2 Synopsis Study Period: Estimated date of last patient completed was extended. 
3 OBJECTIVES AND ENDPOINTS Table 5 Study objectives/Secondary 
Objective/Endpoint/Variable: Correction of typo in the evaluation schedule of CGM. 
6.3.1 Methods for ensuring blinding: Description was clarified. 
6.5.3 Rescue medication: Target period for rescue medication was clarified. 
8 STUDY ASSESSMENTS AND PROCEDURES: Correction of the amount of blood draw. 
8.7 Pharmacodynamics: Description was clarified. 
Version 7.0, 17 May 2019 
1.2 Synopsis Study Period: Estimated date of last patient completed was extended. 
8 STUDY ASSESSMENTS AND PROCEDURES: Change the amount of blood. 
8.6 Immunogenicity: Description of follow-up ADA data handling was added. 
Version 8.0, 12 June 2019 
8 STUDY ASSESSMENTS AND PROCEDURES: Correction of the amount of blood and 
description was clarified. 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
VERSION HISTORY ............................................................................................................... 2 
TABLE OF CONTENTS .......................................................................................................... 4 
1 
PROTOCOL SUMMARY ..................................................................................... 8 
1.1 
Schedule of Activities (SoA) .................................................................................. 8 
1.2 
Synopsis ................................................................................................................ 15 
1.3 
Schema .................................................................................................................. 18 
2 
INTRODUCTION ................................................................................................ 19 
2.1 
Study rationale ...................................................................................................... 19 
2.2 
Background ........................................................................................................... 19 
2.3 
Benefit/risk assessment ......................................................................................... 23 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 24 
4 
STUDY DESIGN ................................................................................................. 25 
4.1 
Overall design ....................................................................................................... 25 
4.2 
Scientific rationale for study design ..................................................................... 25 
4.2.1 
Rationale for Study Population ............................................................................. 25 
4.2.2 
Rationale for Endpoints ........................................................................................ 26 
4.2.2.1 
Rationale for Primary Endpoints .......................................................................... 26 
4.2.2.2 
Rationale for Secondary Endpoints ...................................................................... 26 
4.2.2.3 
Rationale for Exploratory Endpoints .................................................................... 27 
4.3 
Justification for dose ............................................................................................. 27 
4.4 
End of study definition ......................................................................................... 29 
5 
STUDY POPULATION ....................................................................................... 29 
5.1 
Inclusion criteria ................................................................................................... 29 
5.2 
Exclusion criteria .................................................................................................. 31 
5.3 
Lifestyle restrictions ............................................................................................. 32 
5.3.1 
Meals and dietary restrictions ............................................................................... 32 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 33 
5.3.3 
Activity ................................................................................................................. 33 
5.4 
Screen failures ...................................................................................................... 33 
6 
STUDY TREATMENTS ..................................................................................... 33 
6.1 
Treatments administered ....................................................................................... 34 
6.1.1 
Investigational products ........................................................................................ 34 
6.1.2 
Medical devices .................................................................................................... 34 
6.2 
Preparation/handling/storage/accountability ........................................................ 35 
6.3 
Measures to minimise bias: randomisation and blinding ..................................... 36 
6.3.1 
Methods for ensuring blinding ............................................................................. 37 


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6.4 
Treatment compliance .......................................................................................... 38 
6.5 
Concomitant therapy ............................................................................................. 38 
6.5.1 
Prohibited concomitant medication ...................................................................... 38 
6.5.2 
Other concomitant treatment ................................................................................ 39 
6.5.3 
Rescue medication ................................................................................................ 39 
7 
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 40 
7.1 
Discontinuation of study treatment ....................................................................... 40 
7.1.1 
Procedures for discontinuation of study treatment ............................................... 40 
7.2 
Lost to follow-up .................................................................................................. 41 
7.3 
Withdrawal from the study ................................................................................... 41 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................... 41 
8.1 
Efficacy assessments ............................................................................................ 42 
8.1.1 
Mixed-meal Test ................................................................................................... 42 
8.1.2 
Weight .................................................................................................................. 42 
8.1.3 
HbA1c, Fasting plasma glucose and fructosamine ............................................... 43 
8.1.4 
Continuous glucose monitoring (CGM) ............................................................... 43 
8.2 
Safety assessments ................................................................................................ 44 
8.2.1 
Clinical safety laboratory assessments ................................................................. 44 
8.2.2 
Physical examinations .......................................................................................... 46 
8.2.3 
Vital signs ............................................................................................................. 46 
8.2.4 
Electrocardiograms ............................................................................................... 46 
8.2.5 
Other safety assessments ...................................................................................... 47 
8.2.5.1 
Ambulatory Blood Pressure Monitoring .............................................................. 47 
8.2.5.2 
Daily Diaries ......................................................................................................... 47 
8.3 
Collection of adverse events ................................................................................. 48 
8.3.1 
Method of detecting AEs and SAEs ..................................................................... 48 
8.3.2 
Time period and frequency for collecting AE and SAE information ................... 48 
8.3.3 
Follow-up of AEs and SAEs ................................................................................ 49 
8.3.4 
Adverse event data collection ............................................................................... 49 
8.3.5 
Causality collection .............................................................................................. 50 
8.3.6 
Adverse events based on signs and symptoms ..................................................... 50 
8.3.7 
Adverse events based on examinations and tests ................................................. 50 
8.3.8 
Hy’s law ................................................................................................................ 50 
8.4 
Safety reporting and medical management .......................................................... 51 
8.4.1 
Reporting of serious adverse events ..................................................................... 51 
8.4.2 
Pregnancy ............................................................................................................. 51 
8.4.2.1 
Maternal exposure ................................................................................................ 52 
8.4.3 
Overdose ............................................................................................................... 52 
8.4.4 
Medical device incidents (including malfunctions) .............................................. 53 
8.4.4.1 
Time period for detecting medical device incidents ............................................. 53 
8.4.4.2 
Follow-up of medical device incidents ................................................................. 53 
8.4.4.3 
Reporting of medical device incidents to sponsor ................................................ 54 
8.4.4.4 
Regulatory reporting requirements for medical device incidents ......................... 54 
8.4.5 
Medication error ................................................................................................... 54 


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8.5 
Pharmacokinetics .................................................................................................. 54 
8.5.1 
Determination of drug concentration .................................................................... 55 
8.5.2 
Storage and destruction of pharmacokinetic samples ........................................... 55 
8.6 
Immunogenicity .................................................................................................... 55 
8.7 
Pharmacodynamics ............................................................................................... 56 
8.7.1 
Collection of samples ........................................................................................... 56 
8.7.2 
Storage, re-use and destruction of pharmacodynamic samples ............................ 56 
8.8 
Genetics ................................................................................................................ 56 
8.9 
Biomarkers ............................................................................................................ 56 
9 
STATISTICAL CONSIDERATIONS ................................................................. 57 
9.1 
Statistical hypotheses ............................................................................................ 57 
9.2 
Sample size determination .................................................................................... 57 
9.3 
Populations for analyses ....................................................................................... 58 
9.4 
Statistical analyses ................................................................................................ 58 
9.4.1 
Efficacy analyses .................................................................................................. 58 
9.4.2 
Safety analyses ..................................................................................................... 59 
9.4.3 
Other analyses (PK) .............................................................................................. 59 
9.5 
Interim analyses .................................................................................................... 59 
9.5.1 
Data monitoring committee (DMC) ..................................................................... 59 
10 
REFERENCES ..................................................................................................... 60 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 61 
 
LIST OF TABLES 
Table 1 
Schedule of Screening Procedures ................................................................ 8 
Table 2 
Schedule of Treatment Period Procedures .................................................. 10 
Table 3 
Example Schedule for Mixed Meal Test (MMT) on Day -1 ...................... 14 
Table 4 
Example Schedule for Pharmacokinetics (PK) sampling and MMT test 
on Day 48 .................................................................................................... 15 
Table 5 
Study objectives .......................................................................................... 24 
Table 6 
Identity of investigational product(s) .......................................................... 34 
Table 7 
Criteria for initiation of rescue therapy during the randomised treatment 
period ........................................................................................................... 40 
Table 8 
Laboratory safety variables ......................................................................... 44 
Table 9 
Study D5670C00002: Treatment-emergent Vomiting and/or Nausea by 
Study Day – All Cohorts – As-treated Population ...................................... 83 


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Table 10 
Study D5670C00011: Number and Percentage of Subjects with Nausea 
and/or Vomiting and Associated Event Rate by Dosing Period – Cohort 
1 - As-treated Population ............................................................................ 86 
 
LIST OF FIGURES 
Figure 1 
Study design ................................................................................................ 19 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, ethical and study oversight considerations .............................. 62 
Appendix B 
Adverse event definitions and additional safety information ..................... 66 
Appendix C 
Handling of Human Biological Samples ..................................................... 71 
Appendix D 
Genetics ....................................................................................................... 73 
Appendix E 
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law ............................................................................... 77 
Appendix F 
Medical device incidents: definition and procedures for recording, 
evaluating, follow-up, and reporting ........................................................... 81 
Appendix G 
Summary of gastrointestinal events in Studies D5670C00002 and 
D5670C00011 ............................................................................................. 83 
Appendix H 
Abbreviations .............................................................................................. 92 
 


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1 
PROTOCOL SUMMARY 
1.1 
Schedule of Activities (SoA) 
Table 1 
Schedule of Screening Procedures 
Study Period 
Screening 
Visit Number 
V1 
Procedure/Study Day 
Day -14 to Day -2 
Written general informed consent/assignment of SID number (E code) 
X 
Optional informed consent for sample for future genetic research 
X 
Verify eligibility criteria 
X 
Demographics 
X 
Medical and disease history (including smoking and alcohol history) 
X 
Full physical examination (including structured neurological 
examination) a 
X 
Vital signs 
X 
12-lead digital ECG (also printed on paper) 
X 
Body height  
X 
Body weight 
X 
Calculate eGFR to confirm eligibility 
X 
Collect blood for: 
 
Pancreatic amylase, lipase, calcitonin, and TSH 
X 
Hepatitis B and C serology b 
X 
HbA1c 
X 
Serum chemistry panel 
X 
Hematology and coagulation panels 
X 
TG 
X 
Total Ig and subsets (Ig A/E/G/M) 
X 
Collect urine for: 
 
Urinalysis (dipstick) 
X 
Pregnancy test 
X 
Assessment of AEs/SAEs c 
X 
Concomitant medications 
X 
Check ability to self-administer investigational product d 
X 
CGM device demonstration 
X 
CGM measurement 
Day -8 to Day -2 e 
AE = adverse event; CGM = continuous glucose monitoring; ECG = electrocardiogram; eGFR = estimated 
glomerular filtration rate; HbA1c = glycated hemoglobin; Ig = immunoglobulin; SAE = serious adverse event; 
SID = subject identification; TSH = thyroid-stimulating hormone; V = visit. 


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a. 
Only the screening physical examination will be a full examination including a structured neurological 
examination. For all time points thereafter, only a targeted physical examination is required. 
b. 
Serum hepatitis B surface antigen and hepatitis C antibody should be negative. 
c. 
SAEs collected after informed consent signed and AEs after randomization will be assessed. 
d. 
The subject’s ability to self-administer investigational product will be verified using placebo or normal 
saline subcutaneous injections. 
e. 
CGM should be started anytime from Day -14 to Day -8 and measured for at least 7 days. The CGM sensor 
should be removed at later time than the time that was applied. 
 


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Table 2 
Schedule of Treatment Period Procedures 
 
Pre-dose
Treatment period 
Follow-up 
 
 
 
Dose Level 1 
Dose Level 2
Dose Level 3
Dose Level 4 
 
 
V2 
V3 
V4-7 
V8 
V9 
V10 
V11 
V12 
/ Withdrawal o
V13 
Study Day 
-1 
1 
2-5 
6 
13 
20 
34 
48 
7-14 Days 
Post Last 
Dose 
Allowance 
-1 
 
 
 
 
 
+1 
 
 
Procedure 
Verify eligibility criteria 
X 
 
 
 
 
 
 
 
 
Targeted physical examination 
 
X 
 
X 
X 
X 
X 
X 
X 
Body weight a 
 
X 
 
X 
X 
X 
X 
X 
X 
Randomization 
X b 
X b 
 
 
 
 
 
 
 
Collect blood for: 
Hematology panel (predose) 
 
X 
 
X 
 
X 
X 
X 
X 
Serum chemistry panel 
(predose) 
 
X 
 
X 
 
X 
X 
X 
X 
Pancreatic amylase and lipase 
(predose) 
 
X 
 
 
 
 
 
X 
 
Lactate (predose) 
 
X 
 
X 
 
X 
X 
X 
 
HbA1c (predose) 
X 
 
 
 
 
 
 
X 
 
Fructosamine 
 (predose) 
X 
 
 
 
 
X 
 
X 
 
Fasting lipid profile (before 
breakfast and predose as 
applicable) 
X 
 
 
 
 
 
 
X 
 
Optional future genetic 
research c 
 
 
 
 
 
 
 
X 
(X) 


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Table 2 
Schedule of Treatment Period Procedures 
 
Pre-dose
Treatment period 
Follow-up 
 
 
 
Dose Level 1 
Dose Level 2
Dose Level 3
Dose Level 4 
 
 
V2 
V3 
V4-7 
V8 
V9 
V10 
V11 
V12 
/ Withdrawal o
V13 
Study Day 
-1 
1 
2-5 
6 
13 
20 
34 
48 
7-14 Days 
Post Last 
Dose 
Allowance 
-1 
 
 
 
 
 
+1 
 
 
Collect urine sample for: 
Urinalysis (dipstick) 
 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy test (only for 
premenopausal women)  
X 
 
 
 
 
 
 
X 
X 
ECG d 
X 
X 
 
X 
X 
X 
 
X 
 
Vital signs (BP, pulse, body 
temperature, RR) e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24-hour ABPM f 
X 
 
 
 
 
X 
 
X 
 
Subject completes 
Daily Diary g 
X 
X 
X 
X 
X 
X 
X 
X 
 
Staff review Daily Diary with 
subject 
 
X 
X 
X 
X 
X 
X 
X 
 
Train subject on self-
administration 
X 
X 
X 
X 
 
 
 
 
 
Train subject on at-home dose 
preparation 
X 
X 
X 
X 
X 
X 
X 
 
 
Staff train subject in Daily Diary 
completion 
X 
X 
 
X 
 
 
 
 
 
IP administration by staff 
 
X 
X 
 
 
 
 
 
 
IP administration by subject 
 
 
 
X 
X 
X 
X 
X 
 
IP dispense 
 
X 
 
X 
X 
X 
X 
 
 


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Table 2 
Schedule of Treatment Period Procedures 
 
Pre-dose
Treatment period 
Follow-up 
 
 
 
Dose Level 1 
Dose Level 2
Dose Level 3
Dose Level 4 
 
 
V2 
V3 
V4-7 
V8 
V9 
V10 
V11 
V12 
/ Withdrawal o
V13 
Study Day 
-1 
1 
2-5 
6 
13 
20 
34 
48 
7-14 Days 
Post Last 
Dose 
Allowance 
-1 
 
 
 
 
 
+1 
 
 
PK for MEDI0382 h 
 
X 
X 
X 
X 
X 
X 
X 
X 
MMT i 
X 
 
 
 
 
 
 
X 
 
Blood samples for glucose and 
insulin i 
X 
 
 
 
 
 
 
X 
 
Blood samples for pro insulin 
and c peptide, GLP-1, and 
glucagon i 
X 
 
 
 
 
 
 
X 
 
CGM j 
 
X (D1 to D5) 
X  
(D6 to D12)
X  
(D13 to D19)
 
 
X  
(D41 to D47) 
 
CGM sensor 
application/change k 
 
 
 
 
 
 
 
 
 
ADA l 
 
X 
 
 
X 
X 
 
X 
X 
AEs/SAEs m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site assessment n 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ABPM = ambulatory blood pressure monitoring; ADA = antidrug antibody; AE = adverse event; BP = blood pressure; CGM = continuous glucose monitoring;  
D = day; ECG = electrocardiogram;  GLP-1 = glucagon-like peptide-1; HbA1c = glycated hemoglobin; IP = investigational product; min = minutes; MMT = 
mixed-meal test; PK = pharmacokinetic(s); RR = respiration rate; SAE = serious adverse event; V = Visit. 
Note: Whenever vital signs, ECGs, and blood draws are scheduled for the same nominal time, the ECG should occur first, then vital signs, and blood draws 
should occur last. The timing of the ECGs and/or vital signs should be such that it allows the blood draw (e.g., for PK) to occur as close as possible to 
the scheduled time. Ten minutes of supine rest should precede these assessments. 
a. 
Body weight measurement should be taken in the morning before breakfast. 


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b. 
Randomization may occur on either Day -1 or Day 1 after all eligibility criteria were confirmed. 
c. 
There is a consent form with check boxes available for the genetic future research sample and the non-genetic future research sample. Only sample(s) which 
the subject has consented to collect will be taken. Samples should be taken hat Visit 12 or Withdrawal visit. 
d. 
Digital ECGs will be captured on Day -1; and pre-dose and 6 hours (± 15 min) post-dose on Days, 1, 6, 13, 20 and 48. All ECGs should be printed.  
e. 
Vital Signs Schedule: On Day 1, vital signs are to be recorded predose, and at 30, 60 and 90 minutes, 2 and 4 hours postdose. From Visit 4 to 11, vital signs 
are to be recorded predose, Also, vital signs are to be taken at all PK time points.  
f. 
ABPM device will be fitted at a convenient time on the day stated and worn for 24 hours, and subjects will receive training from study site staff on how to 
fit and wear the device during the day and whilst sleeping. On Visit 10, the ABPM device should be fitted as soon as possible after the subject arrives at the 
unit that morning 
g. 
The subject should undergo a Ketostix® test daily on non-clinic-visit days during the at-home self-administration period; the subject will indicate whether 
the result is negative or positive in the Daily Diary, and be instructed to call the site if the result is positive. 
h. 
PK Sampling Schedule for MEDI0382:  
Pre-dose PK sample will be collected on Days 1 to 6, 13, 20, 34 and 48. 
Follow-up: 7 to 14 days after administration of the last dose in the study. 
PK sample at follow-up will be taken on the same day as that for ADA sampling. 
i. 
MMT Schedule: Following a minimum 8-hour fast, blood samples for the tests indicated will be taken 15 minutes before the subject drinking 1 entire can of 
Ensure H as a standardised meal. On Day -1, and Day 48, after consumption of the standardised meal, blood samples will additionally be taken at 15, 30, 45, 
60, 90, 120, 180, and 240 minutes (± 5 min) for glucose and insulin; 15, 45, 90, 180, and 240 minutes (± 5 min) for pro-insulin, c-peptide, GLP-1 and 
glucagon. If subject discontinues the investigational product, MMT should not be performed at the withdrawal visit. 
j. 
CGM device to be fitted and worn continuously during the measurement period. 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 to. The sensor applied to the skin is for single use and may not be reattached once 
removed.  
k. 
CGM sensors should be changed at each interval at the same time of day (± 20 minutes). 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 6, Day 13 and Day 41. If the sensor fails, or needs to be replaced, it should be reapplied as soon 
as possible. The sensor can be replaced on Day 34 if the subject cannot visit on Day 41.  
l. 
ADA Sampling Schedule:  Day 1 (V3) predose; Day 13 (V9) predose; Day 20 (V10) predose; Day 48 (V12) predose; and 7 to 14 days after administration 
of the last dose in the study. 
m. SAEs collected after informed consent signed and AEs after randomization will be assessed. 
n. 
Injection Site Assessment Schedule: The injection site will be assessed by site staff at 4 hours postdose on Day 1 and the first day of each new dose level, 
and at 24 hours (prior to next dose) postdose on Day 1.  The site staff will not be required to assess injection sites except for the above time points. Subjects 
will be instructed to contact the site if there is any abnormality observed at the injection site. 
o 
For withdrawal subjects, assessment should be done after decision of the withdrawal. 
 


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Table 3 
Example Schedule for Mixed Meal Test (MMT) on Day -1 
Example Clock Time 
MMT Blood sampling 
(time window ± 5 minutes) 
(minimum 8-hour fast) 
9:15 
15 minutes before Test Meal 
9:30 a                                    Ensure H 
(Ensure H to be consumed within 5 minutes, actual start time to be recorded in eCRF) 
9:45 
15 minutes 
10:00 
30 minutes 
10:15 
45 minutes 
10:30 
60 minutes 
11:00 
90 minutes 
11:30 
120 minutes 
12:30 
180 minutes 
13:30 
240 minutes 
13:45                                                              Go home (Mid-day Meal) 
a. 
Ensure H should be taken between 9:00 and 9:30. 
 


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Table 4 
Example Schedule for Pharmacokinetics (PK) sampling and MMT test 
on Day 48 
Example Clock Time 
Time Relative to Dosing
MEDI0382 
PK sampling 
MMT Blood sampling 
(time window ± 5 minutes)
(minimum 8-hour fast) 
6:45 
Pre-dose 
-15 minutes (± 10 min) 
- 
7:00 a                                                                      Administer IP 
9:00 
2 hours postdose 
- 
- 
9:15 
 
- 
15 minutes before  
Test Meal 
9:30 Ensure H 
(Ensure H to be consumed within 5 minutes, actual start time to be recorded in eCRF) 
9:45 
 
- 
15 minutes 
10:00 
 
- 
30 minutes 
10:15 
 
- 
45 minutes 
10:30 
 
- 
60 minutes 
11:00 
4 hours postdose 
- 
90 minutes 
11:30 
 
- 
120 minutes 
12:30 
 
- 
180 minutes 
13:30 
6.5 hours postdose 
- 
240 minutes 
13:45                                                              Go home (Mid-day Meal) 
a. 
IP should be administered between 6:30 and 7:30. 
 
1.2 
Synopsis 
MEDI0382 is a synthetic peptide with glucagon-like peptide-1 (GLP-1) and glucagon receptor 
co-agonist activity. The combination of GLP-1 and glucagon activity is expected to cause 
significant weight loss and lead to improvement in glycemic control and lipid profiles. 
This is a Phase 2a study designed to assess the safety and tolerability of MEDI0382 titrated up 
to a dose level of 300 µg from 50 µg across 48 days in Japanese subjects. 
Protocol Title:  
A Phase IIa, Randomised, Parallel, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Efficacy, and Pharmacokinetics of MEDI0382 in Japanese Preobese or Obese Subjects 
with Type 2 Diabetes Who Have Inadequate Glycemic Control with Diet and Exercise  


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Rationale:  
Results of this study will provide information about the safety and tolerability, the blood 
glucose-lowering effect as well as body weight reduction of MEDI0382 titrated up to a dose 
level of 100, 200 or 300 µg and the pharmacokinetic (PK) profile. 
Objectives and Endpoints 
 
Primary objective: 
Endpoint/variable: 
To characterise the safety profile and tolerability of 
MEDI0382 titrated up to a dose level of 100, 200 or 
300 μg during dosing and follow-up 
Measures of safety and tolerability (24-hour heart rate 
and blood pressure, other vital signs, 
electrocardiogram [ECG], laboratory test results, and 
adverse event [AE]s) 
To assess the effects of MEDI0382 titrated up to a 
dose level of 100, 200 and 300 μg on glucose control 
and body weight versus placebo after 48-day 
treatment 
• 
Percentage change in glucose area under the 
curve (AUC) 0-4h as measured by a standardised 
MMT from baseline to the end of 48-day 
treatment  
• 
Percentage change in body weight from baseline 
to the end of 48-day treatment 
Secondary objective: 
Endpoint/variable: 
To assess the effects of MEDI0382 titrated up to a 
dose level of 100, 200 or 300 μg on additional 
measures of glucose control versus placebo after 48-
day treatment 
• 
Change in glycated hemoglobin (HbA1c) from 
baseline to the end of 48-day treatment 
• 
Change in fasting plasma glucose from baseline 
to the end of 48-day treatment 
• 
Change in fructosamine from baseline to the end 
of 48-day treatment 
To assess the effect of MEDI0382 on glucose 
lowering during different meals and times of the day 
as measured by continuous glucose monitoring 
(CGM) 
 
• 
Change in percentage of time in hyperglycaemia 
(defined as > 7.8 mmol/L or > 140 mg/dL) and 
hypoglycaemia (defined as < 3 mmol/L or 
< 54 mg/dL) from the last day of baseline CGM 
over 24 hours to the end of dosing at each dose 
level (Days 5, 12, 19, and 47) 
• 
Change in percentage of time in hyperglycaemia 
and hypoglycaemia at each dose level over 
5 days for 50 µg and 7 days for other dose levels 
(Days 1 to 5, Days 6 to 12, Days 13 to 19, and 
Days 41 to 47) 
To characterise the PK profile of 50, 100, 200 and 
300 μg of MEDI0382 
PK endpoints: 
Trough plasma concentration (Ctrough) 
To characterise immunogenicity of 100, 200 and 
300 μg of MEDI0382 
Development of anti-drug antibodies and titre (if 
confirmed positive) 
Exploratory Objective: 
Endpoint/variable: 
To assess the effect of MEDI0382 on pancreatic and 
incretin hormone profiles at baseline and during the 
MMT 
• 
Change in insulin, GLP-1, and glucagon (AUC 
and levels) from baseline after 48-day treatment.
• 
Change in pro-insulin, c-peptide levels, pro-
insulin/c-peptide ratio from baseline after 48-
day treatment. 


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Objectives and Endpoints 
 
To assess the effects of MEDI0382 in insulin 
resistance and beta cell function. 
• 
Change in percentage of Homeostatic model 
assessments (HOMA)-Beta and HOMA-R from 
baseline after 48-day treatment. 
 
Overall design: 
This is a Phase 2a study designed to assess the safety, tolerability, and efficacy of MEDI0382 
titrated up to a dose level of 100, 200 or 300 μg from 50 μg across 48 days, compared with 
Placebo. 
Study Period: 
Estimated date of first patient enrolled: July 2018 
Estimated date of last patient completed: Jan 2020 
Number of Subjects: 
 
MEDI0382 100 μg group: n=15 
 
MEDI0382 200 μg group: n=15 
 
MEDI0382 300 μg group: n=15 
 
Placebo group: n=15 
 
Treatments and treatment duration: 
 
MEDI0382 100 µg group: Start 50 μg/day for 5 days and dose up to 100 μg/day for 
43 days 
 
MEDI0382 200 µg group: Start 50 μg/day for 5 days, dose up to 100 μg/day for 7 days 
and dose up to 200 μg/day for 36 days 
 
MEDI0382 300 µg group: Start 50 μg/day for 5 days, dose up to 100 μg/day for 7 days, 
dose up to 200 μg/day for 7 days and dose up to 300 μg/day for 29 days 
 
Placebo group: MEDI0382 matched placebo for 48 days 
 
Statistical methods 
Analysis Sets 
The full analysis set (FAS) for the efficacy evaluation will be the primary analysis set and will 
include all randomized subjects who received at least one dose of Investigational Product (IP), 
and will be analysed according to their randomised treatment group. 
The Safety analysis set, which includes all subjects receiving at least one dose of any study IP, 
will be analysed according to the treatment they actually received. 


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The PK set includes all subjects who received at least one dose of MEDI0382 and had at least 
one post-baseline MEDI0382 PK sample taken that is above the lower limit of quantification. 
Sample size determination 
Approximately 60 patients are to be randomized to Placebo, MEDI0382 100 g, MEDI0382 
200 μg, and MEDI0382 300 μg in a ratio 1:1:1:1. 
Anticipating approximately 10% drop out during the 48-day treatment period, approximately 
13 subjects are expected to be evaluable per treatment group. 
Assuming standard deviation of percent change in MMT glucose AUC(0-4h) for 20%, 
approximately 13 patients per arm would provide more than 80% power to detect 23% 
difference in percent change of MMT glucose AUC(0-4h) for pairwise comparison between 
each of MEDI0382 dose group and Placebo each at two-sided alpha = 0.05, without formal 
multiplicity adjustment. 
Assuming standard deviation of percent change from baseline in body weight for 2.5%, the 
same number of subjects would provide approximately 68% power to detect mean difference 
of 2.5% at two-sided alpha =0.05. 
Statistical analysis methods 
Safety data will be descriptively summarised with respect to AEs/serious adverse event 
(SAE)s, safety laboratory measurements, vital signs (including 24-hour ambulatory blood 
pressure monitoring [ABPM]) and ECGs, by treatment group.  
Percent change from baseline in MMT Glucose AUC(0-4h) to Day 48 will be analysed with 
analysis of covariate (ANCOVA) model with treatment group as a factor and baseline as a 
covariate. Least-square mean and their 95% (CI for percent changes from baseline for each 
treatment group, as well as difference in Least-square mean, 95% CI and nominal p-values 
will be provided for pairwise comparison of each MEDI0382 dose vs. Placebo group. Percent 
change (and absolute change) from baseline in body weight will be analysed similarly. 
Analyses will be based on the FAS, which includes all randomised subjects who received at 
least one dose of IP. Secondary and exploratory variables will be descriptively summarised by 
treatment and analysed by ANCOVA or other appropriate models. 
1.3 
Schema 
The general study design is summarised in Figure 1. 


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Figure 1 
Study design 
   
R=Randomisation, MMT=Mixed-Meal Test, CGM=Continuous Glucose Monitoring 
2 
INTRODUCTION 
2.1 
Study rationale 
MEDI0382 is a synthetic peptide with both GLP-1 and glucagon receptor co-agonist 
activity. Combination of GLP-1 and glucagon activity is expected to improve glucose 
metabolism and lipid profiles, and result in significant weight loss. Currently MEDI0382 is 
under development for patients with type 2 diabetes mellites (T2DM).  
This is a Phase 2a study designed to evaluate the safety and tolerability of MEDI0382 titrated 
up to a dose level of 100, 200 or 300 µg from 50 µg across 48 days in preobese/obese 
Japanese population with type 2 diabetes. Results of this study will also provide information 
about the blood glucose-lowering and weight loss effect of MEDI0382 as well as the PK 
profile. This study is designed based on the prior clinical experience with MEDI0382 in 
clinical studies D5670C00002 and D5670C00012. 
According to the overseas study results and Japanese Phase 1 results as given above, the study 
D5674C00001 can be conducted with a reasonable expectation of safety and tolerability in 
Japanese T2DM patients. The design of this study has taken into account the known benefits 
and risks of GLP-1 receptor agonists and glucagon receptor agonists as well as the translatable 
effects observed in nonclinical studies of MEDI0382, such that benefit-risk balance for the 
Japanese preobese and obese patients with T2DM in this study is considered favourable. 
2.2 
Background 
The rising prevalence of 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 


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weight or more) can promote improvements in glycaemic control, cardiovascular risk and 
mortality rates, and may even slow or reverse disease progression. Many existing therapies for 
T2DM focus upon lowering blood glucose; however, there is a major unmet need for 
treatments that both improve glycaemic control and achieve clinically meaningful weight loss. 
Average body mass index (BMI) in Japanese type 2 diabetes has been increasing gradually 
over past 10 years reaching BMI 24.7 in 2016 (The Japan Diabetes Society). In addition, 
accumulation of visceral fat causes insulin resistance even in Japanese type 2 diabetes patients 
with lower BMI. Therefore a medicine which improves both glycemic control and insulin 
resistance by reducing visceral fat is required in Japan. 
MEDI0382 is a synthetic peptide with both glucagon-like peptide-1 (GLP-1) and 
glucagon-receptor co-agonist activity which is under development for the treatment of T2DM. 
GLP-1 receptor agonists are established treatments for T2DM which improve glycaemic 
control, delay gastric emptying and depress appetite leading to modest, weight loss (typically 
4% to 5.4% placebo-subtracted weight loss at 1 year) (Astrup et al. 2012). Glucagon has 
similar effects to GLP-1 on gastric emptying and appetite, and has also been shown to 
promote increased energy expenditure (Lynch et al. 2014; Habegger et al. 2013). 
Oxyntomodulin, a naturally occurring peptide with GLP-1 and glucagon receptor co-agonist 
activity has been shown to promote weight loss through effects on appetite and energy 
expenditure (Wynne et al. 2006) and co-infusion of GLP-1 and glucagon has synergistic 
effects on reducing food intake and promoting weight loss in human subjects (Cegla et al. 
2014). 
As of the cut off date of J-IB version 1.0, a Phase 1/2 study (Study D5670C00002) was 
completed, and is in the reporting phase with data analysis ongoing. A Phase 1 study (Study 
D5670C00001) was completed. Three Phase 1 (Studies D5670C00003, D5670C00008, and 
D5670C00009) and 2 Phase 2 (Studies D5670C00004 and D5670C00011) studies are 
ongoing. One Phase 1（D5670C00012）and 3 Phase 2 (Studies D5671C00001, 
D5670C00007, and D5670C00013) studies are planned. 
Study D5670C00001, a first-time-in-human, single-ascending-dose study assessing the safety, 
tolerability, and PK of MEDI0382 in healthy subjects, was completed, with 6 subjects each 
receiving 1 of 6 doses of MEDI0382 (5, 10, 30, 100, 150, or 300 µg) and 12 subjects receiving 
placebo. In this study, dose escalation proceeded from 5 to 300 µg as planned per the protocol; 
however, 300 µg was not tolerated as evidenced by events of significant vomiting, and the 
dose was de-escalated to 150 µg for the final cohort. A higher proportion of subjects in the 
MEDI0382 group (21/36 subjects, 58.3%) than in the placebo group (2/12 subjects, 16.7%) 
had at least one treatment emergent adverse event (TEAE), with vomiting, nausea, dizziness, 
and headache being the most frequent (incidence > 10% of subjects) in the MEDI0382 group; 
the majority of these TEAEs occurred at the highest two doses (150 and 300 µg). All of the 
TEAEs were mild or moderate in severity. There were no deaths and one subject (10 µg of 


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MEDI0382) had a treatment emergent serious adverse event (TESAE; atrioventricular block 
second degree); this was not deemed to be related to the investigational product.  
After administration of increasing single subcutaneous (SC) doses (5, 10, 30, 100, 150, and 
300 µg), MEDI0382 was in general moderately absorbed with median peak plasma 
concentration observed between 4.5 and 9 hours postdose. After this time, concentrations 
declined slowly between the peak and 48 hours postdose. The median terminal half-life (t1/2) 
could not be estimated accurately in the lowest dose groups (5 and 10 µg) but was comparable 
in the other dose groups (30 to 300 µg) and was about 10 to 12 hours. No subject developed 
antidrug antibody (ADA) in this study.  
A glucose lowering effect was seen in plasma glucose levels of subjects treated with 
MEDI0382 in Study D5670C00001. This effect was visible at low doses, especially around 
the first meal time.  
Study D5670C00002, a Phase 1/2, multiple-ascending dose study assessing the efficacy, 
safety, and PK of MEDI0382 in overweight and obese subjects with T2DM was completed, 
and its Clinical Study Report (CSR) is available. Cohorts 1 through 3 (Part A of the study) 
established an up-titration schedule for MEDI0382 and an effective repeat dose of 200 µg. 
Subjects in Cohort 4 were dosed for an extended period (≥ 41 days) with 200 µg MEDI0382 
(Part B of the study), following a period of up titration, to assess the effect of MEDI0382 on 
glucose control and body weight. Part C assessed the safety and tolerability of a 300 µg dose 
of MEDI0382, and explored 2 possible up-titration schedules from 100 to 300 µg from a 
tolerability, safety, and PK/pharmocodynamic (PD) perspective. 
Overall, there were no deaths reported in the study, 2 subjects had a TESAE and 6 subjects 
had a TEAE that led to withdrawal from the study. The majority of subjects in all cohorts 
experienced at least 1 TEAE, with TEAEs in the Gastrointestinal Disorders System Organ 
Class being the most common. The majority of TEAEs were mild or moderate in severity. 
Preliminary PK results collected from Study D5670C00002, suggest that MEDI0382, in the 
range of 100 to 300 µg, showed a linear PK after daily repeated SC administration, with t1/2 of 
approximately 8 to 11 hours, which provided minimal accumulation after daily repeat dosing. 
Steady state was achieved, based on trough plasma concentration (Ctrough) observation, 
between Days 4 and 7 at all doses tested. Plasma concentrations after 7 days at the highest 
dose (300 µg) seem to have been independent of the titration scheme adopted. Maximal 
plasma concentrations in the dose range tested and with the titration scheme adopted, ranged 
between 1.98 and 34.3 ng/mL.  
The co-primary endpoints, the percent change from baseline to the end of treatment in MMT 
glucose area under the concentration time-curve from time zero to 4 hours (AUC0-4h), and the 
change from baseline in body weight in kg to end of treatment, were assessed after ≥ 41 days 


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dosing of MEDI0382 up-titrated to 200 µg (Cohort 4). MEDI0382 treatment was associated 
with a mean change of -32.78% in MMT glucose AUC0-4h (90% CI -36.98, -28.57) vs 10.16% 
(90% CI 14.10, -6.21) in placebo, p < 0.0001, and a mean change of 3.84 kg from baseline in 
body weight (90% CI - 4.55, -3.12) vs 1.70 kg (90% CI -2.40, -1.01) in placebo, p = 0.0008. 
MEDI0382 treatment was associated with numerically greater mean reductions in MMT 
glucose AUC0-4h and body weight vs placebo in all cohorts. There were no unexpected safety 
signals and no increases in systolic or diastolic blood pressure (BP). With respect to heart rate, 
a trend towards a mean change from baseline in the order of 10 bpm that appeared to be 
consistent across Cohorts 1 to 3 was observed during office based measurements. In Cohort 4 
an increase in heart rate of 11.7 bpm on Day 13 was observed and it reduced to 6.9 bpm on 
Day 41.  Dosing was associated with increased gastrointestinal (GI) adverse events (AEs) with 
40 vomiting related AEs observed in 8 (32%) subjects on MEDI0382 in Cohort 4, however 
the number of events diminished in frequency with dose up-titration. Tolerability was 
comparable to marketed GLP-1 receptor agonists. A Phase I, randomized, blinded 
(investigators and the subjects were blinded to the treatment assignment and the sponsor was 
unblinded to the treatment assignment) study (D5670C00012) to evaluate the safety, 
tolerability, PK, and immunogenicity of MEDI0382 administered as single SC doses to 
preobese/obese but otherwise healthy adult male and female subjects of Japanese and Chinese 
descent was finished (CSR preparation is ongoing). In Part A, 24 subjects of Japanese descent 
across 3 cohorts (8 subjects in each cohort) received single SC doses of 50  µg, 100 µg, and 
150 µg of MEDI0382 or placebo in a 3:1 ratio. In Part B, approximately 8 subjects of Chinese 
descent received a single SC dose of 100 µg MEDI0382 or placebo in a 3:1 ratio. Increased GI 
adverse events (nausea, vomiting, etc.) were observed at the 150 μg dose level, which resulted 
in halting planned dose escalation to 200 μg. A higher proportion of subjects in the 
MEDI0382 group (6/24 subjects, 33.3%) than in the placebo group (1/6 subjects, 16.7%) had 
at least one TEAE, with vomiting, nausea, dizziness, and headache being the most frequent in 
the MEDI0382 group; the majority of these TEAEs occurred at the 150 µg dose level. All of 
the TEAEs were mild or moderate in severity.  One subject (150 µg of MEDI0382) had 
atrioventricular block second degree; this was not deemed to be related to the investigational 
product. Increased heart rate was observed in 100 and 150 µg dose levels that follows the 
same pattern as reported previously, although a small number of patients experienced higher 
magnitude of changes in their heart rate from baseline in Study D5670C00002. In Study 
D5670C00011, in which dosing started from 50 μg and up-titrated to a maximum of 300 μg, 
there were no cases of arrhythmia reported. To date, there is no evidence to suggest the 
existence of a relationship between MEDI0382 dosing and clinically significant arrhythmia. 
Increase in heart rate was observed, consistent with what had been observed previously. No 
deaths or serious AEs were reported and no subject withdrew from the study due to AE. In 
conclusion, MEDI0382 was well tolerated in healthy male and female subjects of Japanese 
and Chinese descent. Overall, tolerability is comparable between studies D5670C00001 and 


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D5670C00012, and with up-titration from low dose to the final dose level, tolerable use of 
MEDI0382 is expected, which is supported by Study D5670C00002. 
After administration of increasing single SC doses, from the preliminary data on 50 and 
100 μg dose levels, MEDI0382 was in general moderately absorbed with median peak plasma 
concentration observed between 6 and 8 hours postdose. The median t1/2 was about 10 hours. 
The available MEDI0382 plasma concentration data between Studies D5670C00001 and 
D5670C00012 are similar. No subject developed ADA in this study. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of MEDI0382 is 
provided in the Investigator’s Brochure. 
2.3 
Benefit/risk 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 Harmonisation 
(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. 
However, it should be noted that given the short treatment durations in Study D5674C00001 
little, if any, direct benefit to the patient’s underlying T2DM should be expected. 
The study design aims to minimize potential risks to subjects participating in this study based 
on the proposed inclusion/exclusion criteria, safety monitoring, and up-titration dosing 
schedule. All subjects will be monitored throughout the study to ensure adequate glycemic 
control. Subjects will be given appropriate training in for SC injection administration as well 
as use of any devices. Refer to the current MEDI0382 IB for further information on the 
potential benefits of MEDI0382 and an assessment of the potential and known risks. Identified 
risks for Study D5674C00001 include nausea and vomiting. 


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3 
OBJECTIVES AND ENDPOINTS 
 
Table 5 
Study objectives 
Primary Objective: 
Endpoint/Variable: 
To characterise the safety profile and tolerability of 
MEDI0382 titrated up to a dose level of 100, 200 or 
300 µg during dosing and follow-up 
Measures of safety and tolerability (24-hour heart rate 
and blood pressure, other vital signs, ECG, laboratory 
test results, and AEs) 
To assess the effects of MEDI0382 titrated up to a 
dose level of 100, 200 or 300 µg on glucose control 
and body weight versus placebo after 48 days of 
treatment 
• 
Percentage change in glucose AUC0-4h as 
measured by a standardised MMT from baseline 
to the end of 48-day treatment  
• 
Percentage change in body weight from baseline 
to the end of 48-day treatment 
Secondary Objective: 
Endpoint/Variable: 
To assess the effects of MEDI0382 titrated up to a 
dose level of 100, 200 or 300 µg on additional 
measures of glucose control versus placebo after 48- 
day treatment 
• 
Change in HbA1c from baseline to the end of 
48-day treatment 
• 
Change in fasting plasma glucose from baseline 
to the end of 48-day treatment 
• 
Change in fructosamine from baseline to the end 
of 48-day treatment 
To assess the effect of MEDI0382 on glucose 
lowering during different meals and times of the day 
as measured by CGM 
 
• 
Change in percentage of time in hyperglycaemia 
(defined as > 7.8 mmol/L or > 140 mg/dL) and 
hypoglycaemia (defined as < 3 mmol/L or 
< 54 mg/dL) from the last day of baseline CGM 
over 24 hours to the end of dosing at each dose 
level (Days 5, 12, 19, and 47) 
• 
Change in percentage of time in hyperglycaemia 
and hypoglycaemia at each dose level over 
5 days for 50 µg and 7 days for other dose levels 
(Days 1 to 5, Days 6 to 12, Days 13 to 19, and 
Days 41 to 47) 
To characterise the PK profile of 50, 100, 200 and 
300 µg of MEDI0382 
PK endpoint: 
Trough plasma concentration (Ctrough) 
To characterise immunogenicity of 100, 200 and 
300 µg of MEDI0382 
Development of anti-drug antibodies and titre (if 
confirmed positive) 
Exploratory Objective: 
Endpoint/Variable: 
To assess the effect of MEDI0382 on pancreatic and 
incretin hormone profiles at baseline and during the 
MMT 
• 
Change in insulin, GLP-1, and glucagon (AUC 
and levels) from baseline after 48-day treatment.
• 
Change in pro-insulin, c-peptide levels, pro-
insulin/c-peptide ratio from baseline after 48-day 
treatment. 
To assess the effects of MEDI0382 in insulin 
resistance and beta cell function. 
Change in percentage of HOMA-Beta and HOMA-R 
from baseline after 48-day treatment. 


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4 
STUDY DESIGN 
4.1 
Overall design 
This is a randomized, parallel-group, placebo-controlled, double-blind, multicenter Phase IIa 
study to evaluate the safety, efficacy, and pharmacokinetics of MEDI0382 in Japanese 
preobese and obese subjects with type 2 diabetes who have inadequate glycemic control with 
diet and exercise. Subject fulfilling all of the inclusion criteria and none of the exclusion 
criteria will be randomised in a 1:1:1:1 ratio to four treatment arms. For an overview of the 
study design see, Section 1.3. For details on treatments given during the study, see Section 6.1 
Treatments Administered.  
For details on what is included in the safety and efficacy endpoints, see Section 3: Objectives 
and Endpoints.  
4.2 
Scientific rationale for study design 
This is a Phase IIa study designed to evaluate the dose range for MEDI0382 to explore the 
safety profile, as well as blood glucose control and weight loss effects of MEDI0382 in 
Japanese patients with T2DM. The design of this study has taken into account the known 
benefits and risks of GLP-1 receptor agonists and glucagon receptor agonists as well as the 
translatable effects observed in nonclinical studies of MEDI0382, such that benefit-risk 
balance for the Japanese preobese and obese patients with T2DM in this study is considered 
favourable. A treatment period of 48 days is required to properly evaluate the dose range and 
safety and tolerability in three different doses. Inclusion of placebo in the study allows 
appropriate basis of AEs, glycaemic control, and weight loss. Benefits related to participation 
in this trial include close follow-up of a subject’s diabetes and treatment with anti-diabetes 
agents. Although one of possible treatments is placebo, appropriate rescue therapy for 
worsening glycaemic control will be implemented if required (see Section 6.5.3).  
4.2.1 
Rationale for Study Population 
Recruitment of subjects with T2DM and a body mass index 24 to 40 kg/m2 
MEDI0382 is a GLP-1 and glucagon receptor co-agonist which relies upon glucose-dependent 
insulin release (the incretin effect) for glucose-lowering effect, and therefore targets subjects 
with T2DM.  
Subjects with T2DM who are preobese or obese are likely to benefit most from losing weight. 
The entry criteria with respect to T2DM and BMI 24 - 40 kg/m2 both will provide safety, 
tolerability, and expected efficacy data in the likely intended clinical population. 


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Recruitment of subjects with an HbA1c of 7.0% to 10.5% 
Subjects with inadequate blood glucose control, defined as HbA1c between 7.0% and 10.5% 
will be enrolled to represent the likely clinical use setting. Only subjects who are treated with 
diet and excise will be enrolled; this will ensure that subjects with an early stage of T2DM are 
treated in this first Japanese study. Rescue therapy will be provided to ensure the safety of 
subjects during the trials. Subjects with acutely decompensated blood glucose control will not 
be enrolled. 
4.2.2 
Rationale for Endpoints 
4.2.2.1 
Rationale for Primary Endpoints 
Safety and Tolerability 
The goal is to ensure that repeated dosing with MEDI0382 shows acceptable safety profile for 
further clinical development, particularly with respect to GI AE profile and effect on heart rate 
(HR) and BP. Given the mechanism of action of MEDI0382, GI events including nausea, 
vomiting, abdominal bloating and diarrhea may be seen with increased frequency. Elevations 
in HR and alterations in BP may also be seen and effects on the QTcF interval will be 
evaluated. 
Measures of Glucose Lowering and Weight Loss 
Co-primary endpoints of glucose AUC and weight loss are adequate to evaluate the efficacy 
of up to 300 µg dose level to assess the benefit of a GLP-1 and glucagon receptor co-agonist 
for 48 days. Percentage change in weight will also be measured. 
4.2.2.2 
Rationale for Secondary Endpoints 
Additional Measures of Glucose Control 
HbA1c and fasting plasma glucose (FPG) tests are used to monitor patient's diabetes control 
level. For the HbA1c test there are firm data that a chronically elevated HbA1c level predicts 
an increased risk for certain diabetic complications. Change from baseline through end of 
treatment in HbA1c should enable modelling for longer-term Phase 2b study design. 
Fructisamine changes more rapidly than HbA1c and represents blood glucose of one to two 
weeks. Therefore, fructisamine can monitor rapid changing blood glucose compared to 
HbA1c. 
Glucose Lowering during different meals and times of the day as measured by CGM 
CGM is obtained with a minimally invasive device applied to the skin in the upper arm that 
provides a measure of interstitial glucose levels every 15 minutes. In this study, results of 
CGM will be used to calculate the average glucose level over 24-hour and 5-day periods or 7-
day periods, to observe glucose excursions during different meals and at different times of the 
day, and to determine the percentage of time subjects have abnormally high or low blood 
glucose levels. 


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Pharmacokinetic Profile and Immunogenicity 
PK information collected in previous single and multiple dose clinical studies (Studies 
D5670C00001 and D5670C00002) suggest that MEDI0382 has a linear profile in the dose 
range 5 to 300 μg with a half-life of approximately 8 to 13 hours in non-Japanese subjects, 
which allows minimal accumulation after repeated daily administration and achievement of 
steady state between 4 and 7 days. Preliminary PK results in Japanese subjects (Study 
D5670C00012) suggested that single dose PK profiles of MEDI0382 are comparable between 
Japanese and non-Japanese subjects. The goal for PK endpoint is to ensure that plasma levels 
of MEDI0382 in Japanese subjects achieve steady state during repeated daily administration 
in similar manner to that in non-Japanese subjects. Plasma concentrations of MEDI0382 from 
50 µg up to 300 µg will be used to evaluate the PK profile (Ctrough) at each dose level to 
establish steady state achievement. 
ADA incidence rate and titre will be tabulated for each treatment to monitor immunogenicity. 
Tiered analyses will be performed to include screening, confirmatory and titre assay 
components; samples confirmed positive for ADA will be tested and analysed for antibody 
titre and reported and may be utilised for further characterisation of the ADA response. 
4.2.2.3 
Rationale for Exploratory Endpoints 
Pancreatic and incretin hormone profiles 
Changes in pancreatic and incretin hormone levels (active and total GLP-1, glucagon, C 
peptide, and insulin) will be measured during the MMT to stratify treatment response to 
MEDI0382. 
Insulin resistance and beta cell function 
Homeostatic model assessments (HOMA); HOMA-S, HOMA-β and HOMA-IR determined 
by fasting glucose, C-peptide, and insulin levels, will be used to assess the effect of 
MEDI0382 on insulin sensitivity, beta cell function, and insulin resistance respectively after 
48 days of treatment, with improvements in these scores likely to correlate with delayed 
progression of T2DM. 
4.3 
Justification for dose 
Based on PK/PD modelling conducted using available clinical literature data on GLP-1 and 
glucagon modulators, the clinically efficacious dose of MEDI0382 was predicted to be in the 
range of 300 to 2000 µg/day; however, in the Study D5670C00001 conducted overseas in 
healthy subjects, multiple episodes of vomiting was observed at the 300 μg dose administered 
as a single dose without up-titration.   Given this observation, in the overseas Study 
D5670C00002 in patients with T2DM, a regimen of 100 µg once daily dosing for 7 days was 
employed, which demonstrated glucose lowering effect without gastrointestinal disorders.  In 
addition, by initiating from 100 µg followed by step-wise dose increase, decreases of 


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gastrointestinal disorders were observed. The gastrointestinal disorders observed initially also 
did not increase as dose increased, and the tolerability and efficacy of up to 300 μg was 
confirmed.  In Study D5670C00001 in healthy subjects and Study D5670C0002 in patients 
with T2DM performed overseas, linear and time-independent PK after single and multiple 
dosing was suggested.  It was also suggested that the single dosing data allows accurate 
estimation of PK after multiple dosing.  In Study D5670C00011 in patients with T2DM, 
starting from 50 µg followed by gradual increase up to 300 µg then changed to repeated 
dosing, the frequency of initial gastrointestinal disorders was more than halved while showing 
similar efficacy compared to Study D5670C00002.  The principle of dose up-titration to 
achieve greater tolerability at higher than initial doses, as described above, is well established 
with daily GLP-1 agents (Victoza SPC, 2014).  
In Study D5670C000012 in Japanese healthy subjects, after single dosing of MEDI0382 at 3 
doses (50, 100 and 150 µg), 50 and 100 µg were tolerated, however, increase in 
gastrointestinal disorders compared to placebo group was confirmed for 150 µg dose. The 
severity of the observed gastrointestinal disorders, however, was Grade 1 in all the patients, 
showing similar tolerability as that in Study D567000001 in overseas healthy subjects.  The 
preliminary PK analysis also presented dose-related exposure increase at 50 and 100 µg, and 
similar PK as that observed at a dose of 100 µg in Study D5670C00001.  Given these results, 
we conclude that it is possible to estimate the safety and tolerability of repeated dosing in 
Japanese patients with T2DM from the result of Study D5670C00011 in non-Japanese patients 
with T2DM. In Study D5670C00011, Cohort 1 was designed to explore the 300 µg dose for 
28 days as part of a 49-day dosing period. The up-titration schedule began at 50µg, to evaluate 
the tolerability profile, principally to see if starting at a lower dose improved the tolerability 
profile with respect to gastro-intestinal related adverse events. With the exception of 1 severe 
event, all nausea and vomiting TEAEs were transient, and mild (Grade 1) or moderate (Grade 
2) in severity, which had resolved by the end of the study. One subject in the Cohort 1 
MEDI0382 dose group had a vomiting TEAE that was severe (Grade 3) and that led to 
interruption of investigational product. This event was not serious and resolved the same day. 
In Cohort 1, MEDI0382 treatment group, nausea TEAEs were reported in 19.2% of subjects 
and vomiting TEAEs were reported in 11.5% of subjects; no nausea or vomiting were reported 
in placebo subjects. Higher frequency of nausea and vomiting was observed at the beginning 
of the up-titration period, which is following the similar pattern as seen in the Study 
D5670C00002 (Appendix G). Furthermore, Study D5670C00011 showed association of one-
week titration with directional trend towards less nausea and vomiting, as well as dose 
initiation at 50 µg reduced the number of subjects experiencing nausea and vomiting 
comparing to the Study D5670C00002. Therefore, the initial dose of this study will be 50 µg 
followed by dose up-titration to 100 µg, 200 µg or 300 µg. It should be noted that the 
investigators should check the safety of each subject such as presence or absence of 
gastrointestinal disorders before dose up-titration. 


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Taken together, we believe that the dosage and administration in this study will allow 
evaluation of both the appropriate dose titration schedule for repeated doses of MEDI0382 and 
a maximal effective repeat-dose, while ensuring safety, in patients with T2DM. 
4.4 
End of study definition 
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study. 
See Appendix A 6 for guidelines for the dissemination of study results. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomised to a study intervention. Under no circumstances can 
there be exceptions to this rule. Subjects who do not meet the entry requirements are screen 
failures, refer to Section 5.4. 
In this protocol, “enrolled” subjects are defined as those who sign informed consent.  
“Randomized” subjects are defined as those who undergo randomization and receive a 
randomization number. 
For procedures for withdrawal of incorrectly enrolled subjects see Section 7.3. 
5.1 
Inclusion criteria 
Subjects are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply: 
Informed consent 
1 
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol. 
2 
Provision of signed and dated, written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses.  
The ICF process is described in Appendix A 3. 
Age 
3 
Subjects must be 20 years of age or older at the time of signing the informed consent 
form. 


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Type of subject and disease characteristics 
4 
Individuals whose HbA1c range of 7.0% to 10.5% (inclusive) at screening. 
5 
Individuals who are diagnosed with T2DM 
6 
Individuals whose current condition at enrolment (Visit 1) is drug naïve defined as: 
 
Never received medical treatment for diabetes (insulin and/or other anti-diabetic 
agents [oral or injection]) 
OR 
 
Received medical treatment for diabetes for less than 30 days since diagnosis. In 
addition, during the 30-day period prior to screening did not receive oral anti-diabetic 
agents for more than 3 consecutive or more than 7 non-consecutive days. Subjects 
also should not have a history of insulin therapy within 2 weeks of screening (with 
the exception of insulin therapy during a hospitalization for other causes or use in 
gestational diabetes) 
OR 
 
Previously received medical treatment for diabetes but have not been treated within 
6 weeks of enrolment 
Weight 
7 
BMI within the range of 24 – 40 kg/m2 (inclusive) at screening 
Sex 
8 
Male and/or female 
Reproduction 
9 
For women of childbearing potential: 
 
Female subjects must be surgically sterile, or using an acceptable method of 
contraception (an acceptable method of contraception is defined as a barrier method 
in conjunction with a spermicide) for the duration of the study (from the time they 
sign consent) and for 4 weeks after the last dose of IP to prevent pregnancy. In 
addition, oral contraceptives, approved contraceptive implant, long-term injectable 
contraception, intrauterine device, or tubal ligation are allowed. Oral contraception 
alone is not acceptable; additional barrier methods in conjunction with spermicide 
must be used. 
 
Must have a negative serum or urine pregnancy test within 72 hours prior to the start 
of IP 
 
Must not be breastfeeding 
 
Female subjects must be 1-year post-menopausal. 


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5.2 
Exclusion criteria  
Medical conditions 
1 
As judged by the investigator, history of, or any existing condition that would interfere 
with evaluation of the IP, put the subject at risk, influence the subject’s ability to 
participate or affect the interpretation of the results of the study 
2 
Positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis C virus core 
antigen, at screening 
3 
Known to have tested positive for human immunodeficiency virus 
4 
Severe allergy/hypersensitivity to any of the proposed study treatments or excipients 
5 
Symptoms of acutely decompensated blood glucose control, a history of type 1 diabetes 
mellitus or diabetic ketoacidosis, or if the subject has been treated with daily SC insulin 
for a period longer than 2 weeks within 90 days prior to screening 
6 
Acute or chronic pancreatitis.  Subjects with serum triglyceride concentrations above 
1000 mg/dL (11 mmol/L) at screening as this can precipitate acute pancreatitis 
7 
Significant inflammatory bowel disease or other severe disease or surgery affecting the 
upper GI tract (including weight-reducing surgery and procedures) which may affect 
gastric emptying or could affect the interpretation of safety and tolerability data 
8 
Significant hepatic disease (except for non-alcoholic steatohepatitis or non-alcoholic fatty 
liver disease without portal hypertension or cirrhosis) and/or subjects with any of the 
following results at screening: 
 
Aspartate transaminase (AST) ≥ 2.5 × upper limit of normal (ULN)  
 
Alanine transaminase (ALT) ≥ 2.5 × ULN  
 
Total bilirubin (TBL) ≥ 2 × ULN 
9 
Impaired renal function defined as estimated glomerular filtration 
rate≤ 60 mL/minute/1.73 m2 at screening (glomerular filtration rate estimated according 
to the formula of Japanese Society of Nephrology) 
10 Severely uncontrolled hypertension defined as systolic BP ≥ 180 mmHg and/or diastolic 
BP ≥ 110 mmHg on the average of two seated measurements after being at rest for at least 
5 minutes 
11 Unstable angina pectoris, myocardial infarction, transient ischaemic 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 
12 Severe congestive heart failure (New York Heart Association Class IV) 
13 Any clinically important abnormalities in rhythm, conduction or morphology of the 
resting ECG and any abnormalities in the 12-lead ECG that, as considered by the 


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investigator, may interfere with the interpretation of QTc interval changes, including 
abnormal ST-T-wave morphology or left ventricular hypertrophy. 
14 Known history of drug or alcohol abuse within 3 months of screening 
15 Basal calcitonin level >50 ng/L or pg/mL at screening or history/family history of 
medullary thyroid carcinoma or multiple endocrine neoplasia 
16 Haemoglobinopathy, haemolytic anaemia, or chronic anaemia (hemoglobin concentration 
< 11.5 g/dL [115 g/L] for males, < 10.5 g/dL [105 g/L] for females) at screening or any 
other condition known to interfere with interpretation of HbA1c measurement 
17 History of neoplastic disease within 5 years prior to screening, except for adequately 
treated basal cell, squamous cell skin cancer, or in situ cervical cancer 
18 History of psychosis or bipolar disorder. History of major depressive disorder within the 
past year with the subject being clinically unstable, or any history of suicide attempt or 
history of suicidal ideation within the past year. 
Prior/concurrent clinical study experience 
19 Participation in another clinical study with an investigational product administered in the 
last 30 days or 5 half-lives of the drug (whichever is longer) at the time of screening 
Other exclusions 
20 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
21 Judgment by the investigator that the subject should not participate in the study if the 
subject is unlikely to comply with study procedures, restrictions and requirements. 
22 Previous randomisation in the present study.  
23 For women only - currently pregnant (confirmed with positive pregnancy test) or breast-
feeding. 
24 Substance dependence likely to impact subject safety or compliance with study 
procedures 
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 re-screening. 
5.3 
Lifestyle restrictions 
Once screened and qualified for entry, subjects will be instructed as follows: 
5.3.1 
Meals and dietary restrictions 
 
Fast overnight for at least 8 hours prior to study site visits, i.e., no food or beverage 
except water. 
 
 


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5.3.2 
Caffeine, alcohol, and tobacco 
 
Withhold alcohol, and refrain from intense exercise for 24 hours prior to each study site 
visit. 
 
5.3.3 
Activity 
 
The subjects should not take investigational products on the morning of the clinic visit. 
 
Any new prescription medications or over-the-counter preparations must be reported to 
study site staff.  For restrictions on concomitant medications, see Section 5.1 and Section 
5.2 (Inclusion and Exclusion Criteria) and Section 6.1.1 (Investigational Product). 
 
Do not donate blood for the duration of the study. 
 
5.4 
Screen failures 
Screen failures are defined as subjects who signed the informed consent form to participate in 
the clinical study but are not subsequently randomly assigned to Study treatment in the study.  
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure subjects to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once.  Rescreened subjects should be assigned the same subject number as for the 
initial screening. However, rescreening should be documented so that its effect on study 
results, if any, can be assessed. 
These subjects should have the reason for study withdrawal recorded in the electronic case 
report form (eCRF). 
6 
STUDY TREATMENTS 
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study 
participant according to the study protocol. Study treatment in this study refers to MEDI0382 
or placebo. 
A once-daily dose is to be self-administered by SC injection as soon as practicable upon 
waking each morning prior to breakfast. If the subject forgets to administer the investigational 
product before the breakfast, s/he should self-administer his/her dose before the following 
meal (lunch or supper) on the same day.  If the investigational product is not administered 
until the time after supper, the subject should skip the dose for the day and will self-administer 
from the next planned dose. 


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6.1 
Treatments administered 
6.1.1 
Investigational products 
Table 6 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
1 vial MEDI0382 solution for injection 2 mg/mL 
Solution for injection, 2 mg/mL, 1 mL per vial 
pre-filled syringe MEDI0382 solution for injection 
100 g 
0.5 mg/mL,1 mL long pre-filled syringe, 0.2 mL Fill, 
100 μg per dose, 1 dose 
pre-filled syringe MEDI0382 solution for injection 
200 g 
0.5 mg/mL,1 mL long pre-filled syringe, 0.4 mL Fill, 
200 μg per dose, 1 dose  
pre-filled syringe MEDI0382 solution for injection 
300 g 
0.5mg/mL,1 mL long pre-filled syringe, 0.6 mL Fill, 
300 μg per dose, 1 dose  
1 vial MEDI0382 solution for injection placebo A 
Solution for injection, 2 mg/mL 1 mL 
pre-filled syringe MEDI0382 solution for injection 
placebo B 
Solution for injection, 1 mL long pre-filled syringe, 
0.3 mL Fill, 1 dose 
  
For the 50 μg, dilution steps will need to be carried out by site staff at the clinical unit. 
The MEDI0382 50 μg and placebo A will be packed into kits, supplied as blinded kits each 
containing one vial. A unique identifying number will appear on both the vials and kit label. 
The MEDI0382 100 μg, 200 μg, 300 μg and placebo B will be packed into kits enough for 
1-week treatment, supplied as blinded kits each containing 8 pre-filled syringes. A unique 
identifying number will appear on both the syringes and kit label. Each container will be 
labelled in accordance with Good Manufacturing Practice (GMP) Annex 13 and per Japan’s 
regulatory requirement. 
6.1.2 
Medical devices 
The Medimmune manufactured medical device provided for use in this study is  
 
1.0 mL pre-filled syringe 
Other medical devices (not manufactured by or for AstraZeneca) provided for use in this study 
are  
 
Digital ECG 
 
CGM device 
 
24-hour ABPM 
 
For medical device incidences, see Appendix F. 


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Any medical device incidents, including those resulting from malfunctions of the device, must 
be detected, documented, and reported by the investigator throughout the study (see Section 
8.4.4) 
6.2 
Preparation/handling/storage/accountability 
Store investigational product at the clinical site at 2°C to 8°C. Investigational product taken 
home by the subject must be stored in a refrigerator at ≤ 8°C. The subject is to avoid the risk 
of freezing the investigational product by carefully placing the investigational product within 
their refrigerator, and they should not use investigational product if it has been frozen. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
Only subjects enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment.  All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
For the first 5 days (Visit 3 to Visit 7), subjects will receive one dose/day of 50 μg or placebo 
A by SC injection at site. For doses of 50 µg a 10-fold diluted stock concentration of 
0.2 mg/mL will be prepared by site staff at the clinical unit, prior to administration. To make a 
10-fold diluted MEDI0382, it is recommended to take 0.1 mL of MEDI0382 investigational 
product using a needle and 1-mL syringe, add it into a sterile empty vial, followed by addition 
of 0.9 mL of diluent into the same vial using a needle and 1-mL syringe. Then administer 
0.25 mL/day. The vial should be mixed by swirling gently to make a homogenous final 
admixture. Do not shake. The diluted dose should be administered using a 1-mL syringe. The 
same procedures are required to placebo A. 
Investigational product should be stored at 2°C to 8°C in the original container. 
Investigational products do not contain preservatives and any unused portion must be 
discarded. Preparation of syringes for dose administration is to be performed aseptically. Total 
in-use storage time from needle puncture of the investigational product vial to start of 
administration should not exceed 4 hours. If storage time exceeds these limits, a new dose 
must be prepared from new vials. 


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At Visit 8 onward, subjects will receive the MEDI0382 100 μg, 200 μg, 300 μg or placebo B 
by SC injection. These IPs are pre-filled syringe, and subjects will receive one dose/day of the 
randomized drug for 43 days. 
Further guidance and information for the final disposition of unused study treatment are 
provided in the ‘Procedures for drug accountability’ and ‘Procedures for drug dissolution and 
usage’. 
6.3 
Measures to minimise bias: randomisation and blinding 
All subjects will be assigned to randomised study treatment using an interactive voice/web 
response system (IVRS/IWRS).  Before the study is initiated, the telephone number and call-
in directions for the IVRS and/or the log-in information and directions for the IWRS will be 
provided to each site.  
If a subject withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused.  Withdrawn subjects will not be replaced.  
Blinded studies 
using IVRS/ 
IWRS 
 
The IVRS/IWRS will provide to the Investigator(s) or pharmacists the kit 
identification number to be allocated to the patient at the dispensing visit.
Routines for this will be described in the IVRS/IWRS user manual that 
will be provided to each centre. 
The randomisation code should not be broken except in medical 
emergencies when the appropriate management of the subject requires 
knowledge of the treatment randomisation.  The Investigator documents 
and reports the action to AstraZeneca, without revealing the treatment 
given to subject to the AstraZeneca staff. 
AstraZeneca retains the right to break the code 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.  Randomisation codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from 
each individual subject have been made and documented. 


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Blind Break 
(IVRS/IWRS) 
The IVRS/IWRS will be programmed with blind-breaking instructions.  
The blind may be broken if, in the opinion of the investigator, it is in the 
subject’s best interest for the investigator to know the study treatment 
assignment.  The sponsor must be notified before the blind is broken 
unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study 
treatment will affect the immediate management of the subject’s 
condition (e.g., antidote available).  In this case, the sponsor must be 
notified within 24 hours after breaking the blind.  The date and reason 
that the blind was broken must be recorded in the source documentation 
and eCRF, as applicable. Study unblinding should not occur until 
database lock and all decisions on the evaluability of the data from each 
individual subject have been made and documented. 
 
6.3.1 
Methods for ensuring blinding 
The study will be conducted in a double-blind fashion for MEDI0382 and placebo. Pre-filled 
syringes of MEDI0382 three different doses and placebo are visually distinct from one 
another. Clear, colourless solutions of MEDI0382 (0.5 mg/mL) will be supplied in 1 mL pre-
filled syringes containing between 0.2 mL and 0.6 mL, depending on the dose. Buffer placebo 
will be supplied in 1 mL pre-filled syringe containing 0.3 mL. The different fill volumes and 
the relative position of the plunger rods will be visually distinct during administration. The IP 
kit cartons are identical in appearance which will be opened exclusively by subjects, just 
before taking the study drug (preferably at home). When administration occurs at the study 
site, subjects must open the kit and administer in absence of the site staff. The investigator 
should instruct subjects to ask only IP manager for any questions about study medication. The 
sponsor staff, the subjects, and the Investigators involved in the treatment of subjects or in the 
clinical evaluation of subjects will not be aware of the treatment received (ICH E9). IP will be 
handled by a designated individual (IP manager – pharmacist/study nurse) at the study site 
who will not be involved in the management or evaluation of study subjects. The tasks will/ 
may include dispensing of IP, collection of used IP boxes along with unused doses, drug 
accountability, instructing the subject on self-administration. This designated individual may 
also administer the IP during the subject’s on-site visit, and answer the subject’s questions 
related to the IP administration.  IP managers should keep documents of drug accountability 
away from the site stuff who are involved in the management or evaluation of study subjects. 
There may also be a designated site Monitor to verify drug accountability performed by 
designated IP manager. 
The results for FPG, HbA1c, S-Glucose, fructosamine and the measurement result of efficacy 
evaluation (see Section 8.1)are blinded to the Investigator for all visits except Visits 1 and 2. 


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Body weight is not blinded measurement item. S-Glucose values are blinded to the Investigator 
site until the unblinding criteria for rescue therapy is met. Once the criteria is met, S-Glucose 
will be reported from the Central Laboratory to the site for an individual subject. Previous values 
will remain blinded and the site will only receive the values going forward from the point the 
criteria is met. The central laboratory will notify the Investigator to repeat S-Glucose without 
providing an explanation, and if the repeated S-Glucose value is at or above the defined level 
for the visit an instruction will be sent to the site by the Central Laboratory to start glycaemic 
rescue therapy in the subject. 
 
6.4 
Treatment compliance 
Any change from the dosing schedule, does interruptions, dose reductions, dose 
discontinuations should be recorded in eCRF. 
The Investigational Product Storage Manager is responsible for managing the IP from receipt 
by the study site until the destruction or return of all unused IP. The Investigator(s) is 
responsible for ensuring that the subject has returned all unused IP. 
6.5 
Concomitant therapy 
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject is receiving at the time of enrolment or receives 
during the study must be recorded along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose and frequency 
 
6.5.1 
Prohibited concomitant medication 
Use of the following medications are restricted, generally speaking, from the time specified in 
the entry criteria until after the final follow-up visit: 
 
Use of other concomitant medications, including over-the-counter medications, herbal 
supplements, multivitamins, and vitamins containing selenium, that are thought to play a 
role in control of body weight or appetite, is prohibited from 1 week prior to Day 1 until 
after the final follow-up visit. Subjects must be instructed not to take any medications, 
including over-the-counter products, without first consulting with the investigator. 
 
Use of any anti-hyperglycaemic medication is prohibited (from the time of signing the 
informed consent form until after the final follow-up visit). 
 
Systemic corticosteroids are prohibited within 28 days prior to screening and throughout 
the study, except if needed to treat a generalized allergic reaction or anaphylaxis (Inhaled, 
intranasal, topical, and intra-articular corticosteroids are permitted). Systemic 
corticosteroid use should first be discussed with and permitted by the medical monitor.  


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 
Compounds known to prolong the QTc interval are prohibited (from the time of signing 
the informed consent form until after the final follow-up visit). 
 
Refer to https://www.crediblemeds.org/healthcare-providers/. 
 
6.5.2 
Other concomitant treatment 
Other medication than that those described above, which is considered necessary for the 
subject’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form. 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications described in Section 6.5.1. 
Subjects may also continue to take their regular prescribed dose of statin during the study. 
Statins are allowed in all cohorts. 
Subjects should receive full supportive care during the study in accordance with their 
institutional guidelines. In the event of nausea or vomiting subjects should be encouraged to 
reduce oral intake of food until symptoms pass. In the event that symptoms do not improve, 
subjects should be offered a centrally acting anti-emetic such as a 5 hydroxytryptamine-3 
antagonist in the first instance, rather than a prokinetic agent such as domperidone or 
metoclopramide. Hormone replacement therapy and agents for benign prostatic hyperplasia 
are also permitted. 
Appropriate measures should also be taken when a subject reports adverse event due to self 
injection. 
6.5.3 
Rescue medication 
Subjects with inadequate glycemic control based on glycemic criteria as outlined in Table 7 
should remain in the study and can receive rescue therapy with any anti-hyperglycemics 
excluding DPPIVi, SGLT2i, GLP-RA). Unless they still have glycemic control improved with 
the rescue therapy, the investigators may discuss with the AstraZeneca physician to decide to 
discontinue the treatment. From Visit 3 to Visit 12, if the results of S-Glucose at the visit show 
more than 270 mg/dL, the investigators should set up extra visit some other day in order to 
recheck the S-Glucose at the Central Laboratory. If the results of S-Glucose show more than 
270 mg/dL consecutively at this second visit, the investigators can consider starting rescue 
treatment. See 6.3.1 for details of S-Glucose reports from the Central Laboratory. If 
significant vomiting (defined as 3 or more episodes in a day or two consecutive days despite 
change of food intake) occurs, adjust aqueous electrolytes balance while monitoring 
electrolytes and urea measured by the site, at the discretion of the investigators. 
 


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Table 7 
Criteria for initiation of rescue therapy during the randomised 
treatment period 
Period 
Central Laboratory S-Glucose 
From Visit 3 (Day 1) to Visit 12 (Day 48) 
S-Glucose > 270 mg/dL (twice in a row) 
 
7 
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL 
7.1 
Discontinuation of study treatment  
Subjects may be discontinued from investigational product (IP) in the following situations. 
Note that discontinuation from study treatment is NOT the same thing as a complete 
withdrawal from the study and reasonable effort should be made for the subject to remain in 
the study. 
 
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment. 
 
Adverse Event 
 
Severe non-compliance with the Clinical Study Protocol 
 
Withdrawal of consent from further treatment with investigational product 
 
 Lost to follow-up 
 
An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing 
 
 Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation at study entry and continuing 
investigational product, in the decision of the investigator, might constitute a safety risk. 
 
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (e.g., refusal to adhere to scheduled visits). 
 
See the SoA for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed. 
7.1.1 
Procedures for discontinuation of study treatment 
The investigator should instruct the subject to contact the site before or at the time of 
docontinuation of investigational product. If the investigational product is permanently 
discontinued as judged by the Investigator, the subject will be followed for protocol-specified 
assessments at Visit 12/Withdrawal  except for MMT as well as Visit 13. Any AEs that are 
not resolved at the subject's last AE assessment in the study are followed up as instructed in 
the Section 8.3.3.  The date of last intake of Study treatment should be documented in the 
eCRF. All investigational product should be returned by the subject at their next on-site study 


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visit (e.g., Visit 13). Subjects permanently discontinuing Study treatment should be given 
locally available standard of care therapy, at the discretion of the Investigator. 
7.2 
Lost to follow-up 
A subject will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.   
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule. 
 
Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject or next of kin by e.g. repeat telephone calls, 
certified letter to the subject´s last known mailing address or local equivalent methods. 
These contact attempts should be documented in the subject’s medical record.  
 
Should the subject be unreachable at the end of the study the subject should be considered 
to be lost to follow up with unknown vital status at end of study and censored at latest 
follow up contact. 
 
7.3 
Withdrawal from the study 
A subject may withdraw from the study (e.g., withdraw consent), at any time at his/her own 
request, without prejudice to further treatment.  A subject who discontinues study medication 
should be encouraged to continue in the study. 
If the subject withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a subject withdraws from the study, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records.   
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up subjects as medically indicated.  
See SoA, Table 2, for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. All investigational product should 
be returned by the subject. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarised in the SoA.   


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The investigator will ensure that data are recorded on the eCRFs. The Electronic Data Capture 
(EDC) system will be used for data collection and query handling.   
The investigator ensures the accuracy and completeness of study data. For eCRFs, this 
includes: legibility and timeliness of the data recorded and of the provision of answers to data 
queries according to the Clinical Study Agreement. The investigator will sign the completed 
electronic Case Report Forms. A copy of the completed electronic Case Report Forms will be 
archived at the study site. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue Study treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.   
Procedures conducted as part of the subject’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilised for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA. 
The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed about 352.9 mL. Repeat 
or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
Efficacy assessments  
8.1.1 
Mixed-meal Test 
Refer to Section 8.7 
8.1.2 
 Weight  
Weight will be measured at the time points specified in the schedules of procedures by 
cohort(s), after the subject has toileted and removed bulky clothing including shoes.  
Whenever possible, the same (properly calibrated) scale should be used for each measurement 
for any given subject. 


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8.1.3 
HbA1c, Fasting plasma glucose and fructosamine 
Blood samples for measurement of HbA1c, fasting plasma glucose and fructosamine  will be 
collected according to the schedule presented in the Study Plan (Table 1 and Table 2).  The 
instructions for collection, processing, packaging, and shipping of the samples will be detailed 
in the Laboratory Manual. 
8.1.4 
Continuous glucose monitoring (CGM) 
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 for 2 weeks continuously, and does not require any calibration or periodic near 
touch/ blue-tooth 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, and the investigator should avoid review of baseline readings taken on at 
screening.  
Data collected by FreeStyleLibrePro will be stored at the study site as source data.  An unblinded study 
site personnel will electronically store the data collected by FreeStyleLibrePro in a secure external 
media managed by an unblinded Sponsor personnel.  The unblinded Sponsor personnel will regularly 
review integrity of the data provided by the study site.  Frequency and procedure of the data provision 
by the study site as well as the procedure to review and manage the data by the unblinded Sponsor 
personnel will be specified separately as a procedure manual. 
The CGM sensor, which is a small plastic circular device of 35 mm diameter and 5 mm depth, 
should be applied to the back of the upper arm, taking into account subject preference and the 
side where the ABPM device will be sited. The selected site should be shaved where 
necessary, and a sterile alcohol wipe supplied with the kit 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, and are to be advised that they 
may bathe and shower, and swim in 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 close to the original site, but taking into account 
the subject’s preference on site. CGM sensors are single-use only and cannot be reapplied 
once removed and 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. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 
Clinical safety laboratory assessments 
See Table 8 for the list of clinical safety laboratory tests to be performed and to the SoA for 
the timing and frequency.  All protocol-required laboratory assessments, as defined in the 
table, must be conducted in accordance with the laboratory manual and the SoA.   
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables.   
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.  The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF. 
The clinical chemistry, haematology and hemostasis will be performed at a central laboratory. 
The urinalysis will be performed at a local laboratory. 
Table 8 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum) 
B-Haemoglobin 
S-Creatinine 
B-Leukocyte count 
S-Bilirubin, total 
B-Leukocyte differential count (absolute count) 
S-Alkaline phosphatise (ALP) 
B-Platelet count 
S-AST 
B-Red blood cell 
S-ALT 
B-Hematocrit 
S-Albumin 
B-Mean corpuscular volume 
S-Potassium 
B-Mean corpuscular hemoglobin concentration 
S-Calcium 
 
S-Sodium 
Coagulation 
S-Chloride 
Prothrombin time (screening only) 
S-Gamma glutamyl transferase 


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Activated partial thromboplastin time (screening 
only) 
S-Blood urea nitrogen 
 
S-Glucose 
U-Urinalysis 
S-Bicarbonate 
Colour/Appearance 
beta-hydroxybutyrate 
Specific gravity 
 
potential of hydrogen 
 
Protein 
 
Glucose 
 
Ketones 
 
Blood 
 
Leucocyte esterase 
 
Bilirubin 
 
Urobilinogen 
 
Nitrite 
 
Notes: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently and assessed concurrently. 
Urinalysis for specific gravity, pH, protein, glucose, ketones, blood, leucocyte esterase, bilirubin, urobilinogen, 
and nitrite may be performed at the site using a licensed test (dipstick). 
NB. In case a subject shows an AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN please refer to 
Appendix E ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for further 
instructions. 
Other Tests 
• 
Calcitonin (screening only), thyroid-stimulating hormone (screening only), pancreatic 
amylase, lipase 
• 
Blood lactate 
• 
HbA1c 
• 
Anti-drug antibodies  
• 
Total immunoglobulin (Ig) and subsets (Ig A/E/G/M) 
• 
Urine or serum (human chorionic gonadotropin) pregnancy test (females only) 
• 
Hepatitis B surface antigen, hepatitis C antibody (screening only) 
• 
Glucose metabolism panel for MMT: Timed glucose, insulin, pro-insulin, c-peptide, GLP-
1, and glucagon.  
• 
Fructosamine 
 


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• 
Fasting lipid profile: HDL-C, LDL-C, TG, and FFA 
• 
TG 
8.2.2 
Physical examinations 
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including 
spine and extremities) and neurological systems. 
Targeted examinations (evaluation of selective body systems at the judgement of the 
physician or qualified designee based on subject presentation) are sufficient for the remaining 
time points after the screening. 
Physical examination will be performed at timelines as specified in the SoA, Investigators 
should pay special attention to clinical signs related to previous serious illnesses, new or 
worsening abnormalities may qualify as adverse events, see Sections 8.3.6 and 8.3.7 for 
details. Height will be measured at screening. 
8.2.3 
Vital signs 
 
Axillary temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
 
Blood pressure and pulse measurements will be assessed in the supine position for at least 
10 minutes with a completely automated device.  Manual techniques will be used only if 
an automated device is not available. 
 
Blood pressure and pulse measurements should be preceded by at least 10 minutes of rest 
for the subject in a quiet setting without distractions (e.g., television, cell phones). 
 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute).  The average of the 3 blood pressure readings 
will be recorded on the eCRF. 
 
ABPM will be used for the 24-hour period at Visit 2 (as a baseline) and at Visit 10, Visit 
12 after receipt of the SC dose at the clinic visit. 
 
The subject should do a Ketostix® test daily on non-clinic-visit days during the at-home 
self-administration period 
 
8.2.4 
Electrocardiograms 
Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 1.1) using an 
ECG machine that automatically calculates the heart rate and measures respiration rate, pulse 
rate, QRS, and QT intervals. Derived parameters (such as HR, QTcF and others as applicable) 
will be calculated. 


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At each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart.  The full set of triplicates should be 
completed within 5 minutes. 
8.2.5 
Other safety assessments 
8.2.5.1 
Ambulatory Blood Pressure Monitoring 
Subjects will be given training at their local study site about how to set up and apply the 
ABPM device. In brief, an appropriate size cuff encircling 80% to 100% of the arm will be 
selected and the device will be fitted to the nondominant arm of the subject, with the bladder 
placed over the artery and an initial test reading performed. The subjects will be advised that 
for the first reading the device will inflate to a pressure of 180 mmHg, and thereafter the 
device will adapt to inflate to a pressure just above the last recorded BP. The subject will be 
advised to undergo normal daily activities while wearing the cuff, and he/she will be advised 
to avoid any strenuous form of activity, bathing, or showering while wearing the cuff. The 
subject will be advised to remain still during a measurement with the arm relaxed at heart 
level. The subject will also be given advice on how to wear the device during the day and at 
night while sleeping, and what to expect in terms of frequency of readings during the day 
(every 15 minutes) and overnight (every 30 minutes). During ABPM, systolic BP, diastolic 
BP, pulse pressure, pulse rate, and mean arterial pressure readings will be recorded over a 
period of 24 hours. 
Data collected by ABPM device will be stored at the study site as source data.  The data collected by 
ABPM device will be stored in a secure external media managed by the Sponsor.  The Sponsor will 
regularly review integrity of the data provided by the study site.  Frequency and procedure of the data 
provision by the study site as well as the procedure to review and manage the data by the Sponsor will 
be specified separately as a procedure manual. 
8.2.5.2 
Daily Diaries 
On Day -1 (Visit 2), each subject will be trained on how to complete the Daily Diary according 
to the schedule outlined in SoA. Subjects will be encouraged to complete the Daily Diary as 
accurately as possible. 
The following entries will be made daily into the Daily Diary and collected and reviewed by 
site staff at the appropriate visits: 
 Date 
 Confirmation that the acceptable temperature was maintained  
 Unique kit number of dose 
 Time of self-dose administration 
 Start time of each meal 


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 Daily Ketostix® result (negative or positive) (Note: In case a Ketostix® [ketone] test result 
is positive, the subject will be instructed to call the site.) 
 Any new medications or changes to standard medications (Note: Subjects will be 
instructed to contact the site in the event of any new medications or changes to 
medication.) 
 Any vomiting and time of each episode 
 Any other events 
 
If the subject forgets to fill in any requested information, it will not be considered a protocol 
deviation. 
8.3 
Collection of adverse events 
The investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section 
The definitions of an AE or SAE can be found in Appendix B. 
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).   
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see section 8.3.3. 
8.3.1 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.   
8.3.2 
Time period and frequency for collecting AE and SAE information  
Adverse Events will be collected from Visit 2 or Visit 3 (randomisation) throughout the 
treatment period and including the follow-up period, Visit 13. 
SAEs will be recorded from the time of signing of informed consent form. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B.  The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject’s last visit 


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and he/she considers the event to be reasonably related to the Study treatment or study 
participation, the investigator may notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE is provided in 
Appendix B. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts.  All SAE/non-serious AEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up.  
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF.  AstraZeneca 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. 
8.3.4 
Adverse event data collection 
'The following variables will be collected for each AE: 
 
AE  
 
The date when the AE started and stopped 
 
Maximum intensity 
 
Whether the AE is serious or not 
 
Investigator causality rating against the Investigational Product(s) (yes or no) 
 
Action taken with regard to Investigational Product(s) 
 
AE causing subject’s withdrawal from study (yes or no) 
 
Outcome. 
In addition, the following variables will be collected for SAEs: 
 
Date AE met criteria for serious AE 
 
Date Investigator became aware of serious AE 
 
AE is serious due to 
 
Date of hospitalisation 
 
Date of discharge 
 
Probable cause of death 
 
Date of death 
 
Autopsy performed 
 
Causality assessment in relation to Study procedure(s) 
 
Causality assessment to other medication 


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8.3.5 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’ 
For SAEs, causal relationship will also be assessed for other medication and study procedures 
and/or AstraZeneca (AZ) Medical device.  Note that for SAEs that could be associated with 
any study procedure the causal relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit?’, or 
revealed by observation will be collected and recorded in the eCRF.  When collecting AEs, 
the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms.  However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
8.3.7 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR.  Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs and physical examinations should therefore only be reported as 
AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of treatment 
with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low hemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
8.3.8 
Hy’s law 
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 


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be reported as SAEs.  Please refer to Appendix E for further instruction in the case of 
increases in liver biochemistry and evaluation of Hy’s Law 
8.4 
Safety reporting and medical management 
8.4.1 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca 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 adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. 
If the EDC system is not available, then the Investigator or other study site staff reports an 
SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.   
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol. 
8.4.2 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for: 
 
If the pregnancy is discovered before the study subject has received any study drug 
 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy. 
 
If the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product, then the investigator or other site personnel will 


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inform the appropriate sponsor representatives within 24 hours of learning of the 
pregnancy. 
 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 
8.4.2.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event 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 AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy. 
8.4.3 
Overdose 
For this study, any dose of MEDI0382 greater than the dose at > 300 µg will be considered an 
overdose. The investigator should report an overdose to the sponsor when the subject injects 
more than once a day. 
No specific treatment is recommended for an overdose. 
 
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 
 


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If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
 
For overdoses associated with a SAE, the standard reporting timelines apply, see  
Section 8.3.2.  For other overdoses, reporting must occur within 30 days. 
 
8.4.4 
Medical device incidents (including malfunctions) 
Medical devices are being provided for use in this study.  In order to fulfil regulatory reporting 
obligations worldwide, the investigator is responsible for the detection and documentation of 
events meeting the definitions of incident or malfunction that occur during the study with such 
devices.   
The definition of a Medical Device Incident can be found in Appendix F 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined 
in Section 8.3 and Appendix B.   
8.4.4.1 
Time period for detecting medical device incidents 
 
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported during all periods of the study in which the medical 
device is used.   
 
If the investigator learns of any incident at any time after a subject has been discharged 
from the study, and such incident is considered reasonably related to a medical device 
provided for the study, the investigator will promptly notify the sponsor. 
 
The method of documenting Medical Device Incidents is provided in Appendix F. 
8.4.4.2 
Follow-up of medical device incidents 
 
All medical device incidents involving an AE will be followed and reported in the same 
manner as other AEs (see Section 8.3.3). This applies to all subjects, including those who 
discontinue Study treatment. 
 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident. 
 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator. 
 


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8.4.4.3 
Reporting of medical device incidents to sponsor 
 
Medical device incidents will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical device 
incident. 
 
Medical Device Incident will be reported via eCRF.  If eCRF is unavailable, then e-mail 
communication should be utilized. 
 
The same individual will be the contact for the receipt of medical device reports and SAE. 
 
If an investigational medical device is used, the Study Representative will send the SAE 
report to AZ data entry site within one calendar day. 
 
8.4.4.4 
Regulatory reporting requirements for medical device incidents 
 
The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfil the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety 
information relating to medical devices being used in clinical studies. 
 
The investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of incidents to the IRB/IEC. 
 
8.4.5 
Medication error 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors. 
The definition of a Medication Error can be found in Appendix B. 
8.5 
Pharmacokinetics 
Blood samples for determination of MEDI0382 in plasma will be taken at the times presented 
in the Study Plan (Table 2). 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.  


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8.5.1 
Determination of drug concentration 
Samples for determination of drug concentration will be analysed by a selected laboratory on 
behalf of AstraZeneca, using an appropriate bioanalytical method.  Full details of the 
analytical method used will be described in a separate bioanalytical report. 
8.5.2 
Storage and destruction of pharmacokinetic samples 
PK samples will be disposed of after the Bioanalytical Report finalization or six months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses.  
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling.  
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method.  Any results from such analyses may be 
reported separately from the CSR. 
8.6 
Immunogenicity 
Instructions for MEDI0382 immunogenicity (ADA) sample collection, processing, storage, 
and shipment can be found in the Laboratory Manual. Serum samples for analysis of ADA 
will be collected for subjects on MEDI0382/Placebo arms according to the schedule presented 
in the Study Plan (Table 2). A screening assay will be used to determine ADA-positive 
samples. This will be in the form of a traditional ligand-binding “bridging” assay using 
electrochemiluminescence. Any positive samples will be tested in a confirmatory assay 
whereby the specificity of the ADA response will be confirmed as either positive or negative 
with respect to MEDI0382. Cross-reactivity of ADA-positive samples to GLP-1 and glucagon 
may also be assessed in the confirmatory assay. Titre evaluation will be performed on samples 
that are confirmed positive for ADA. For subjects with a confirmed positive ADA result, a 
qualitative analysis of incretin hormone levels in response to MMT (i.e., glucagon, GLP-1, 
glucose, and insulin) will also be performed to assess whether any correlation exists between 
the response and ADA positivity. 
At the end of study visit, if a subject’s sample is confirmed ADA positive, the subject will be 
asked to return to provide another sample in as close as 3 months at the end of study visit to 
evaluate whether or not ADA positivity is persist. If the sample taken in 3 months is ADA 
positive, the subject will be asked to return to provide a sample in another 3 months 
(Approximately 6 months after the end of study visit). If the sample is ADA positive at 6 
months, the investigator and the study physician will discuss what further action will be taken. 
The results of ADA in 3 months and 6 months at the end of study will not be recorded in the 
CRF module and the database. Serum samples collected for ADA should be stored for 2 years 
after marketing approval, and they may be utilised for further characterisation of the antibody 
response. 


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8.7 
Pharmacodynamics 
Mixed-meal Test 
Following a minimum 8-hour overnight fast and at 2.5 hours after administration of IP, the 
subject will undergo a MMT. For the MMT, the subject will consume a standardised meal 
(ENSURE H, a nutritional supplement containing the components of fat, carbohydrate and 
protein, which make up a standard MMT) within 5 minutes, and timed serial blood samples 
will be obtained for measurement of glucose and parameters related to glucose metabolism 
through 240 minutes after consumption of the standardised meal (with no additional food 
intake during this time). The MMT procedures will be performed at the time points specified 
in the schedules. The time points are also summarized in SoA. 
The timed pre- and post-MMT blood sample collections are for measurement of a panel of 
glucose metabolism markers: glucose, insulin, pro-insulin, c-peptide, GLP-1 and glucagon, as 
indicated in the example schedule for PK and PD/efficacy in Table 3 and Table 4. Glucose 
measurements from these pre- and post-MMT samples will be used for the primary efficacy 
assessment. All MMT test results will be used to generate PD profiles.  
8.7.1 
Collection of samples 
Blood will be drawn 15 minutes before consuming the standardised meal, and at 15, 30, 45, 
60, 90, 120, 180, and 240 minutes (± 5 minutes) after consumption. Blood sampling should 
occur as close as possible to the specified times for the MMT. Sampling ± 5 minutes of the 
specified time will not be considered a protocol deviation but the exact time of sampling 
should be recorded.  
8.7.2 
Storage, re-use and destruction of pharmacodynamic samples 
The primary PD samples will be stored for a maximum of 15 years from the date of the Last 
Subject’s Last Visit, after which they will be destroyed. The results of any investigation will 
be reported either in the CSR itself or as an addendum, or separately in a scientific report or 
publication. 
8.8 
Genetics 
Participation is optional.  Subjects who do not wish to participate in the genetic research may 
still participate in the study. 
See Appendix D for Information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in Appendix D. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 


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9 
STATISTICAL CONSIDERATIONS  
9.1 
Statistical hypotheses 
One of the primary objectives of this study is to assess the safety of MEDI 0382 100 g, 
200 g, or 300 g up-titration regimen compared with Placebo, as measured by the incidence 
of AEs (including SAEs), 24-hour heart rate and ABPM, safety laboratory measurements and 
digital ECGs. For the safety objective, no formal hypothesis testing will be carried out. Safety 
evaluation will be done in a descriptive manner.  
The other primary objective is to explore the efficacy of MEDI0382 100 g, 200 g or 300 g 
up-titration regimen compared with placebo, as measured by percent change from baseline to 
Day 48 in MMT glucose AUC(0-4h) and body weight. For efficacy objective, pair-wise 
comparison of each MEDI0382 dose vs. Placebo will be made in an exploratory manner, each 
at significance level of 0.05, without multiplicity adjustment.  
9.2 
Sample size determination  
Approximately 60 patients are to be randomized to Placebo, MEDI0382 100 g, 200 g, and 
300 g in a ratio 1:1:1:1.  
Assuming approximately 10% drop out during study, approximately 13 subjects are expected 
to be evaluable per treatment groups. 
Assuming standard deviation of percent change in MMT glucose AUC(0-4h) of 20%, 
approximately 13 patients per arm would provide more than 80% power to detect 23% 
difference in percent change of MMT glucose AUC(0-4h) for pair‐wise comparison between 
each of MEDI0382 dose group and Placebo each at two-sided alpha = 0.05, without formal 
multiplicity adjustment. 
Assuming standard deviation of percent change from baseline in body weight of 2.5%, the 
same number of subjects would provide approximately 68% power to detect mean difference 
of 2.5% at two-sided alpha =0.05 without formal multiplicity adjustment.           
 
 
 
 
 


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9.3 
Populations for analyses 
For purposes of analysis, the following populations are defined:  
Population 
Description 
Enrolled 
All subjects who signed the ICF 
Randomised Set 
All subjects who received randomisation number.  
Full Analysis Set 
All randomised subjects who received at least one dose of IP. 
Subjects will be analysed according to randomized treatment.  
Safety analysis set 
All randomised subjects who take at least 1 dose of IP. 
Subjects will be analysed according to treatment they received. 
PK analysis set 
The PK population includes all subjects who received at least 
one dose of MEDI0382 and had at least one post-baseline 
MEDI0382 PK sample taken that is above the lower limit of 
quantitation. 
 
9.4 
Statistical analyses 
All personnel involved with the analysis of the study will remain blinded until database lock 
and Clinical Study Protocol deviations identified.   
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan (SAP) will be developed and finalised before database lock and will describe the 
subject populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data.  This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints.  Any deviations from this plan will be reported in the 
clinical study report. 
9.4.1 
Efficacy analyses 
Efficacy analyses will be carried out for FAS.  
Percent change from baseline in MMT Glucose AUC(0-4h) to Day 48 will be analysed with 
ANCOVA model with treatment group as a factor and baseline as a covariate. Least squares 
mean (LSMean)s and their 95%CIs for percent changes from baseline for each treatment 
group, as well as difference in LSMeans, 95%CI and nominal p-values will be provided for 
pair-wise comparison of each MEDI0382 dose vs. Placebo group. For subjects who 
prematurely discontinued study drug, the last on-treatment measurement regardless of rescue 
will be used for this analysis. Percent change from baseline to Day 48 in body weight will be 
analysed similarly. 


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Secondary efficacy variables will be analysed by ANCOVA or other appropriate models. 
Details will be provided in Statistical Analysis Plan. 
9.4.2 
Safety analyses 
Safety analysis will be based on Safety set. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The type, incidence, severity and relationship to investigational product of each 
AE will be summarized by MedDRA System Organ Class and Preferred Term, using number 
and percentage of patients with certain events. AEs with onset on or after first day of IP will 
be mainly evaluated. Other safety variables such as 24-hour ABPM, vital signs, ECG and 
safety laboratory tests will be summarized descriptively by treatment and visit, as appropriate. 
9.4.3 
Other analyses (PK) 
Individual MEDI0382 plasma concentrations will be summarised by treatment and visit. 
MEDI0382 plasma concentration at trough (Ctrough) may be summarised by treatment and visit 
using descriptive statistics for the MEDI0382 treatment arms.  
A population PK analysis may be performed to further evaluate the PK properties of 
MEDI0382, but will not be reported in the CSR.  
The immunogenicity of MEDI0382 will be evaluated. The number and percentage of subjects 
with confirmed positive serum antibodies to MEDI0382 will be reported by dose level. Data 
on titres and cross-reactivity to GLP-1 and glucagon (where applicable) will be listed. If 
warranted by the data, the association of ADA positive with observed PK data may be 
explored. 
Pharmacodynamic, and biomarker exploratory analyses will be described in the SAP finalised 
before database lock.  The pharmacodynamic analyses will be presented separately from the 
main CSR.   
9.5 
Interim analyses  
Not applicable. 
9.5.1 
Data monitoring committee (DMC) 
Not applicable. 


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10 
REFERENCES 
FDA Guidance for Industry (issued in July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’ 
Astrup et al. 2012 
Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean MEJ, et al.  Safety, tolerability 
and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide.  
Int J Obes. 2012;36:843-54. 
Cegla et al. 2014 
Cegla J, Troke RC, Jones B, Tharakan G, Kenkre J, McCullough KA, et al.  Coinfusion of 
low-dose GLP-1 and glucagon in man results in a reduction in food intake.  Diabetes 2014; 
63(11):3711-20.  
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.   
Victoza SPC, 2014 
Victoza (liraglutide) 6 mg/mL for injection in pre-filled pen (Summary of Product 
Characteristics [SPC]). May 2014; Novo Nordisk Limited, West Sussex, United Kingdom. 
Available at: 
https://www.medicines.org.uk/EMC/medicine/21986/SPC/Victoza+6+mg+ml+solution+for+i
njection+in+pre-filled+pen  
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. 
 


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11 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 


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Appendix A Regulatory, ethical and study oversight considerations 
A 1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
 
Applicable ICH GCP Guidelines 
 
Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.   
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.   
The head of the study site will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
 
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples. 
A 2 
Financial disclosure 
Not applicable. 
A 3 
Informed consent process 
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legal 
representatives will be required to sign a statement of informed consent that meets the 


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requirements of local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act, where applicable, and the IRB/IEC or study centre.   
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained.  
The authorised person obtaining the informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.   
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.   
The investigator or authorised designee will explain to each subject the objectives of the 
exploratory research.  Subjects will be told that they are free to refuse to participate and may 
withdraw their consent at any time and for any reason during the storage period.  The subject 
will give a separate agreement to allow any remaining specimens to be used for exploratory 
research.  Subjects who decline to participate in this optional research will indicate this in the 
ICF.  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 already have been analysed 
at the time of the request, AstraZeneca will not be obliged to destroy the results of this 
research. 
A 4 
Data protection 
Each subject will be assigned a unique identifier by the sponsor.  Any subject records or data 
sets transferred to the sponsor will contain only the identifier; subject names or any 
information which would make the subject identifiable will not be transferred.   
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the subject.   
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
A 5 
Committee’s structure 
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators. 


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A 6 
Dissemination of clinical study data 
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical trial and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted. 
A 7 
Data quality assurance 
All subject data relating to the study will be recorded on printed or eCRF unless transmitted to 
the sponsor or designee electronically (e.g., laboratory data).  The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing 
the eCRF.   
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.   
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.   
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.   
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  
A 8 
Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The investigator may need 
to request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available. 


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Definitions of what constitutes source data can be found in Clinical Study Agreement. 
A 9 
Publication policy 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission.  This allows the sponsor to protect proprietary information and to provide 
comments.   
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 


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Appendix B Adverse event definitions and additional safety information 
B 1 
Definition of adverse events 
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.   An AE can therefore be any unfavourable and 
unintended sign (e.g.  an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.   
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered. 
B 2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
 
Results in death 
 
Is immediately life-threatening 
 
Requires in-subject hospitalisation or prolongation of existing hospitalisation  
 
Results in persistent or significant disability or incapacity.   
 
Is a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above. 
B 3 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the 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 (e.g., hepatitis that resolved without hepatic failure). 
B 4 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., 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. 


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B 5 
Important medical event or medical treatment 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment 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 
judgement must be used. 
Examples of such events are: 
 
Angioedema not severe enough to require intubation but requiring iv 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 (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
 
Development of drug dependency or drug abuse 
B 6 
Assessment of Severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below. 
Grade 1  
An event of mild intensity that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Grade 2  
An event of moderate intensity that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Grade 3  
A severe event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical status of the 
subject. 
Grade 4  
An event, and/or its immediate sequelae, that is associated with an imminent risk 
of death. 
Grade 5  
Death (loss of life) as a result of an event. 


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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 Appendix B 2. A 
Grade 3 AE needs 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. 
B 7 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
 
Time Course.  Exposure to suspect drug.  Has the subject actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
 
No alternative cause.  The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a re-
challenge. 
 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
 
Is this a recognized feature of overdose of the drug? 
 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 


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Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
B 8 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.   
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error.   
 
occurred 
 
was identified and intercepted before the participant received the drug 
 
did not occur, but circumstances were recognised that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
 
Drug name confusion 
 
Dispensing error e.g.  medication prepared incorrectly, even if it was not actually given to 
the participant 
 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
 
Drug not taken as indicated e.g.  tablet dissolved in water when it should be taken as a 
solid tablet  
 
Drug not stored as instructed e.g.  kept in the fridge when it should be at room 
temperature  
 
Wrong participant received the medication (excluding IVRS/IWRS errors) 
 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
 
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error  
 
Participant accidentally missed drug dose(s) e.g.  forgot to take medication 
 
Accidental overdose (will be captured as an overdose) 
 
Participant failed to return unused medication or empty packaging 
 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product  


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Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 


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Appendix C Handling of Human Biological Samples 
C 1 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 
The Investigator at each centre keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate). 
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. 
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers. 
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle. 
C 2 
Withdrawal of Informed Consent for donated biological samples  
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 analysed, 
AstraZeneca is not obliged to destroy the results of this research. 
As collection of the biological sample(s) is an optional part of the study, then the subject may 
continue in the study. 
The Investigator: 
 
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca 
 
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 
 
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site 
 
Ensures that the subject and AstraZeneca are informed about the sample disposal 
 
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 


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C 3 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories  For transport purposes the classification of infectious substances according to 
risk groups was removed from the Dangerous Goods Regulations in the 46th edition (2005). 
Infectious substances are now classified either as Category A, Category B or Exempt. There is 
no direct relationship between Risk Groups and Categories A and B. 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are e.g., Ebola, Lassa fever 
virus: 
 
are to be packed and shipped in accordance with IATA Instruction 602. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name: 
 
UN 3373 – Biological Substance, Category B 
 
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
 
Clinical trial samples will fall into Category B or exempt under IATA regulations 
 
Clinical trial samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging  
 
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
 
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable 
 
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used. 


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Appendix D Genetics 
D 1 
Use/analysis of deoxyribonucleic acid (DNA) 
Genetic variation may impact a subject’s response to therapy, susceptibility to, and severity 
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease aetiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting subjects. 
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.   
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies. 
Genetic research may consist of the analysis of the structure of the subject´s DNA, i.e. the 
entire genome.  
The results of genetic analyses may be reported in the CSR or in a separate study summary. 
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
The samples will be retained while research on Study treatment or Study treatments of this 
class or indication continues but no longer than 15 years or other period as per local 
requirements. 
D 2 
Genetic research plan and procedures 
Selection of genetic research population 
Subject selection record 
All subjects will be asked to participate in this genetic research.  Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit.  The subject will 
not be excluded from any aspect of the main study. 
Inclusion criteria 


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For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol, and provide informed consent for the genetic 
sampling and analyses. 
Exclusion criteria 
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following: 
 
Previous allogeneic bone marrow transplant 
 
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection 
 
Withdrawal of consent for genetic research  
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7.3. 
Collection of samples for genetic research 
The blood sample for genetic research will be obtained from the subjects predose at Visit 12.  
If for any reason the sample is not drawn at Visit 12, it may be taken at Visit 13.  Only one 
sample should be collected per subject for genetics during the study.  Samples will be 
collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  Samples will be stored for a maximum of 
15 years, from the date of last subject last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached. 
An additional second code will be assigned to the blood sample either before or at the time of 
DNA extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA). 
The link between the subject enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 


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designated organisations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent. 
Ethical and regulatory requirements 
The principles for ethical and regulatory requirements for the study are outlined in 
Appendix A . 
Informed consent 
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre.  The 
investigator is responsible for ensuring that consent is given freely and that the subject 
understands that they may freely withdrawal from the genetic aspect of the study at any time. 
Subject data protection 
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data.  In addition, Regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate. 
Data management 
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples. 
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies.  This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease.  The researchers can 


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only use this information for health-related research purposes.  Researchers may see summary 
results but they will not be able to see individual subject data or any personal identifiers.   
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database. 
Statistical methods and determination of sample size 
The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan may be prepared where appropriate. 


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Appendix E Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law 
E 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.   
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational 
medicinal product (IP).   
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting AE and SAE according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
E 2 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study 
following the start of study medication 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 
IP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on 
the same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur. 


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E 3 
Identification of potential Hy’s Law cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination: 
 
ALT ≥ 3 × ULN 
 
AST ≥ 3 × ULN 
 
TBL ≥ 2 × ULN 
When a subject meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the 
AstraZeneca representative).   
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will: 
 
Notify the AstraZeneca representative 
 
Request a repeat of the test (new blood draw) by the central laboratory 
 
Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result 
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay: 
 
Determine whether the subject meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results) 
E 4 
Follow-up 
E 4.1 
Potential Hy’s Law criteria not met 
If the subject does not meet PHL criteria the Investigator will: 
 
Inform the AstraZeneca representative that the subject has not met PHL criteria. 
 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
E 4.2 
Potential Hy’s Law criteria met 
If the subject does meet PHL criteria the Investigator will: 
 
Determine whether PHL criteria were met at any study visit prior to starting Study 
treatment (See Appendix E 2) 
 
Notify the AstraZeneca representative who will then inform the central Study Team  


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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 aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.  
 
Complete the three Liver CRF Modules as information becomes available  
 
If at any time (in consultation with the Study Physician the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
E 5 
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 Study 
Physician contacts 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 IP. 
The AstraZeneca Global Clinical Lead or equivalent 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 AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 
 
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca 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. 


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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: 
 
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 amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 


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Appendix F Medical device incidents: definition and procedures for 
recording, evaluating, follow-up, and reporting 
F 1 
Definitions of a Medical Device Incident 
The detection and documentation procedures described in this protocol apply to all sponsor 
provided medical devices provided for use in the study (see Section 6.1.2) for the list of 
sponsor provided medical devices). 
Medical Device Incident Definition 
 
A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labelling or the 
instructions for use which, directly or indirectly, might lead to or might have led to the 
death of a subject/user/other person or to a serious deterioration in his/her state of 
health. 
 
Not all incidents lead to death or serious deterioration in health.  The non-occurrence of 
such a result might have been due to other fortunate circumstances or to the treatment of 
health care personnel. 
It is sufficient that: 
 
An incident associated with a device happened. 
AND 
 
The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health. 
 
A serious deterioration in state of health can include any of the following: 
 
Life-threatening illness 
 
Permanent impairment of body function or permanent damage to body structure 
 
Condition necessitating medical or surgical treatment to prevent one of the above  
 
Foetal distress, foetal death, or any congenital abnormality or birth defects 
Examples of incidents: 
 
A subject, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse. 
 
A subject’s Study treatment is interrupted or compromised by a medical device failure. 
 
A misdiagnosis due to medical device failure leads to inappropriate treatment. 
A subject’s health deteriorates due to medical device failure. 
Documenting medical device incidents 


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Medical device incident documentation 
 
Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical practice, 
and on the appropriate form of the eCRF. 
 
For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
eCRF page will be completed as described in Appendix B. 
 
The eCRF will be completed as thoroughly as possible and signed by the investigator 
before transmittal to the sponsor or designee. 
 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by the sponsor) at the time of the initial AE 
or SAE report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident. 
 
A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of an incident.  This 
includes any amendment to the device design to prevent recurrence. 
 
 


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Appendix G Summary of gastrointestinal events in Studies D5670C00002 
and D5670C00011 
Table 9 
Study D5670C00002: Treatment-emergent Vomiting and/or Nausea by 
Study Day – All Cohorts – As-treated Population 
 


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Table 10 
Study D5670C00011: Number and Percentage of Subjects with Nausea 
and/or Vomiting and Associated Event Rate by Dosing Period – Cohort 
1 - As-treated Population 
 


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Appendix H  Abbreviations  
Abbreviation or  
special term 
Explanation 
ADA 
antidrug antibody 
AE 
adverse event 
ABPM 
ambulatory blood pressure monitoring 
ALP 
alkaline phosphatise 
ALT 
alanine transaminase 
ANCOVA 
analysis of covariate 
AST 
aspartate transaminase  
AUC 
area under the curve 
AZ 
AstraZeneca 
BMI 
body mass index 
BP 
blood pressure 
CGM 
continuous glucose monitoring 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
Ctrough 
trough plasma concentration 
DNA 
deoxyribonucleic acid  
ECG 
electrocardiogram  
eCRF 
electronic case report form  
EDC 
Electronic Data Capture 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1  
GMP 
Good Manufacturing Practice 
HbA1c 
glycated hemoglobin 
HOMA 
Homeostatic Model Assessment 
HR 
heart rate 
IATA 
International Airline Transportation Association 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IP 
investigational product 


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Abbreviation or  
special term 
Explanation 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LSMean 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMT 
mixed-meal test 
PD 
pharmacodynamics 
PHL 
potential Hy’s Law 
PK 
pharmacokinetics 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event  
SAP 
statistical analysis  
SC 
subcutaneous  
SoA 
Schedule of Activities 
TBL 
total bilirubin 
TEAE 
treatment emergent adverse event 
TESAE 
treatment emergent serious adverse event 
t1/2 
terminal half-life  
T2DM 
Type 2 diabetes mellitus 
ULN 
upper limit of normal 
 
 

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Statistical Analysis Plan
Study Code
D5674C00001
Edition Number
2.0
Date
19-Dec-2018
A Phase IIa, Randomised, Parallel, Double-Blind, Placebo-Controlled Study 
to Evaluate the Safety, Efficacy, and Pharmacokinetics of MEDI0382 in 
Japanese Preobese or Obese Subjects with Type 2 Diabetes Who Have 
Inadequate Glycemic Control with Diet and Exercise






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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
SIGNATURE OF STUDY STATISTICIAN......................................................................... 2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ................................................... 3
TABLE OF CONTENTS...................................................................................................... 4
LIST OF ABBREVIATIONS ............................................................................................... 7
AMENDMENT HISTORY................................................................................................... 9
1
STUDY DETAILS ........................................................................................... 10
1.1
Study objectives................................................................................................ 10
1.2
Study design ..................................................................................................... 11
1.3
Number of subjects........................................................................................... 11
2
ANALYSIS SETS ............................................................................................ 12
2.1
Definition of analysis sets................................................................................. 12
2.1.1
Enrolled (All patients)....................................................................................... 12
2.1.2
Randomized Set (All randomized patients) ....................................................... 12
2.1.3
Full Analysis Set............................................................................................... 12
2.1.4
Safety analysis set............................................................................................. 12
2.1.5
PK analysis set.................................................................................................. 12
2.2
Violations and deviations.................................................................................. 12
3
PRIMARY AND SECONDARY VARIABLES ............................................... 12
3.1
Primary Efficacy Variables ............................................................................... 12
3.2
Secondary Efficacy Variables ........................................................................... 13
3.2.1
PK/ADA........................................................................................................... 13
3.3
Exploratory Variables ....................................................................................... 13
3.4
Safety Variables (Primary)................................................................................ 13
4
ANALYSIS METHODS................................................................................... 14
4.1
General principles............................................................................................. 14
4.1.1
Objectives and hypotheses ................................................................................ 14
4.1.2
Definitions........................................................................................................ 14
4.1.2.1
Last Observation Carried Forward (LOCF).................................................................. 14
4.1.2.2
Mixed Meal Test glucose AUC(0-4h) ............................................................................. 15
4.1.2.3
Percentage of time in certain glucose range as measured by CGM ............................... 15
4.1.2.4
Homeostatic model assessments (HOMA)-Beta and HOMA-R.................................... 15
4.1.2.5
Use Rescue Medication ............................................................................................... 16
4.1.2.6
Analysis of covariance model (ANCOVA).................................................................. 16
4.2
Analysis methods.............................................................................................. 16


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4.2.1
Study Population............................................................................................... 16
4.2.1.1
Subject disposition ...................................................................................................... 16
4.2.1.2
Important protocol deviations...................................................................................... 17
4.2.1.3
Demographic and other subject characteristics............................................................. 17
4.2.1.4
Medical and surgical history........................................................................................ 19
4.2.1.5
Pre-study, concomitant, and post-study treatment(s) .................................................... 19
4.2.1.6
Measurements of treatment compliance....................................................................... 19
4.2.2
Efficacy ............................................................................................................ 20
4.2.2.1
Primary Efficacy Variables.......................................................................................... 20
4.2.2.2
Analysis of Secondary Efficacy variables .................................................................... 20
4.2.2.3
Analyses of exploratory efficacy variables................................................................... 22
4.2.2.4
Other supplemental tables............................................................................................ 23
4.2.3
Safety ............................................................................................................... 23
4.2.3.1
Extent of exposure....................................................................................................... 23
4.2.3.2
Adverse events............................................................................................................ 23
4.2.3.3
Nausea and vomiting................................................................................................... 25
4.2.4
Clinical Safety Laboratory Values..................................................................... 25
4.2.5
Electrocardiograms........................................................................................... 25
4.2.6
24-hr ABPM..................................................................................................... 26
4.2.7
Vital Signs (other than 24hr ABPM) ................................................................. 26
4.2.8
Pregnancy Test ................................................................................................. 26
5
INTERIM ANALYSES (NOT APPLICABLE) ................................................ 26
6
CHANGES OF ANALYSIS FROM PROTOCOL (NOT APPLICABLE) ........ 26
7
REFERENCES (NOT APPLICABLE) ............................................................. 26
8
APPENDIX ...................................................................................................... 26
8.1
Conventions...................................................................................................... 26
8.1.1
Baseline Measurements..................................................................................... 26
8.1.2
Change and Percent Change from Baseline ....................................................... 26
8.1.3
Analysis Visit Mapping .................................................................................... 27
8.1.4
Fasting status.................................................................................................... 27
8.1.5
Descriptive statistics ......................................................................................... 27
LIST OF TABLES
Table 1
Demographic Characteristics ............................................................................. 17
Table 2
Patient Characteristics ....................................................................................... 18


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Table 3
Diabetes-Related Characteristics........................................................................ 18
Table 4
DM Complications ............................................................................................ 19
Table 5
Categorical evaluation of QT prolongation ........................................................ 25
LIST OF FIGURES
Figure 1
Study Diagram .................................................................................................. 11


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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
ADA
antidrug antibody
AE
adverse event
ABPM
ambulatory blood pressure monitoring
ALP
alkaline phosphatise
ALT
alanine transaminase
ANCOVA
analysis of covariate
AST
aspartate transaminase 
AUC
area under the curve
AZ
AstraZeneca
BMI
body mass index
BP
blood pressure
CGM
continuous glucose monitoring
CI
confidence interval
CRF
case report form
CSR
clinical study report
Ctrough
trough plasma concentration
DAE
adverse events leading to discontinuation of study drug
DBP
diastolic blood pressure
ECG
electrocardiogram 
eCRF
electronic case report form 
eGFR
estimated glomerular filtration rate
FAS
full analysis set
FWER
family wise error rate
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide-1 
HbA1c
glycated hemoglobin
HOMA
Homeostatic Model Assessment
HR
heart rate
ICF
informed consent form
ICH
International Conference on Harmonisation
IP
investigational product


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Abbreviation or special 
term
Explanation
LSMean
least squares mean
MedDRA
Medical Dictionary for Regulatory Activities
MMT
mixed-meal test
PD
Pharmacodynamics
PK
Pharmacokinetics
PT
preferred term
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event 
SAP
statistical analysis plan
SBP
systolic blood pressure
SC
subcutaneous 
SOC
system organ class
TBL
total bilirubin
t1/2
terminal half-life 
T2DM
Type 2 diabetes mellitus
ULN
upper limit of normal
Q1
1st quartile (25 percentile) 
Q3
3rd quartile (75 percentile)


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AMENDMENT HISTORY
Date
Brief description of change
N/A
19-Dec-2018
Update to reflect change for protocol 

Change of secondary variable Glycoalbumin to Fructosamine 

Correction of CGM interval for alignment 

Change of baseline definition to appropriately reflect the planned study schedule 

Added derivation for HOMA-beta and HOMA-R


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1
STUDY DETAILS
1.1
Study objectives
Objectives and Endpoints
Primary objective:
Endpoint/variable:
To characterise the safety profile and tolerability of 
MEDI0382 titrated up to a dose level of 100, 200 or 
300 μg during dosing and follow-up
Measures of safety and tolerability (24-hour heart rate 
and blood pressure, other vital signs, 
electrocardiogram [ECG], laboratory test results, and 
adverse event [AE]s)
To assess the effects of MEDI0382 titrated up to a 
dose level of 100, 200 and 300 μg on glucose control 
and body weight versus placebo after 48-day 
treatment
•
Percentage change in glucose area under the 
curve (AUC) 0-4h as measured by a standardised 
MMT from baseline to the end of 48-day 
treatment 
•
Percentage change in body weight from baseline 
to the end of 48-day treatment
Secondary objective:
Endpoint/variable:
To assess the effects of MEDI0382 titrated up to a 
dose level of 100, 200 or 300 μg on additional 
measures of glucose control versus placebo after 48-
day treatment
•
Change in glycated hemoglobin (HbA1c) from 
baseline to the end of 48-day treatment
•
Change in fasting plasma glucose from baseline 
to the end of 48-day treatment
•
Change in fructosamine from baseline to the end 
of 48-day treatment
To assess the effect of MEDI0382 on glucose 
lowering during different meals and times of the day 
as measured by continuous glucose monitoring 
(CGM)
•
Change in percentage of time in hyperglycaemia 
(defined as > 7.8 mmol/L or > 140 mg/dL) and 
hypoglycaemia (defined as < 3 mmol/L or 
< 54 mg/dL) from the last day of baseline CGM 
over 24 hours to the end of dosing at each dose 
level (Days 5, 12, 19, and 47)
•
Change in percentage of time in hyperglycaemia 
and hypoglycaemia at each dose level over 
5 days for 50 µg and 7 days for other dose levels 
(Days 1 to 5, Days 6 to 12, Days 13 to 19, and 
Days 41 to 47)
To characterise the PK profile of 50, 100, 200 and 
300 μg of MEDI0382
PK endpoints:
Trough plasma concentration (Ctrough)
To characterise immunogenicity of 100, 200 and 
300 μg of MEDI0382
Development of anti-drug antibodies and titre (if 
confirmed positive)
Exploratory Objective:
Endpoint/variable:
To assess the effect of MEDI0382 on pancreatic and 
incretin hormone profiles at baseline and during the 
MMT
•
Change in insulin, GLP-1, and glucagon (AUC 
and levels) from baseline after 48-day treatment.
•
Change in pro-insulin, c-peptide levels, pro-
insulin/c-peptide ratio from baseline after 48-
day treatment.
To assess the effects of MEDI0382 in insulin 
resistance and beta cell function.
•
Change in percentage of Homeostatic model 
assessments (HOMA)-Beta and HOMA-R from 
baseline after 48-day treatment.


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1.2
Study design
This is a randomized, parallel-group, placebo-controlled, double-blind, multicenter Phase IIa 
study to evaluate the safety, efficacy, and pharmacokinetics of MEDI0382 in Japanese 
preobese and obese subjects with type 2 diabetes who have inadequate glycemic control with 
diet and exercise. Subject fulfilling all of the inclusion criteria and none of the exclusion 
criteria will be randomised in a 1:1:1:1 ratio to four treatment arms (MEDI0382 100ug, 
200ug, 300ug or Placebo). MEDI0382 dose will be up-titrated from 50ug to the randomized 
target dose of MEDI0382 100ug, 200ug or 300ug, respectively, as shown in Figure 1.
Figure 1
Study Diagram
1.3
Number of subjects
Approximately 60 patients are to be randomized to Placebo, MEDI0382 100 μg, MEDI0382 
200 μg, and MEDI0382 300 μg in a ratio 1:1:1:1.
Anticipating approximately 10% drop out during the 48-day treatment period, approximately 
13 subjects are expected to be evaluable per treatment group.
Assuming standard deviation of percent change in MMT glucose AUC(0-4h) for 20%, 
approximately 13 patients per arm would provide more than 80% power to detect 23% 
difference in percent change of MMT glucose AUC(0-4h) for pairwise comparison between 
each of MEDI0382 dose group and Placebo each at two-sided alpha = 0.05, without formal 
multiplicity adjustment.
Assuming standard deviation of percent change from baseline in body weight for 2.5%, the 
same number of subjects would provide approximately 68% power to detect mean difference 
of 2.5% at two-sided alpha =0.05.


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2
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Enrolled (All patients) 
All patients who signed the ICF. 
2.1.2
Randomized Set (All randomized patients) 
All subjects who received randomization number. 
2.1.3
Full Analysis Set 
The full analysis set (FAS) for the efficacy evaluation will be the primary analysis set and will 
include all randomized subjects who received at least one dose of Investigational Product (IP), 
and will be analysed according to their randomised treatment group.
2.1.4
Safety analysis set 
The Safety analysis set, which includes all subjects receiving at least one dose of any study IP, 
will be analysed according to the treatment they actually received.
2.1.5
PK analysis set
The PK analysis set includes all subjects who received at least one dose of MEDI0382 and 
had at least one post-baseline MEDI0382 PK sample taken that is above the lower limit of 
quantification.
2.2
Violations and deviations
Protocol deviations will be identified programmatically or manually and reviewed in a blinded 
fashion and documented prior to the un-blinding the study. 
Important protocol deviations would include but not limited to:

Patients who were randomised but did not meet inclusion and exclusion criteria

Patients who developed withdrawal from study criteria but were not withdrawn

Patients who received incorrect treatment or dose

Patients who were randomised but took no study medication

Patients who received prohibited concomitant medication
3
PRIMARY AND SECONDARY VARIABLES
3.1
Primary Efficacy Variables
Primary efficacy variables are 


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
Percentage change in glucose area under the curve (AUC) 0-4h as measured by a 
standardised MMT from baseline to the end of 48-day treatment 

Percentage change in body weight from baseline to the end of 48-day treatment
3.2
Secondary Efficacy Variables
Following secondary efficacy variables will be evaluated : 

Change in glycated hemoglobin (HbA1c) from baseline to the end of 48-day treatment

Change in fasting plasma glucose from baseline to the end of 48-day treatment

Change in fructosamine from baseline to the end of 48-day treatment

Change in percentage of time in hyperglycaemia (defined as > 7.8 mmol/L or > 140 
mg/dL) and hypoglycaemia (defined as < 3 mmol/L or < 54 mg/dL) from the last day of 
baseline CGM over 24 hours to the end of dosing at each dose level (Days 5, 12, 19, and 
47)

Change in percentage of time in hyperglycaemia and hypoglycaemia at each dose level 
over 5 days for 50 µg and 7 days for other dose levels (Days 1 to 5, Days 6 to 12, Days 13 
to 19, and Days 41 to 47)
3.2.1
PK/ADA

PK : Trough plasma concentration (Ctrough)

ADA : Development of anti-drug antibodies and titre (if confirmed positive)
3.3
Exploratory Variables

Change in insulin, GLP-1, and glucagon (AUC and levels) from baseline after 48-day 
treatment.

Change in pro-insulin, c-peptide levels, pro-insulin/c-peptide ratio from baseline after 48-
day treatment.

Change in percentage of Homeostatic model assessments (HOMA)-Beta and HOMA-R 
from baseline after 48-day treatment
3.4
Safety Variables (Primary) 
Safety evaluation will be done with the following variables.

Adverse Events (including SAEs)

24-hour ABPM (Heart Rate and Systolic/Diastolic Blood Pressure)

Other Vital Signs

Electrocardiogram [ECG]

Safety Laboratory parameters


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4
ANALYSIS METHODS
4.1
General principles
The SAS® software, version 9.2 or higher, will be used in order to generate all the statistical 
outputs. 
Unless otherwise specified, all efficacy analyses will be carried out on the FAS and all safety 
analyses will be based on the Safety analysis set. Efficacy summary results during the 
treatment phase will be presented based on randomized treatment group (MEDI0382 100ug, 
MEDI0382 200ug, MEDI0382 300ug and Placebo). Safety summary results will be presented 
based on treatment they actually received. For Safety analysis, patients who discontinued 
before reaching target dose would be included in their randomized treatment group. Patients 
who wrongly took higher dose of MEDI0382 than randomized target dose will be analysed 
according to the highest dose of study medication received. 
4.1.1
Objectives and hypotheses 
The one of primary objectives of this study is to characterize the safety profile of MEDI0382 
100ug ,200ug and 300ug up-titration regimens compared with Placebo, measured by the 
Adverse Events (including SAEs), 24-hr ABPM heart rate and blood pressures, other vital 
sings, safety laboratory tests, and ECGs. The safety evaluation will be conducted through 
descriptive manner and no statistical testing will be performed for safety analysis. 
The other primary objective is to assess the efficacy of MEDI0382 doses, as measured by 
percent change from baseline in MMT glucose AUC(0-4h) to Day 48 and by percent change in 
body weight from baseline to Day 48.  Statistical hypotheses testing will be conducted by 
pair-wise comparisons between MEDI0382 each dose group vs. Placebo each at two-sided 
alpha of 0.05. Strong control of Family Wise Error Rate (FWER) will not be pursuit. 
4.1.2
Definitions
4.1.2.1
Last Observation Carried Forward (LOCF) 
In the analysis of change (or percent change) from baseline, as well as response endpoint at 
Day t LOCF, the Day t measurement will be used. If no Day t measurement is available 
(subject has discontinued before Day t, or the subject has not discontinued, but the 
measurement was not taken at Day t), the last post-baseline measurement prior to Day t will 
be used. Unless specified otherwise, all data, regardless of rescue medication, will be used for 
the calculation of LOCF values.


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4.1.2.2
Mixed Meal Test glucose AUC(0-4h)
MMT will be conducted at baseline (Day -1) and Day 48. Following a minimum 8-hour fast, 
blood samples for the tests indicated will be taken 15 minutes before the subject drinking 1 
entire can of Ensure H as a standardised meal. After consumption of the standardised meal, 
blood samples will additionally be taken at 15, 30, 45, 60, 90, 120, 180, and 240 minutes for 
glucose and insulin; 15, 45, 90, 180, and 240 minutes (± 5 min) for pro-insulin, c-peptide, 
GLP-1 and glucagon. 
MMT glucose AUC(0-4h) will be derived by the trapezoidal method. 



1
1
1
2
n
i
i
i
i
i
M
M
T
T













Where 
i
M is the glucose test at time 
iT and 
1

i
M
is the subsequent non-missing glucose 
measured at time 
1

iT
. 
1T and 
nT are the time of the first (0 min) and last (240 min) glucose 
measurement. AUC(0-4h) for other parameters will be derived in a similar manner. 
4.1.2.3
Percentage of time in certain glucose range as measured by CGM
Percent of CGM readings falling within a range over a 24-hour period will be calculated as the 
number of readings during a 24-hour period within the corresponding range divided by the 
total number of available readings during the same 24-hour period. 
4.1.2.4
Homeostatic model assessments (HOMA)-Beta and HOMA-R
Beta cell function (HOMA beta) and insulin sensitivity (HOMA-IR, Matsuda index) will be 
derived by Glucose (in mg/dL) and insulin (in mU/L) taken during MMT. 

Beta cell function: HOMA-beta (%) (based on fasting glucose and insulin from 
MMT data for each visit)
360 Insulin[mU/L]
HOMA- [%]= Glucose[mg/dL]
63




Insulin sensitivity: HOMA-IR (%) (based on fasting glucose and insulin from MMT 
data for each visit)
Glucose[mg/dL] Insulin[mU/L]
HOMA-IR[%]=
405


Insulin sensitivity: Matsuda Index (no unit) (based on glucose and insulin from 
MMT data at 0, 30, 60, 90, and 120 minutes for each visit)


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Here, gt indicates glucose [mg/dL] value at time t [min] and it indicates insulin[mU/L] value at 
time t [min] during MMT.
4.1.2.5
Use Rescue Medication
Start date of rescue medication is defined as the earliest of the dates of first insulin or 
injectable or oral antidiabetic drugs initiated as rescue medication. Treatment intensification 
starting on the first or last day of study medication will not be defined as rescue medication.
4.1.2.6
Analysis of covariance model (ANCOVA)
In summaries of efficacy endpoints examining changes from baseline at Day t or Day t LOCF, 
ANCOVA of the differences between post-baseline and baseline measurements will be 
performed, with treatment group as a factor and the baseline measurement as a covariate. The 
following ANCOVA model will be used: 
Dt,ij = intercept + ß [Y0,ij ] + τi  + errorij   
where

Dt,ij = Yt,ijk - Y0,ijk = the Week t or Week t LOCF (percent) change from baseline of 
subject j in treatment group i),

Y0,ijk is the baseline measurement of subject j in treatment group i, 

Yt,ijk is the Week t or Week t LOCF measurement of subject j in treatment group i,

ß is the slope of Dt,ij regressing on the baseline measurement and, 

τi is the mean effect of treatment group i.

Intercept, ß and τi  are unknown parameters to be estimated from the data.
The model will provide least squares mean estimates and 2-sided 95% confidence intervals 
(CIs) for mean changes from baseline within and (when warranted) differences in mean 
change from baseline between treatments.
4.2
Analysis methods
4.2.1
Study Population
4.2.1.1
Subject disposition
Subject disposition will be described including information on number and percentage of 
subjects enrolled, randomized, not randomized, reason for not randomized, started treatment, 


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not started treatment, reason for not started treatment, completed treatment, not completed 
treatment, reason for not completed treatment, completed study, not completed study and 
reason for not completed the study. This summary will include all enrolled subjects, i.e. all 
subjects who signed informed consent, and be done by randomized treatment group and in 
total.
4.2.1.2
Important protocol deviations
Patients with important protocol deviations will be summarized by treatment and in total using
all randomized patients. Important protocol deviations will be collected as described in section 
2.2.
4.2.1.3
Demographic and other subject characteristics
Demographic and other subject characteristics, including diabetes-related characteristics will 
be summarized by treatment and in total using the FAS. 
All summaries of continuous characteristics will be based on non-missing observations. For 
categorical characteristics, percentages should be calculated based on the number of patients 
in the analysis set (i.e., each denominator includes the number of subjects with 
missing/unknown values for the characteristic). 
Age will be calculated as (date of informed consent – birth date + 1 )/365.25. 
The duration of type 2 diabetes will be calculated as (date of informed consent - date of 
Diabetes Mellitus Type II First Diagnosed + 1)/365.25. If the birth date, or the date of type II 
DM diagnosis is partially missing, the following rules will be implemented: 

If year is missing: No imputation will occur to neither year, month or day. 

If month and day is missing: -06-30 will be imputed. 

If day is missing: -15 will be imputed
Table 1
Demographic Characteristics
Characteristic
Summarized as
Categories
Gender
Categorical
Male 
Female
Age (years)
Categorical and 
continuous 
< 50
≥ 50 and <65 
≥ 65 and <75 
≥ 75


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Table 1
Demographic Characteristics
Characteristic
Summarized as
Categories
Race 
Categorical
White
Black or African American
Asian
Native Hawaiian or Other Pacific Islander
American Indian or Alaska Native 
Other
Region
Categorical
Asia/Pacific
Europe
North America
South America
Country 
Categorical 
Japan
Ethnicity 
Categorical
Hispanic/Latino
Non Hispanic/Latino
Table 2
Patient Characteristics
Characteristic
Summarized as
Categories
Height (cm)
Continuous
Body Weight (kg)
Continuous
Body Mass Index (kg/m2)
Categorical and 
continuous
< 25
≥ 25 and <30
≥ 30 and <35
≥ 35 and <40
≥ 40
Table 3
Diabetes-Related Characteristics
Characteristic
Summarized as
Categories
Duration of Type 2 Diabetes (years)
Categorical and continuous
< 3
≥ 3 and < 10
≥ 10
Baseline HbA1c (%)
Categorical and continuous
< 8.0
≥ 8.0 and < 9.0 
≥ 9.0
Baseline fasting plasma glucose 
(mg/dl)
Continuous
Baseline fasting c-peptide (ng/ml)
Continuous
Baseline Systolic and Diastolic BP, 
pulse (mmHg)
Continuous


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Table 3
Diabetes-Related Characteristics
Characteristic
Summarized as
Categories
eGFR (mL/min/1.73m2)*
Categorical and continuous
< 20
≥ 20 and <30
≥ 30 and <60 
≥ 60 and <90 
≥ 90
*eGFR is derive based on formula provided by JSN (Japan Society of Nephrology).


2
1.094
0.287
eGFR[mL/min/1.73m ]
194 SCr[mg/ dL]
Age[years]
0.739forfemale






4.2.1.4
Medical and surgical history 
The number and percentage of subjects with medical and surgical history findings will be 
summarized per SOC/PT by treatment and in total using the FAS. In addition, specific DM 
complications will be summarized. 
Table 4
DM Complications
Characteristic
Summarized as
Categories
Diabetes Mellitus Complications
Categorical
Retinopathy
Neuropathy Autonomic 
Neuropathy Peripheral
Nephropathy
Angiopathy
Other 
4.2.1.5
Pre-study, concomitant, and post-study treatment(s) 
The number and percentage of subjects with the following will be summarized according to 
ATC code and generic name, by treatment and in total using FAS: 

Medication used prior to study treatment

Concomitant medication 
Concomitant medications is defined as medications taken on or at least one day after the 
study drug start date and before or on the last day on study drug.
4.2.1.6
Measurements of treatment compliance 
For each subject receiving at least one dose of study treatment percent compliance will be 
calculated as: 100 x number of injections/(day of last dose in study period – day of first dose + 
1). Treatment compliance will be described using Q1, Median and Q3 by treatment and in 


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total using the FAS. Number and percent of subjects with compliance <80%, ≥80% will be 
summarized.
4.2.2
Efficacy
Efficacy analyses will be carried out for FAS. 
4.2.2.1
Primary Efficacy Variables
Percent Change from baseline in MMT glucose AUC(0-4h)
MMT will be conducted at baseline (Day -1) and Day 48.
Percent change from baseline in MMT Glucose AUC(0-4h) to Day 48 will be analysed with 
ANCOVA model with treatment group as a factor and baseline as a covariate. Least squares 
mean (LSMean)s and their 95%CIs for percent changes from baseline for each treatment 
group, as well as difference in LSMeans, 95%CI and nominal p-values will be provided for 
pair-wise comparison of each MEDI0382 dose vs. Placebo group. 
Due to lack of intermediate visit assessment, it is assumed patients will have at most one post-
baseline MMT assessment regardless of their completion of discontinuation of study drug. 
Primary analysis will include all on-treatment assessment regardless of rescue. 
Percent change from baseline in body weight
Body weight will be collected at selected visits. 
Percent change from baseline in body weight to Day 48 will be analysed with ANCOVA 
model with treatment group as a factor and baseline as a covariate. LSMeans and their 
95%CIs for percent changes from baseline for each treatment group, as well as difference in 
LSMeans, 95%CI and nominal p-values will be provided for pair-wise comparison of each 
MEDI0382 dose vs. Placebo group. For subjects who prematurely discontinued study drug, 
the last on-treatment measurement regardless of rescue will be used for this analysis (LOCF). 
The similar analyses will be also conducted by each post-baseline visit, without LOCF. 
Absolute change from baseline in body weight to Day 48 will be also analysed in the same 
way. 
4.2.2.2
Analysis of Secondary Efficacy variables
Change in glycated hemoglobin (HbA1c) from baseline to the end of 48-day treatment
HbA1c will be measured at baseline and Day 48. 
Change from baseline in HbA1c to Day 48 will be analysed with ANCOVA model with 
treatment group as a factor and baseline as a covariate. LSMeans and their 95%CIs for 


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changes from baseline for each treatment group, as well as difference in LSMeans, 95%CI and 
nominal p-values will be provided for pair-wise comparison of each MEDI0382 dose vs. 
Placebo group. 
Due to lack of intermediate visit assessment, it is assumed patients will have at most one post-
baseline HbA1c assessment regardless of completion or discontinuation of study drug. All 
available on-treatment measurement regardless of rescue will be included in the analyses. 
Change in fasting plasma glucose (FPG) from baseline to the end of 48-day treatment
FPG will be measured at baseline and Day 48. 
Change from baseline in FPG to Day 48 will be analysed with ANCOVA model with 
treatment group as a factor and baseline as a covariate. LSMeans and their 95%CIs for 
changes from baseline for each treatment group, as well as difference in LSMeans, 95%CI and 
nominal p-values will be provided for pair-wise comparison of each MEDI0382 dose vs. 
Placebo group. 
Due to lack of intermediate visit assessment, it is assumed patients will have at most one post-
baseline FPG assessment. All available on-treatment measurement regardless of rescue will be 
included in the analyses. 
Change in fructosamine from baseline to the end of 48-day treatment
Fructosamine will be measured at baseline and Day 20 and 48.
Change from baseline in fructosamine to Day 48 will be analysed with ANCOVA model with 
treatment group as a factor and baseline as a covariate. LSMeans and their 95%CIs for percent 
changes from baseline for each treatment group, as well as difference in LSMeans, 95%CI and 
nominal p-values will be provided for pair-wise comparison of each MEDI0382 dose vs. 
Placebo group. For subjects who prematurely discontinued study drug, the last on-treatment 
measurement regardless of rescue will be used for this analysis. 
The similar analyses will be also conducted by each post-baseline visit, without LOCF. 
Change from baseline in continuous glucose monitoring (CGM) parameters
A CGM sensor will be inserted subcutaneously on protocol specified study days to allow the 
collection of information on subject’s interstitial glucose level over specified intervals: From 
Day -8 ~ -2, Day 1~5, Day 6~12, Day 13~19 and Day 41~47. The system records data 
approximately every 15 minutes. The data will remain blinded to the subject and to the 
investigators during the recording and will be downloaded into a data file.


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All analysis endpoints will be based on the 24-hour readings for every subject. The 24-hour 
period is defined based on the first available time point with a valid CGM glucose reading. 
The last 24-hour readings within each dose intervals will be the last 24-hour intervals within 
that dosing intervals.
Descriptive summary at baseline and each post-baseline visit (the last day or all intervals) as 
changes from baseline for percentage of time in hyperglycemia/hypoglycaemia will be 
provided by treatment group. 
Descriptive summary for 24-hour average glucose readings will be also summarized for the 
last day of each dosing intervals as well as average over each dosing interval.
The glucose reading over 24-hour during baseline (average over Day -8 to Day -2) and during 
last dosing interval (average over Day 41-47) will be plotted for each treatment group .
Coefficient of Variation(CV) of glucose readings over each dose intervals will also be 
summarized with descriptive statistics and will be plotted. 
Pharmacokinetics/ADA
The plasma concentrations/ADA will be summarized descriptively at each time point for the 
MEDI0382 treatment groups excluding values after IP discontinuation. Additional 
pharmacokinetic analyses and/or modelling may be conducted separately, outside of this SAP.
4.2.2.3
Analyses of exploratory efficacy variables 
Change in insulin, GLP-1 and glucagon from baseline after 48-day treatment
Change in fasting measurement from baseline (Day -1) and percent change in 4-hour AUC 
from baseline will be compared between MEDI0382 and placebo as measured by a 
standardised MMT from baseline to the end of 48-day treatment. The above parameters will 
be analysed by ANCOVA model including respective baseline as a covariate and treatment as 
a factor. The last on-treatment measurements regardless of rescue use will be included in 
response variable.
Change in pro-insulin, c-peptide levels, pro-insulin/c-peptide ratio from baseline after 
48-day treatment
Change in fasting measurement from baseline and percent change in 4-hour AUC (except for 
pro-insulin/c-peptide ratio) from baseline will be compared between MEDI0382 and placebo 
as measured by a standardised MMT from baseline to the end of 48-day. The above 
parameters will be analysed by ANCOVA model including respective baseline as a covariate 
and treatment as a factor. The last on-treatment measurements regardless of rescue use will be 
included in response variable.


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Change in percentage of Homeostatic model assessments (HOMA)-Beta and HOMA-R 
from baseline after 48-day treatment
Beta cell function will be derived using the HOMA calculation from fasting glucose and 
insulin data, and insulin sensitivity will be derived from MMT data using the HOMA-IR 
algorithm and the modified Matsuda index calculation (4.1.2.4). 
The above parameters will be analysed by ANCOVA model including respective baseline as a 
covariate and treatment as a factor. The last on-treatment measurements regardless of rescue 
use will be included in response variable.
4.2.2.4
Other supplemental tables

Number and percentage of subjects on rescue medication will be presented by treatment 
group. 

For all efficacy parameters, descriptive summary at each visit and changes from base will 
be provided by treatment group. 
4.2.3
Safety 
Unless otherwise specified, all safety analysis will be performed for the safety set and the 
safety data will be presented using descriptive statistics and no statistical test will be 
performed.
4.2.3.1
Extent of exposure 
The duration of exposure, day of last dose – day of first dose + 1, will be summarized using 
descriptive statistics by treatment and in total using FAS. Also, the cumulative duration of 
exposure will be given for ≥1, ≥5, ≥12, ≥19, and ≥48 days and illustrated with a cumulative 
distribution plot. In addition, the duration of exposure in terms of total patient-years will be 
calculated by treatment.
A listing of patients experience at least one overdose will be provided.
4.2.3.2
Adverse events
Adverse Events (AEs) will be classified by Primary System Organ Class (SOC) and Preferred 
Term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA) version 
at the time of database lock for each study. 
Each AE will be assigned to one or more of the following periods; 

Run-in period: Time prior to randomization date.  

Baseline period: Time from randomization date until the day prior to first dose date. 

On treatment period: Time from first dose date of IP until 3 days after last dose of IP.  


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
Follow up period: Time from last IP dose + more than 3 days . 
AEs will be assigned to the period where they started. For AEs assigned to the on treatment 
period, the number of subject included in safety set and with any of the following will be 
tabulated: 

AEs per category (Any AE, Any AE with outcome of death, Any SAE, Any AE leading 
to discontinuation (DAE)) 

AEs per SOC and PT 

AEs by PT, most common with frequency of at least 2 subjects

AEs by PT and maximum reported intensity

AEs by PT and causality as judged by investigator

AEs with outcome of death by SOC and PT

SAEs by SOC and PT

AEs leading to discontinuation of IP by SOC and PT 
In summaries by SOC and PT, AEs will be sorted by decreasing frequency within each SOC 
and PT according to the highest MEDI0382 dose group. In summaries by PT, AEs will be 
sorted by decreasing frequency within PT according to the highest MEDI0382 dose group.
For AEs assigned to the on treatment period key subject information for patients included in 
safety set will be presented for: 

Adverse events with outcome of death 

SAEs

Adverse events leading to discontinuation of IP
Following listings of AEs will be produced:

Listing of SAEs during the run-in period (All patients)

Listing of AEs during of the baseline period (All randomised patients) 

Listing of AEs during on treatment period (safety set)

Listing of AEs during the follow up period (safety set)
Narratives will be generated for all deaths, DAEs and SAEs.


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4.2.3.3
Nausea and vomiting
The number and percent of patients and the event rate with nausea and vomiting per person-
days will be summarized by treatment. The event rate per person-days over each dosing 
intervals will be tabulated and plotted.
4.2.4
Clinical Safety Laboratory Values
Laboratory values reported at each scheduled visit and the change from baseline will be 
summarized by treatment using descriptive statistics.
Number and percent of subjects with baseline laboratory value within the reference limit but 
with any post-baseline value outside the reference limit will be summarized per treatment. 
Number and percent of subjects with liver enzyme abnormalities (including potential Hy’s 
Law criteria) will be produced by treatment. 
Shift table of the eGFR from baseline to post-baseline will be created. Classification is as 
follows : renal function groups ≥ 90, ≥ 60 to <90, ≥ 30 to < 60, and < 30 mL/min/1.73 m2.
4.2.5
Electrocardiograms 
Electrocardiogram(ECG) per visit and change from baseline will be summarized by treatment 
at each scheduled visit using descriptive statistics. This will include heart rate (HR), PR, QRS, 
QT and QTcF. 
Here QTcF will be derived by below formula. 
1/3
(60 / HR)
QT
QTcF 
where, QT is in msec and HR is in bpm. 
A shift table for ECG in categories of Normal and Abnormal will be summarized by treatment 
from baseline to post baseline. 
Abnormal prolongation of QTcF will be summarized based on criteria specified in the table 
below. The most extreme (highest) value for a subject during on-treatment will be used in this 
summary.
Table 5
Categorical evaluation of QT prolongation
Parameter
Criterion
QTcF
>450 msec
>480 msec
>500 msec


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Table 5
Categorical evaluation of QT prolongation
Parameter
Criterion
Change from baseline in QTcF
>30 msec
>60 msec
4.2.6
24-hr ABPM
Value at visit and change from baseline in 24-hour ABPM (Heart Rate, SBP and DBP) will be 
summarized by treatment group. The similar summary for Daytime average and Nighttime 
average will also be provided by treatment. 
4.2.7
Vital Signs (other than 24hr ABPM)
Vital sign measurements at each visit and change from baseline will be summarized by 
treatment at each scheduled visit using descriptive statistics. 
4.2.8
Pregnancy Test
A listing of subjects with positive pregnancy test results will be provided. 
5
INTERIM ANALYSES (NOT APPLICABLE)
6
CHANGES OF ANALYSIS FROM PROTOCOL (NOT 
APPLICABLE)
7
REFERENCES (NOT APPLICABLE)
8
APPENDIX
8.1
Conventions
8.1.1
Baseline Measurements
Unless specified otherwise, a baseline value should be the last assessment taken prior to the 1st
dose of study medication.  When there is a missing baseline assessment, it should not be
imputed, thus, subjects should be excluded from any changes from baseline analysis for which 
they have a missing baseline value.
8.1.2
Change and Percent Change from Baseline
Change from baseline to any Time t in correction phase double-blind treatment period is 
defined as follows:
CTime t = MTime t - Mbaseline ,
where:


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
CTime t is the change from baseline at Time t,

MTime t is the measurement at Time t,

Mbaseline is the measurement at baseline.
Percent change from baseline to any Time t in correction phase double-blind treatment period 
is defined as follows:
PTime t =100×(MTime t - Mbaseline) / Mbaseline .
Where PTime t is the percent change from baseline at Time t, and MTime t and Mbaseline are defined 
as above.
8.1.3
Analysis Visit Mapping 
In principle, CRF nominal visits will be utilized for by-visit summary presentation. 
For subjects who discontinued study drug prematurely, the measurements obtained at or 
before premature discontinuation visit are considered as “on-treatment” and would be 
included in the efficacy analyses, if appropriate. Efficacy measurements obtained after Day 48 
visit/premature discontinuation visit will be considered as “off-treatment” and will be 
separated in data presentation.
Unscheduled visits will be included in summary of abnormality using most extreme values 
and also for LOCF (if applicable).
8.1.4
Fasting status
For FPG, fasting insulin, fasting c-peptide and fasting lipids, only assessment confirmed as 
measured during fasting state will be included in the analysis.
8.1.5
Descriptive statistics
Summaries of continuous characteristics will be based on non-missing observations. 
Continuous variables will be summarised using descriptive statistics including the number of 
patients included in analysis, mean, standard deviation (SD), minimum, 1st quartile, median, 
3rd quartile and maximum. 
Categorical variable will be based on number and proportions in each category.