Clinical trial NCT03596177
Conditions: Diabetes Mellitus, Type II Obesity
Keywords: Diabetes Mellitus, Type II Obesity MEDI0382
Sponsor: MedImmune LLC
Start date: 2018-09-26; Completion date: 2019-12-22
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An exploratory study to evaluate the effect of MEDI0382 on energy balance in overweight and obese participants with type 2 diabetes mellitus

Detailed description:
An exploratory Phase 2a, randomised, double-blind, placebo-controlled study to evaluate the effect of MEDI0382 on energy balance in overweight and obese participants with type 2 diabetes mellitus

Arms: arm 1: Participants will receive subcutaneous (SC) injection of placebo for 16 days in the single-blind treatment period, and then SC injection of MEDI0382 titrated up to 300 μg for 42 days (100 μg for 4 days, followed by 200 μg for 4 days, and finally 300 μg for 34 days) in double-blind treatment period. arm 2: Participants will receive SC injection of placebo for 16 days in the single-blind treatment period, and then SC injection of placebo matched to MEDI0382 for 42 days in double-blind treatment period.
Interventions: intervention 1: MEDI0382 intervention 2: Placebo
Intervention descriptions: intervention 1: MEDI0382 will be administered subcutaneously, titrated up to 300 μg for 42 days (100 μg for 4 days, followed by 200 μg for 4 days, and finally 300 μg for 34 days) in double-blind treatment period. intervention 2: Placebo will be administered subcutaneously for 16 days in the single-blind treatment period in both MEDI0382 and placebo arms, and SC injection of placebo matched to MEDI0382 for 42 days in double-blind treatment period in placebo arm.

Protocol documents:
Prot_002.pdf: 
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An Exploratory Phase 2a, Randomised, Double-blind, 
Placebo-controlled Study to Evaluate the Effect of MEDI0382 on 
Energy Balance in Overweight and Obese Subjects with Type 2 
Diabetes Mellitus
Sponsor Protocol Number: D5670C00021
Application Number:
EudraCT number 2018-001220-19
Investigational Product:
MEDI0382 
Sponsor:
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca, Milstein Building, Granta Park, Cambridge, CB21 
6GH, UK
Medical Monitor:
Victoria Parker, MBBS, PhD
Medical Monitor, MedImmune
Phone: +44 747 1357172; Fax: +44 1223 890 339
Contract Research Organization: Covance, Inc.
Protocol History, Date:
Original Protocol, 19Apr2018
Amendment 1, 23May2018
Amendment 2, 17Jul2018
Amendment 3, 20Aug2018
Amendment 4, 31Aug2018
Amendment 5, 20Mar2019
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from MedImmune.










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AEs will be counted once for each subject for calculating percentages. In addition, if the same AE occurs 
multiple times within a particular subject, the highest severity and level of relationship observed will be 
reported. All treatment-emergent adverse events will be summarised overall, by MedDRA SOC and PT, and 
by severity and relationship to investigational product. In addition, summaries of deaths, SAEs, and treatment 
discontinuations due to AEs will be provided.
Additional safety data including vital signs, safety laboratory analysis, and ECGs will be summarised 
descriptively at each time point by treatment group.
 
 
 
Patient Reported Outcomes (PRO): Analysis of PROs will be based on the mITT population. The 
exploratory PRO endpoints including change in self-reported hunger and satiety scores from Day 15 to 58 and 
the change in total energy intake in kilojoules (kJ) as recorded in a food diary from Day 16 to 32 and from 
Day 16 to 59 will be analysed by an ANCOVA model similar to that used for the primary efficacy analysis.
Interim Analysis: No interim analyses are planned.








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6.2
Monitoring of the Study.................................................................................... 67
6.2.1
Source Data ...................................................................................................... 68
6.2.2
Study Agreements............................................................................................. 68
6.2.3
Archiving of Study Documents......................................................................... 68
6.3
Study Timetable and End of Study.................................................................... 68
6.4
Data Management............................................................................................. 69
6.5
Medical Monitor Coverage ............................................................................... 69
7
ETHICAL AND REGULATORY REQUIREMENTS...................................... 69
7.1
Subject Data Protection..................................................................................... 69
7.2
Ethics and Regulatory Review .......................................................................... 70
7.3
Informed Consent ............................................................................................. 70
7.4
Changes to the Protocol and Informed Consent Form........................................ 71
7.5
Audits and Inspections...................................................................................... 71
8
REFERENCES................................................................................................. 72
9
CHANGES TO THE PROTOCOL ................................................................... 74
9.1
Protocol Amendment 5, 20Mar2019 ................................................................. 74
9.2
Protocol Amendment 4, 31Aug2018 ................................................................. 75
9.3
Protocol Amendment 3, 20Aug2018 ................................................................. 75
9.4
Protocol Amendment 2, 17Jul2018 ................................................................... 77
9.5
Protocol Amendment 1, 23May2018................................................................. 77
10
APPENDICES.................................................................................................. 80
10.1
Appendix 1 – Signatures................................................................................... 80
10.2
Appendix 2 - Contraception Guidance .............................................................. 81
10.3
Appendix 3 - Additional Safety Guidance......................................................... 82
10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis .......... 85
10.5
Appendix 5 - Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law.............................................................................. 86
10.5.1
Introduction ...................................................................................................... 86
10.5.2
Definitions........................................................................................................ 86
10.5.2.1
Potential Hy’s Law ........................................................................................... 86
10.5.2.2
Hy’s Law.......................................................................................................... 86
10.5.3
Identification of Potential Hy’s Law Cases ....................................................... 87
10.5.4
Follow-up ......................................................................................................... 87
10.5.4.1
Potential Hy’s Law Criteria Are Not Met.......................................................... 87
10.5.4.2
Potential Hy’s Law Criteria Are Met................................................................. 87
10.5.5
Review and Assessment of Potential Hy’s Law Cases....................................... 88
10.5.6
Laboratory Tests............................................................................................... 89
10.6
Appendix 6 - Biological Samples...................................................................... 91
10.6.1
Storage, Re-use and Destruction of Biological Samples .................................... 91
10.6.2
Labelling and Shipment of Biological Samples................................................. 91


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10.6.3
Chain of Custody of Biological Samples........................................................... 91
10.7
Appendix 7 – Genetic Research ........................................................................ 91
10.8
Appendix 8 - Patient-Reported Outcome Questionnaires................................... 96
10.8.1
Dutch Eating Questionnaire (DEBQ) ................................................................ 97
10.8.2
Appendix 8 - Visual Analogue Scale............................................................... 100
10.9
References ...................................................................................................... 101
LIST OF TABLES
Table 1
Primary Objective and Endpoint .............................................................. 17
Table 2
Secondary Objectives and Endpoints ....................................................... 18
Table 3
..................................................... 19
Table 4
24
Table 5
Schedule of Screening Procedures ........................................................... 32
Table 6
Treatment Period Study Procedures ......................................................... 35
Table 7
Schedule of Follow-up Procedures........................................................... 41
Table 8
................................................. 54
Table 9
Summary of Revisions to the Protocol ..................................................... 74
Table 10
Summary of Revisions to the Protocol ..................................................... 75
Table 11
Summary of Revisions to the Protocol ..................................................... 75
Table 12
Summary of Revisions to the Protocol ..................................................... 77
Table 13
Summary of Revisions to the Protocol ..................................................... 78
Table 14
Highly Effective Methods of Contraception............................................. 81
LIST OF FIGURES
Figure 1
Study Flow Diagram and Additional Design Details ................................ 21


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ADA
anti-drug antibody/antibodies
AEE
activity energy expenditure
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase
ANCOVA
analysis of covariance
AST
aspartate transaminase
AUC
area under the concentration-time curve
BMI
body mass index
BP
blood pressure
CI
confidence interval
CKD-EPI
Chronic Kidney Disease-Epidemiology Collaboration
CRO
contract research organization
Cmax
maximal plasma concentration
DEBQ
Dutch Eating Behaviour Questionnaire
DLW
doubly-labelled water
DNA
deoxyribonucleic acid
DPPIV
dipeptidyl peptidase 4 inhibitor
DXA
dual X ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EE
energy expenditure
eGFR
estimated glomerular filtration rate
ExEE
exercise energy expenditure
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
glycated haemoglobin
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form


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Abbreviation or 
Specialized Term
Definition
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFU
Instructions for Use
IVGTT
intravenous glucose tolerance test
IXRS
interactive voice/web response system
kg
kilogram (s)
kJ
kilojoule (s)
LS
least squares
MDRD
Modification of Diet in Renal Disease
MedDRA
medical dictionary for regulatory activities
mITT
Modified Intent-to-treat
MMTT
mixed-meal tolerance test
NOAEL
no-observed-adverse-effect level
Oxm
oxyntomodulin
PD
pharmacodynamic (s)
PK
pharmacokinetic(s)
PRO
patient reported outcome
PT
preferred term
REE
resting energy expenditure
RMR
resting metabolic rate
SAE
serious adverse event
SC
subcutaneous
SGLT2i
sodium-glucose co-transporter inhibitor(s)
SID
subject identification
SOC
system organ class
TEE
total energy expenditure
TBL
total bilirubin
T2DM
type 2 diabetes mellitus
TEF
thermic effect of feeding
TEAE
treatment-emergent adverse event
TEE
total energy expenditure
TESAE
treatment-emergent serious adverse event
TSH
thyroid stimulating hormone
ULN
upper limit of normal
VAS
Visual Analog Scale


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1
INTRODUCTION
1.1
Disease Background
The rising prevalence of type 2 diabetes mellitus (T2DM) and obesity is a cause of substantial 
health and economic burden worldwide. In many cases of T2DM, major weight loss (typically 
5% of body weight or more) can promote improvements in glycaemic control, cardiovascular 
risk, and mortality rates, and may even slow or reverse disease progression (Petersen et al 
2005). Many existing therapies for T2DM focus upon lowering blood glucose; however, there 
is a major unmet need for treatments that both improve glycaemic control and achieve 
disease-modifying weight loss.
1.2
MEDI0382 Background
MEDI0382 is briefly described below. Refer to the current Investigator’s Brochure (IB) for 
details. 
 
 
 
 
 
 
 
 
 
 
1.3
Summary of Nonclinical Experience
 
 
 
 


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1.4
Summary of Clinical Experience
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refer to the current MEDI0382 IB for a complete summary of clinical information.
1.5
Rationale for Conducting the Study
Energy balance describes the relationship between EE and energy intake. Under normal 
physiological conditions, EE is equal to energy intake and promotes stable body weight. 
Energy expenditure is defined as the amount of energy the body requires to maintain essential 
bodily functions and to perform physical activity. Measured total energy expenditure (TEE) is 
a composite of resting energy expenditure (REE), activity energy expenditure (AEE) and the 
thermic effect of feeding (TEF). Resting energy expenditure, also known as resting metabolic 
rate (RMR), is the predominant contributor to TEE. Activity energy expenditure is variable 
and a composite of exercise energy expenditure (ExEE) and non-exercise activity 
thermogenesis. The TEF typically accounts for approximately 10% of TEE (Hill et al 2014).
Generating a negative energy balance, either through increased EE or reduced energy intake 
or both favours weight loss and forms the basis of strategies to treat obesity. Indeed, diets and 
restriction of energy intake are the most common and first-line approaches to achieve weight 
loss. In seeking therapies to promote weight loss, previous studies of receptor agonists, Oxm, 


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and glucagon have shown differing effects on EE and energy intake. In a prior study of Oxm 
injections administered to healthy subjects, significant weight loss was achieved and this 
effect was attributed to both reduced energy intake and increased AEE, but not REE (Wynne 
et al 2006). A second study evaluating short-term administration of either Oxm, GLP-1,
glucagon or co-infusion of GLP-1 and glucagon demonstrated reduced energy intake for all 
drugs tested, but minimal effects on REE (Bagger et al 2015). Studies evaluating the effect of 
GLP-1 analogues have consistently shown a reduction in energy intake, but have revealed 
conflicting results with respect to the effect on EE (Farr et al 2016; Horowitz et al 2012). 
However, studies evaluating the impact of glucagon have recorded an increase in REE 
(Chakravarthy et al 2017), which has been shown to be independent of brown adipose tissue 
activity (Salem et al 2016). 
 
 
 
 like Oxm, promotes weight loss through an effect on energy intake and/or an 
increase in EE. 
1.6
Benefit-risk and Ethical Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice, and applicable regulatory requirements.
 
 
 
 
 
 
 
 
 
 
The study design aims to minimise potential risks to subjects participating in this study based 
on the proposed inclusion/exclusion criteria, safety monitoring, and up-titration dosing 
schedule. All subjects will be monitored throughout the study to ensure adequate glycaemic 














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clinically significant hypoglycaemia and should be reported by investigators as an AE, 
regardless of whether or not subjects experience symptoms. Pharmacological treatments 
administered for hypoglycaemia, eg, dextrose/glucose tablets, glucagon etc, should be 
recorded in the electronic case report form (eCRF) as concomitant medications. 
3.1.4.3
Hyperglycaemia
In the event of suspected persistent hyperglycaemia in a subject based on either symptoms of 
hyperglycaemia (eg, thirst, polyuria, blurred vision) or capillary plasma glucose readings (eg, 
3 readings > 14 mmol/L [260 mg/dL] within 1 week), the investigator should perform 
additional fasting blood glucose level tests as necessary. If 2 or more laboratory plasma 
fasting glucose levels of > 14 mmol/L (260 mg/dL) more than 3 days apart are detected, the 
investigator should consider rescue therapy following discussion with the medical monitor.
In the unlikely event that a subject is unwell and severe persistent hyperglycaemia (eg, fasting 
glucose > 14 mmol/L [260 mg/dL]) is suspected by the investigator, the subject should be 
advised to monitor capillary plasma glucose levels up to 5 times per day and rescue therapy 
should be administered within a 24- to 48-hour time frame if required.
3.2
Rationale for Dose, Population, and Endpoints
MEDI0382 is being developed for the treatment of T2DM and obesity. 
 
 
 
3.2.1
Dose Rationale
 
 
 
 
 
 




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3.2.3
Rationale for Endpoint(s)
3.2.3.1
Primary Endpoint
 
 
eight loss is an established surrogate measure of energy balance and 
therefore percentage change in body weight will provide an overview of net energy balance 
versus placebo across the course of 42 days of MEDI0382 dosing (Hill et al 2014). 
3.2.3.2
Secondary Endpoints
Energy Intake
Given that prior studies undertaken with GLP-1 and glucagon receptor-agonists and oxm have 
revealed significant effects on energy intake, it is likely that MEDI0382 influences energy 
intake. Energy intake may be measured in a more robust way than self-report through 
single-blind assessment of ad libitum meal consumption.
Energy Expenditure
Given the findings of prior research describing an increase in differential components of EE it 
will be important to determine the effect of MEDI0382 on TEE, AEE, and REE (Section 1.2). 
Gold standard methodology including whole room indirect calorimetry and DLW will be used
in addition to an activity monitor to obtain estimates of EE as secondary and exploratory 
endpoints during the study. As fluctuations in weight and fat mass may influence estimates of 
EE,
 
 and all measurements will 
be adjusted for total body fat mass as measured by dual X-ray absorptiometry (DXA)
scanning. In addition, subjects will be asked to abstain from caffeinated drinks for at least 
24 hours prior to measurements as caffeine may increase EE and dietary advice will be given 
to ensure subjects have a neutral energy balance prior to whole calorimetry assessments.
Body Weight and Composition
In addition to the primary endpoint of percentage change in body weight, absolute change in 
body weight will also provide an overview of net energy balance versus placebo across the 
course of 42 days of MEDI0382 dosing.
 
 
 
 
 
 


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Glucose Homeostasis
 
 
Safety and Tolerability
As MEDI0382 remains under development, safety and tolerability will be assessed throughout 
this study.
Standard safety endpoints including vital signs, safety laboratory analysis, treatment-emergent 
adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and 
electrocardiograms (ECGs) will be assessed during treatment and follow-up. 
 
 
Immunogenicity
 
 
 
 
 
3.2.3.3
Exploratory Endpoints
MEDI0382 Exposure
 
 
 
 
 


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 Satiety 
 
 
4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Enrolment of approximately 24 subjects is planned. 
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1
Subjects aged ≥30 and ≤75 years at screening
2
Provision of signed and dated written informed consent (except for consent for genetic 
and non-genetic research and additional optional assessments) prior to any 
protocol-related procedures
3
Body Mass Index > 28 and ≤40 kg/m2 at screening
4
Glycated haemoglobin (HbA1c) ≤8.0% at screening 
5
Diagnosed with T2DM with glucose control managed with metformin, with or without a 
DPPIV inhibitor, SGLT2i, sulfonylurea, or glitinide, where no significant dose change 
(increase or decrease > 50%) has occurred in the 3 months prior to screening; if the 


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subject is on dual therapy, a 4-week washout of the non-metformin therapy (DPPIV 
inhibitor, SGLT2i, sulfonylurea, or glitinide) will be required prior to Visit 4
6
Female subjects of childbearing potential must have a negative pregnancy test at 
screening and randomisation, and must not be lactating 
7
Female subjects of childbearing potential who are sexually active with a non-sterilised 
male partner must be using at least one highly effective method of contraception (see 
Section 10.2 for definition of females of childbearing potential and for a description of 
highly effective methods of contraception) from screening and must agree to continue 
using such precautions up until 4 weeks after the last dose of investigational product
4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1
History of, or any existing condition(s) that, in the opinion of the investigator, would 
interfere with evaluation of the investigational product, put the subject at risk, influence 
the subject’s ability to participate or affect the interpretation of the results of the study
and/or any subject unable or unwilling to follow study procedures
2
Any subject with a cardiac pacemaker or implanted/portable electronic device
3
Any subject who has received another investigational product as part of a clinical study or 
a GLP-1 analogue-containing preparation within the last 30 days or 5 half-lives of the 
drug (whichever is longer) at the time of screening (Visit 1)
4
Any subject who has received any of the following medications within the specified time 
frame prior to Visit 2: herbal preparations or drugs licensed for control of body weight or 
appetite (eg, orlistat, bupropion, naltrexone, phentermine-topiramate, phentermine, 
lorcaserin, opiates, domperidone, metoclopramide, or other drugs known to alter gastric 
emptying)
5
Concurrent participation in another study with an investigational product and prior 
randomisation in this study is prohibited
6
Severe allergy/hypersensitivity to any of the proposed study treatments, excipients, or 
standardised meals
7
Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight 
loss), a history of type 1 diabetes mellitus or diabetic ketoacidosis, or if the subject has 
been treated with daily SC insulin within 90 days prior to screening
8
Abnormal thyroid stimulating hormone (TSH) level of < 0.03 mIU/L or > 10 mIU/L
confirmed on two consecutive tests
9
Regularly engage in high intensity exercise at least three times per week or have done so 
in the prior three months
10 Clinically significant inflammatory bowel disease, gastroparesis or other severe disease or 
surgery affecting the upper GI tract (including weight-reducing surgery and procedures) 


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which may affect gastric emptying or could affect the interpretation of safety and 
tolerability data
11 Acute or chronic pancreatitis with or without amylase > 1000 IU/L and/or lipase 
> 600 IU/L at screening
12 Significant hepatic disease (except for nonalcoholic steatohepatitis or nonalcoholic fatty 
liver disease without portal hypertension or cirrhosis) and/or subjects with any of the 
following results at screening:
(a) Aspartate transaminase (AST) ≥3 × upper limit of normal (ULN)
(b) Alanine transaminase (ALT) ≥3 × ULN
(c) Total bilirubin ≥2 × ULN
13 Impaired renal function defined as estimated glomerular filtration rate (eGFR) 
< 45 mL/minute/1.73 m2 at screening (GFR estimated according to the Chronic Kidney 
Disease-Epidemiology Collaboration (CKD-EPI) or the Modification of Diet in Renal 
Disease (MDRD) using MDRD Study Equation isotope dilution mass 
spectrometry-traceable [SI units]
14 Poorly controlled hypertension defined as:
(a) Systolic BP > 180 mm Hg
(b) Diastolic BP or > 100 mm Hg
After 10 minutes of supine rest and confirmed by repeated measurement at screening. 
Subjects who fail BP screening criteria may be considered for 24-hour ambulatory blood 
pressure monitoring at the discretion of the investigator. Subjects who maintain a mean 
24-hour BP ≤180/100 mmHg with a preserved nocturnal dip of > 15% will be considered 
eligible
15 Unstable angina pectoris, myocardial infarction, transient ischemic attack or stroke within 
3 months prior to screening, or subjects who have undergone percutaneous coronary 
intervention or a coronary artery bypass graft within the past 6 months or who are due to 
undergo these procedures at the time of screening
16 Severe congestive heart failure (New York Heart Association Class III or IV)
17 Basal calcitonin level > 50 ng/L at screening or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia
18 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
19 Any positive results for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody 
and human immunodeficiency virus (HIV) antibody
20 Substance dependence or history of alcohol abuse and/or excess alcohol intake


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21 Involvement of any AstraZeneca, MedImmune, contract research organization (CRO), or 
National Institute for Health Research/Wellcome Trust Cambridge Clinical Research 
Facility employee or their close relatives
4.1.4
Subject Enrolment and Randomisation
Study participation begins (ie, a subject is ‘enrolled’) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by an interactive voice/web response system (IXRS). The SID number will be 
assigned prior to the beginning of screening evaluations to assess study eligibility 
(inclusion/exclusion) criteria. The SID number will be used to identify the subject during the 
screening process and throughout study participation, if applicable. 
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomised), including the reason(s) for screening failure.
Subjects who fail to meet the eligibility criteria (ie, screening failures) should not be 
randomised or receive investigational product. Subjects may be rescreened once and receive a 
new SID number if, in the opinion of the investigator, there is a reason to believe they may be 
eligible.
Subjects who are enrolled, but subsequently found not to meet all the eligibility criteria must 
not be randomised or receive investigational product, and must be withdrawn from the study.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments) at any time, without prejudice to further treatment. Subjects who withdraw 
consent will be asked about the reason(s) and the presence of any AEs. After consent is 
withdrawn, no further study visits or data collection should take place.
4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:
1
Withdrawal of consent from further treatment with investigational product 
2
Lost to follow-up
3
An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing: specific examples include:

Dose-limiting symptoms with respect to GI tolerability and in particular if a subject 
requires intravenous fluids for more than 48 hours to treat volume depletion 


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secondary to nausea and vomiting, even after measures are taken to reduce the risk of 
vomiting, after discussion with the medical monitor

Any subject where Hy’s law criteria on liver function tests is met: AST or 
ALT ≥3 × ULN together with total bilirubin ≥2 × ULN

Any subject who develops a life-threatening arrhythmia including sustained 
ventricular tachycardia, ventricular fibrillation or new ECG changes of second or 
third-degree heart block

Subjects with persistent fasting glucose level of > 260 mg/dL(14.4 mmol/L) despite a 
maximum tolerated dose of rescue therapy to enable optimisation of the subject’s 
glycaemic control
4
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)
5
Pregnancy in a female subject
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including follow-up of any AEs unless consent is 
withdrawn from further study participation (Section 4.1.5), the subject is lost to follow-up, the 
subject starts alternative treatment, or the subject is enrolled in another clinical study.
4.1.7
Replacement of Subjects
Subjects who withdraw from the study will be replaced where possible. A maximum number 
of five subjects may be replaced.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of a SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject (Section 10.6).
Plasma and Muscle Biopsy Samples Obtained for Genetic Research or Future 
Non-genetic Research 
Samples obtained for genetic research or future non-genetic research will be labelled with a 
sample identification number linked to the SID number but will not be labelled with personal 
identifiers such as the subject’s name (Section 10.7). If the subject withdraws consent for 
participating in the genetic research or future non-genetic research, the sponsor will locate the 


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subject’s sample and destroy it. The coding of samples and results is to ensure that these 
research results are kept confidential by keeping the subject’s identity and these results 
separate.
If the subject consents to have his/her samples used for genetic research or future non-genetic 
research, this additional research may not start immediately and may start at any time during 
the storage period. The subject’s sample(s) including any specimens of extracted 
deoxyribonucleic acid (DNA) will be stored by the sponsor with similar samples from other 
subjects at a secure central laboratory. The subject’s samples will not be kept for more than 15
years after the end of the study in which they were collected. If the subject chooses not to 
allow his/her study samples to be used for genetic research or future non-genetic research, the 
samples will be destroyed by the sponsor once they are no longer required for the main study.
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent to 
the sponsor for genetic research or future non-genetic research, the investigator will arrange to 
have it destroyed. If consent is withdrawn after the subject’s sample(s) have been sent to the 
sponsor for genetic research or future non-genetic research, the sponsor and the investigator 
will ensure that these sample(s) are destroyed unless the sample identification number has 
been removed and the subject can no longer be linked to any sample(s). However, if the 
subject’s samples have already been used for research, the sponsor is not required to destroy 
results of this research. In this case only the remaining sample(s) will be destroyed.
4.2
Schedule of Study Procedures
4.2.1
Enrolment/Screening Period
Table 5 shows all procedures to be conducted at the screening visit. 
Table 5
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -28 to Day -1
Written informed consent/ assignment of SID number
X
Optional informed consent for blood samples for future genetic research a
X
Optional informed consent for blood samples for future non-genetic research a
X
Medical history, including smoking and alcohol history
X
Physical examination (full) including structured neurological examination b
X
Verify eligibility criteria
X
Weight, height and BMI calculation
X


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Study Period
Screening
Visit Number
V1
Procedure / Study Day
Day -28 to Day -1
Demographics
X
12-lead ECG c
X
Vital signs (BP d, pulse, body temperature, respiration rate)
X
Alcohol breath test
X
Collect blood for:
    LFTs, Cr and eGFR calculation only
X
    TSH
X
    HbA1c
X
    Calcitonin
X
…Pancreatic lipase and amylase
X
    HIV-1 and -2 antibodies; hepatitis B and C serology
X
    Serum pregnancy test
X
Collect urine for:
    Urine drug screen 
X
    Urine pregnancy test if applicable
X
SC injection self-administration training e
X
Advise on washout of second non-metformin diabetes therapy if applicable f
X
Assessment of AEs and SAEs g
X
Concomitant medications
X
AE = adverse event; BMI = body mass index, BP = blood pressure, Cr = creatinine, DPPIV = dipeptidyl 
peptidase 4 inhibitor; ECG = electrocardiogram, eGFR = estimated glomerular filtration rate, FBC = full blood 
count, HbA1c = glycated haemoglobin, HIV = human immunodeficiency virus, LFTs = liver function tests 
(albumin, alanine transaminase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP] and total 
bilirubin), SAE = serious adverse event; SC = subcutaneous; SGLT2i = sodium-glucose co-transporter 
inhibitor(s); SID = subject identification, TSH = Thyroid stimulating hormone; V = Visit.
a
During the informed consent process subjects will be asked to provide consent for the main study as well as 
for the optional components: future genetic research and future non-genetic research. Only sample(s) for 
which the subject has consented will be taken.
b
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.
c
A single digital ECG recording should be performed after the subject has rested for 10 minutes.
d
Blood pressure should be measured once at heart level in the non-dominant group where possible, with the 
subject either seated or supine and rested for 10 minutes prior to the measurement.
e
Subject’s ability to self-administer investigational product will be verified by using normal saline 
subcutaneous injections.
f
Once the subject’s eligibility has been confirmed, subjects who take a second agent for their diabetes in 
addition to metformin (ie, a DPPIV inhibitor, SGLT2i, sulfonylurea, or glitinide), should be advised to stop 
the therapy 28 days before Visit 4.


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g
AEs and SAEs will be assessed from the time informed consent form is signed.
4.2.2
Randomised Treatment Period
Table 6 shows all procedures to be conducted during the treatment period.


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Table 6
Treatment Period Study Procedures
Study Period
Placebo Period
Treatment Period
Visit Number
V2
V3
(optional)
V4
V5
V6
V7
V8
V9
Procedure / 
Study
Day -1
Day 1-14
Day 15
Day 16
Day 17
Day 21
Day 25
Day 32
Day 41 or 42
Day 58
Day 59
Admit to clinical unit
X
X
Discharge from clinical unit
X
X
Outpatient visit to clinical 
unit
X
X
X
X
X
X
Fasting on the night before 
required a
X
X
X
X
X
X
X
X
X
Physical examination 
(abbreviated)
X
X
X
X b
Weight c
X
X
X
X
ECG
X
X
Vital signs (BP, pulse, body 
temperature, respiration 
rate) d
X
X
X
X
Collect Blood for
Serum chemistry 
X
X
X
X
Haematology
X
X
X
X
Pancreatic lipase and 
amylase
X
X
X
HbA1c
X
X
Serum calcitonin
X
X
Fasting lipid profile
X
X
Serum pregnancy test
X
X
Optional for genetic 
testing
X




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Table 6
Treatment Period Study Procedures
Study Period
Placebo Period
Treatment Period
Visit Number
V2
V3
(optional)
V4
V5
V6
V7
V8
V9
Procedure / 
Study
Day -1
Day 1-14
Day 15
Day 16
Day 17
Day 21
Day 25
Day 32
Day 41 or 42
Day 58
Day 59
SmartPill™capsule 
administration to assess 
gastric emptying
X
X
Fixed standardised meals 
(Meal Type B) n
X
X
Advice on diet prior to 
whole room calorimetry 
(remote contact or during 
visit)
X
(Day 4-11)
X
Subject enters whole room 
calorimeter o
X
X
Exercise sessions p
X
X
Hunger/satiety
questionnaires q
X
X
DXA scan r
X
X
Optional muscle biopsy s
X
X
Hood-based indirect 
calorimetry t
X
X
X
X
X
X
X
Provision of activity 
monitor and device training
X
Activity monitoring
Subjects will be expected to wear the activity monitoring device until the final study visit (V10)
Activity monitoring device
battery check/ charging (as 
required) u
X
X
X
Weight measurement at 
home
Subjects will be expected to weigh themselves every 72 hours whilst at home








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4.2.3
Follow-up Period
Table 7 shows all procedures to be conducted during the follow-up period.
Table 7
Schedule of Follow-up Procedures 
Study Period
Follow-up Period
Visit Number
Final Visit (V10)
Procedure / Study Day
28 days post last dose (± 3 days)
Physical examination (abbreviated)
X
Remove activity monitoring device
X
Weight
X
ECG
X
Vital signs (BP, pulse, body temperature, respiration rate) a
X
Serum chemistry panel
X
Calcitonin b
X
Haematology
X
Urinalysis
X
HbA1c
X
Urine pregnancy test
X
Assessment of TEAEs/TESAEs d
X
Concomitant medications e
X
ADA = anti-drug antibody; AE = adverse event; BP = blood pressure; ECG = electrocardiogram; 
HbA1c = glycated haemoglobin, SAE = serious adverse event; TEAE = treatment-emergent adverse event; 
TESAE = treatment-emergent serious adverse event; ULN = upper limit of normal; V = visit.
a
Blood pressure should be measured once at heart level in the non-dominant arm where possible, with the 
subject seated and rested for 10 minutes prior to the measurement.
b
Only to be repeated if the calcitonin level was > ULN in the sample taken at the end of dosing.
c
See Section 4.3.7 for details.
d
AEs and SAEs will be assessed from the time of signed informed consent form.
e
If a second non-metformin agent was washed out during the screening period the investigator and/or study 
team should consider whether it is appropriate to re-start this therapy.
4.2.4
Early Discontinuation Visit or Unscheduled Study Visit
The following study procedures may be conducted for subjects who prematurely discontinue 
from the study or for subjects who require an unscheduled study visit. The types of procedures 
required will be at the discretion of the investigator.

Targeted physical examination

ECG


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
Vital signs

Body weight


Blood tests including chemistry and haematology panel


Assessment of AEs/serious adverse events (SAEs)

Concomitant medications

Urine pregnancy test (if applicable)
4.3
Description of Study Procedures
4.3.1
Screening/Enrolment, Treatment, and Follow-up 
On Day -1 subjects will attend the clinical unit having fasted for 12 hours overnight (ideally 
subjects will stay at the research facility the night before but have the option to arrive the 
morning of Day -1 if more convenient). Subjects will be weighed and will undergo a hood 
calorimetry assessment (after at least one hour of rest) to measure REE. Subjects will then 
receive a standardised solid meal (Meal Type A) as part of a MMTT with serial blood 
sampling followed by a lunchtime meal on an ad libitum basis (Meal Type C); food 
consumption will be measured in a single-blind fashion and subjects will be expected to 
complete a food diary for the remainder of the day after the ad libitum lunch. During the visit 
subjects will also undergo a DXA scan, blood tests for safety and they will receive a drink of 
doubly labelled water (DLW [2H218O]) and will be required to provide urine samples before 
and after the drink of DLW. In addition, an activity monitor will be fitted and subjects will be 
expected to wear the monitor continuously until the final study visit. Subjects will also be 
required to perform periodic measurements of weight and capillary glucose measurements 
whilst at home for the duration of the study, the results of which will either be recorded 
digitally or in a paper diary.
 
 
 
 
Between Day 4 and 11, subjects will be contacted by the study team at any time to advise 
them on diet in the 72 hours prior to their admission on Day 15 to ensure that they are in a 
neutral energy balance before this visit. On Day 15, subjects will be admitted following a 
12-hour overnight fast to the clinical unit for approximately 48 hours. Upon arrival, subjects 
will enter the whole room calorimeter and remain inside for up to 36 hours. A hood 


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calorimetry assessment will be performed initially and collection of urine for protein 
estimation (on Day 15/16) and DLW assessments (on Day 17) will be undertaken. Subjects 
will receive standardised meals at fixed times (Section 4.3.2.2). Meals (Meal Type B) will be 
formulated to match individual energy requirements using baseline energy expenditure 
readings from the activity monitor or using population-based energy requirement equations. 
Immediately after the first meal subjects will be required to swallow a SmartPill™ to measure 
gastric emptying and they will be restricted to drinking 200 mL water for the first 2 hours after 
swallowing the SmartPill™, but will be permitted to drink unlimited amounts of sugar-free, 
decaffeinated drinks for the remainder of the day after this time. During the time in the 
calorimeter, subjects will be expected to exercise on an exercise bike for 4 × 15-minute 
intervals and to fill out questionnaires to assess hunger and satiety. On Day 16 subjects will 
undergo a hood calorimetry assessment and afterwards will receive a fixed standardised 
breakfast (Meal Type A) followed by a lunch-time meal on an ad libitum basis 
(Meal Type C); food consumption will be measured in a single-blind fashion and subjects will 
be expected to fill in a food diary for the remainder of the day after the ad libitum lunch. On 
Day 17, following an overnight fast of at least 8 hours, 
 
 
 
 
 
 
On Day 32, subjects will attend for a long day visit following an overnight fast of at least 
12 hours. Subjects will undergo hood calorimetry upon arrival (after at least one hour of rest) 
and afterwards they will receive a fixed standardised breakfast (Meal Type A) followed by an 
ad libitum lunch (Meal Type C); again, food consumption will be measured in a single-blind 
fashion. 
 
 
Subjects will either receive a home visit or re-attend for a short visit on either Day 41 or 42 to 
receive DLW and will be requested to provide urine samples before and afterwards. Subjects 
will also be advised on diet in the 72 hours prior to their admission on Day 58 to ensure that 
subjects are in a neutral energy balance before this visit. 
 
 
On Day 58, subjects will be re-admitted to the clinical unit for approximately 48 hours but 
will be permitted to arrive the evening before and stay overnight if that is more convenient for 
them. Upon arrival, subjects will enter a whole room calorimeter for up to 36 hours and 


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undergo the same procedures as before including urine sampling for protein estimation and as 
part of the DLW assessment. 
On Day 59 subjects will be weighed and then receive a fixed solid standardised meal 
(Meal Type A) as part of a MMTT with serial blood sampling followed by a lunchtime ad 
libitum meal (Meal Type C) with a single-blind measure of food consumption and completion 
of a food diary for the remainder of the day. Subjects will also undergo a repeat DXA scan 
and safety bloods will be taken at the same time as the MMTT. A follow-up visit will be 
performed for final safety assessments approximately 28 days after the last dose of 
investigational product.
4.3.2
Efficacy
The following efficacy assessments will be performed and/or measured at the time points 
specified in the schedules of study procedures (Table 6).
4.3.2.1
Mixed-meal Tolerance Test
Following a minimum 12-hour fast the subject will undergo a MMTT at the times specified in 
the schedule of treatment period study procedures (Table 6) which will involve the 
consumption of a standardised solid meal (Meal Type A) within 5 minutes, and timed serial 
blood samples will be obtained for measurement of glucose and gut and pancreatic hormone
levels through 240 minutes with no additional food intake during this time. Subjects will be 
permitted to drink water during this assessment.
4.3.2.2
Standardized Meals
Meal Type A:
A standardised solid breakfast meal that will be provided to subjects at the time points 
specified in the schedule of treatment period study procedures and during the MMTTs 
(Table 6). The same meal should be used for all subjects at the beginning and end of the study.
Meal Type B:
Meal Type B describes the standardised meals that will be administered to subjects during 
their stay in the whole room calorimeter at the time points specified in the schedule of 
treatment period study procedures (Table 6). The solid meals should be balanced nutritionally
and contain fixed ratios of carbohydrate, fat and protein. The total daily calorie content of 
meals should be matched to the subjects EE recorded on the activity monitor worn during the 
single-blind placebo treatment period to ensure neutral energy balance. Alternatively, 
population-based estimates of energy requirement equations may be made. For example, if the 
subject’s average daily calorie expenditure (predicted or measured) = 2000 kcals during the 
placebo treatment period, the total daily calorie content of meals administered while the 
subject is in the calorimeter should equal approximately 2000 kcals. Subjects will be expected 
to consume each meal within 30 minutes. The actual meal choices provided may vary by 


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meal, but ideally subjects should be given the same type of meal at the same time; and the 
same menu should be used between the baseline assessments and at the end of the treatment 
period. If a subject has a strong dislike of a particular meal, it is permissible to substitute the 
meal with an alternative providing that the meal contains the same ratio of carbohydrate, fat,
and protein. Inter-meal snacks should be avoided while the subject is in the calorimeter; 
however, sugar-free caffeine-free drinks are allowed freely during this time (with the 
exception of the 2-hour period after ingestion of the SmartPill™ to measure gastric emptying).
Meal Type C: 
Meal type C is the ad libitum lunch that will follow breakfast (Meal Type A) that will be 
served as a meal with food of known macronutrient content at the time points specified in the 
schedule of treatment period study procedures (Table 6). Subjects will be advised to eat freely 
until they feel comfortably full. There will be no time limit on the duration of the meal. 
During the meal, the quantity of food ingested will be recorded by study site staff; the subjects 
will not be aware food consumption is being recorded. When subjects are finished eating their 
ad libitum lunch, they will be provided with a food diary to complete for the remainder of the 
day (Section 4.3.3.2).
4.3.2.3
Dual X-ray Absorptiometry
The change in total body fat mass will be measured in kilograms (kg) using DXA at the 
beginning of the study and end of the study according to the time points specified in the 
schedule of treatment period study procedures (Table 6). Dual X ray absorptiometry scanning 
will be conducted using a Lunar iDXA scanner (GE healthcare). A single scan is equivalent to 
2 days of background radiation. Subjects will be asked to remove all metal on their body and 
will be provided with surgical scrubs to wear when necessary. Subjects will align themselves 
on the scanner so that the centre of their body is lying on the middle of the scanner. Subjects 
will be advised to be as still as possible for the duration of the scan, which will take between 5 
and 10 minutes depending on the size of the participant. There will be no requirement for 
sedation during the scan.
Analysis of the result will involve alignment of standard lines to outline the following sections 
in the body: left leg, right leg, right trunk, left trunk, right arm, left arm, and head. A read-out 
of the estimated mass of total body tissue, fat, and lean mass fat mass will be generated and 
recorded in the eCRF.
4.3.2.4
 
 
 




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4.3.2.8
Body Weight
Body weight in kilograms (kg) will be measured at clinic visits at the time points specified in 
the schedules of study procedures (Section 4.2) after the subject have removed bulky clothing 
including shoes. Whenever possible, the same (properly calibrated) scale should be used for 
each measurement for any given subject.
Body weight will also be measured by the subject at home every 72 hours; and the subject 
should be given similar instructions for undertaking measurements. Collection of 
home-recorded weights will either be electronic or recorded in a paper diary.
4.3.2.9
Intravenous Glucose Tolerance Test
To measure first phase insulin release, insulin sensitivity, and glucose, at the time points 
specified in the schedule of treatment period study procedures (Table 6), subjects will attend 
the clinical unit having fasted for 12 hours overnight for an intravenous glucose tolerance test 
(IVGTT). During this assessment, an intravenous cannula will be inserted into a vein in the 
antecubital fossa and patency will be checked with a normal saline flush. Once confirmed, a 
bolus of 300 mg/kg (based on body weight or lean mass) of 20% to 30% glucose or dextrose 
solution will be administered intravenously. Blood samples will be drawn before and for up to 
180 minutes after the glucose infusion at time-points detailed in the schedule of procedures.
4.3.2.10
Gastric Emptying Assessment
At the time points specified in the schedule of treatment period study procedures (Table 6), 
subjects will be admitted to the clinical unit following a 12-hour overnight fast and be 
required to swallow a SmartPill™ to measure gastric emptying. The SmartPill™ will be 
consumed immediately after the first standardised meal (Meal type B) while the subject is in 
the whole room calorimeter. After consuming the SmartPill™, the subject will be restricted to 
drinking 200 ml of water for the preceding 2 hours, but thereafter may drink sugar-free and 
decaffeinated drinks freely. If a subject is unable/ unwilling to complete this procedure, they 
should not be withdrawn or discontinued from the study.
The SmartPill™motility capsule (referred to as a SmartPill™) is part of the SmartPill™ 
Motility Testing System (Medtronic) used to measure gastric emptying. The system consists 
of a SmartPill™ which the subject ingests, a receiver worn around the waist and a laptop 
including a docking station. The SmartPill™measures pressure, pH, transit time, and 
temperature as it passes through the entire GI, sending a signal to the receiver once it has been 


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expelled from the body (through the faeces). Once the receiver has indicated that the 
SmartPill™has been passed out of the body, the subject will return the receiver to the site 
who will download the data (the SmartPill™ is a disposable device and should pass through 
the faeces un-noticed; it does not need to be recovered following elimination through the 
faeces). The gastric emptying time is computed automatically by the system software and can 
be verified from the resulting trace which is a feature of the output dataset.
In the event that a subject cannot or will not swallow the SmartPill™ capsule, they may 
continue in the study without it constituting a deviation from the protocol. If for any reason a 
subject is unable to tolerate the SmartPill™they should not be discontinued from the study.
4.3.3
Patient Reported Outcomes
4.3.3.1
Hunger and Satiety 
Questionnaires will provide information on whether MEDI0382 affects hunger, satiety or 
both. Change in hunger and satiety scores at the time points specified in the schedules of 
procedures will be obtained. Results will be recorded in the eCRF.
Dutch Eating Behaviour Questionnaire
The Dutch Eating Behaviour Questionnaire (DEBQ) is a 33-item self-report questionnaire that 
was developed to assess three distinct eating behaviours in adults: (1) emotional eating, 
(2) external eating, and (3) restrained eating. Items on the DEBQ range from 1 (never) to 
5 (very often), with higher scores indicating greater endorsement of the eating behaviour (Van 
Strien et al 1986) (Section 10.8.1). Results will be recorded in the eCRF.
Visual Analogue Scale
A Visual Analogue Scale (VAS) that will be used in this study is a 4-item self-report 
questionnaire that assesses hunger on a scale from ‘not at all’ to ‘extremely.’ A copy of this 
VAS is included in Section 10.8.2. Results will be recorded in the eCRF.
4.3.3.2
Food Diary
Subjects will be provided with a food diary following the ad libitum meal assessment and ask 
to record the amount of food and any drinks consumed for the remainder of the day where 
indicated in the schedule of assessments. The total calories consumed in joules will be 
calculated and recorded in the eCRF.
4.3.4
Safety Assessments
4.3.4.1
Medical History and Physical Examination
Complete medical history will include history (including smoking and alcohol history) and 
current medical conditions, past or present cardiovascular disorders, respiratory, 
gastrointestinal (GI), renal, hepatic, neurological, endocrine, lymphatic, haematologic, 


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immunologic, dermatological, psychiatric, genitourinary, drug and surgical history, or any 
other diseases or disorders.
The full physical examination including a structured neurological examination is required at 
screening (Table 5). Abbreviated physical examinations (evaluation of selective body systems 
at the judgment of the physician or qualified designee based on subject presentation) are 
sufficient for the remaining time points (ie, randomised treatment and follow-up periods) 
(Table 6 and Table 7). Physical examinations will be performed by a physician or qualified 
designee and will include examination of the following body systems: immunologic/allergy; 
head, ears, eyes, nose, and throat; respiratory; cardiovascular; GI; musculoskeletal; 
neurological (structured neurological examination to encompass mental status, cranial nerves, 
nystagmus; motor system-muscle strength, sensory system-sensation, bowel and bladder 
function, deep tendon reflexes, gait, station, coordination, fundoscopy, and cerebellar 
function); psychiatric (to the extent of determining whether or not the subject is willing and 
able to cooperate with the required study procedures in the investigator’s judgment); 
dermatological; haematologic/lymphatic; and, endocrine. 
Any focal deficit identified at baseline should be documented in the eCRF.
Clinically significant abnormal findings will be recorded. 
4.3.4.2
Assessment of the Injection Site
Study centre staff will check the injection site for reactions during study visits as required. 
Injection site reactions may include (but are not limited to); local erythema, pain, tenderness, 
induration, swelling, pruritus, ulceration, and pigmentation changes.
4.3.4.3
Electrocardiograms
At the visits specified in the schedules of study procedures (Table 5, Table 6, and Table 7), 
ECGs will be obtained after 10 minutes supine rest. Only a single digital ECG recording will 
be required at the specified time points.
The same recorder will be used for each subject at each time point, if possible. Date and time 
settings should be checked at the start of each study day and aligned with an official 
timekeeper for all machines used in the study.
Skin preparation should be thorough and electrode positions should be according to standard 
12-lead ECG placement. 
In this study lead II or V2 will be analysed and reported as primary. Lead V5 will be analysed, 
for all visits, as backup for the individual where analysis in lead II or V2 is not deemed 
possible for pre-dose or significant parts of whole visits or whole visits.


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The following variables will be reported: PR, QRS, and QT intervals from the primary lead of 
the digital 12-lead ECG. The investigator may add extra 12-lead ECG safety assessments if 
there are any abnormal findings or if the investigator considers it is required for any other 
safety reason.
4.3.4.4
Vital Signs
Vital sign measurements (BP, pulse rate, body temperature, and respiration rate) will be 
obtained after the subject has rested in either a seated or supine position for at least 10 minutes 
at the time points specified in the schedules of study procedures (Section 4.2). For time points 
where ECG recording precedes vital sign measurement, the 10-minute rest in the supine 
position prior to the ECG suffices for the rest prior to vital sign measurement). Blood pressure 
should be measured once at heart level in the non-dominant arm where possible, with the 
subject seated or supine and rested for 10 minutes prior to the measurement. Route of body 
temperature measurement will be according to local procedures.
4.3.4.5
Weight, Height, and Body Mass Index Calculation
Weight (kg), height (cm), and BMI (kg/m2) will be measured at screening. Weight will be 
measured at all other time points as specified in the schedules of study procedures 
(Section 4.2).
4.3.5
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study. 
Clinical laboratory safety tests will be performed in a licensed central or licensed local clinical 
laboratory. Urine pregnancy tests may be performed at the site using a licensed test (dipstick). 
Abnormal laboratory results should be repeated as soon as possible (preferably within 
24 to 48 hours). 
The following clinical laboratory tests will be performed (refer to time points in the schedules 
of study procedures (Section 4.2): 
Serum Chemistry
•
Potassium
•
Total bilirubin
•
Sodium
•
Creatinine
•
ALT
•
Blood urea
•
AST
•
Albumin
•
ALP
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase.
Notes: 


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Liver function tests = AST, ALT, ALP, total bilirubin, and albumin 
Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently and assessed concurrently. 
Haematology
•
White blood cell count with differential
•
Platelet count
•
Red blood cell count
•
Mean corpuscular volume
•
Haematocrit
•
Mean corpuscular haemoglobin concentration
•
Haemoglobin
Urinalysis
•
Protein
•
Urine drug screen a
•
Glucose
•
Ketones
•
Blood
Notes: 
Urinalysis for protein, glucose, ketones, and blood may be performed at the site using a licensed test (dipstick).
a
Illicit drug panel will test for the following drugs; amphetamines, barbituates, benzodiazepines, cocaine, 
opiates (morphine, heroin), methamphetamine, cannabinoids (marijuana), methodone, phencyclidene, 
methylenedioxy-methamphetamine (ecstasy), propoxyphene, and tricyclic antidepressants. Subjects who 
use tricyclic antidepressants or benzodiazepines for an established clinical indication may be permitted to 
enter the study based upon the judgement of the investigator.
Additional Urine Samples
•
Urine samples for DLW assessment
•
24-hour urine collection for protein assessment
Pregnancy Test (females of childbearing potential only)
•
Serum human chorionic gonadotropin (hCG; screening if applicable, and Day -1 and 17 only)
•
Urine hCG
Other Laboratory/Blood Tests
•
Calcitonin
•
Alcohol screening test (breath- or urine-based test)
•
Pancreatic amylase and lipase
•
Glycated haemoglobin 
•
Anti-drug antibodies (immunogenicity)
•
Hepatitis B surface antigen, hepatitis C antibody (screening only)
•
Human immunodeficiency virus-1, -2 antibodies (screening only)
•
Metabolism panel for MMTT: Timed glucose; insulin, C-peptide, glucagon, GIP, active and total GLP-1, 
and ghrelin
•
Fasting lipid profile: high-density lipoprotein, low-density lipoprotein, triglycerides, total cholesterol, and 
Apo lipoprotein B
•
Thyroid stimulating hormone (TSH; screening only)


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4.3.5.1
Glucose Meter Measured Capillary Plasma Glucose Readings
At the start of the study, each subject will be issued a standardised glucose meter, testing 
strips, and a diary. Subjects will be requested to record a capillary glucose reading 
pre-breakfast every 72 hours and will also be encouraged to perform finger-prick tests if they 
feel unwell, and in particular if they feel the symptoms may be due to hypoglycaemia for the 
duration of the study (Section 3.1.4.2). If the investigator/site staff feel that a subject could be 
experiencing hypo- or hyperglycaemia, capillary plasma glucose should be tested with a 
standardised glucose meter. Capillary plasma glucose levels of < 3 mmol/L (54 mg/dL) should 
be recorded as an AE regardless of whether the subject has symptoms or not. Readings taken 
by the subject at home will be recorded electronically or in a paper diary.
4.3.6
Pharmacokinetic Evaluation and Methods
 
 
 
 
 
4.3.7
Immunogenicity Evaluation and Methods
 
 
 
 
 
 
 
 
 
 
 


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4.3.8
Biomarker Evaluation and Methods
 
 
 
 
 
 
 
 
4.3.9
Genetics
The subject’s consent to participate in the genetic research components of the study is 
optional. See Section 10.6.3 for further information.
4.3.10
Estimate of Volume of Blood to Be Collected
 
 
 
 
 Additional blood samples may be collected at the discretion of the investigator in 
the event of abnormal laboratory findings or an AE.
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or permanently terminate this study at 
any time. The reasons for temporarily suspending or permanently terminating the study may 
include but are not limited to the following: 






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4.5.1.2
Investigational Product Inspection
 
 
 
If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Reporting Product Complaints 
(Section 4.5.1.5) for further instructions. 
4.5.1.3
Treatment Administration
In-clinic Treatment Administration
 
 
 
 
 
At-home Treatment Administration
 
 
 
 


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4.5.1.4
Monitoring of Dose Administration
 
 
 
 
 
4.5.1.5
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labelled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone:
+1-301-398-2105
+1-877-MEDI-411 (+1-877-633-4411)
Fax:
+1-301-398-8800
Mail:
MedImmune
Attn: Product Complaint Department
One MedImmune Way
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.


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4.5.3
Labelling
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice and local regulatory guidelines. 
4.5.4
Storage
All investigational product should be stored at 2°C to 8°C in a secure place under appropriate 
storage conditions. The label on the investigational product kit specifies the appropriate 
storage requirements.
4.5.5
Treatment Compliance
In-clinic Administration
 
At-home Administration
 
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records and will account for all investigational 
product dispensed to and returned by the subject. Study site staff, if applicable, or the site 
monitor delegated to the investigational product management will account for all 
investigational product received at the site, unused investigational product, and for appropriate 
disposition of investigational product in accordance to local procedures. Upon completion of 
the study, copies of investigational product accountability records will be returned to 
MedImmune. All unused investigational product will be returned to a MedImmune authorised 
depot or disposed of upon authorisation by MedImmune.
In the case of a malfunctioning prefilled syringe, the designated investigational product 
manager (pharmacist/study nurse) should contact the site monitor delegated to investigational 
product management to initiate a product complaint process according to Section 4.5.1.5.
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IXRS will be used for randomisation to a treatment group and assignment of 
investigational product kit numbers. A subject is considered randomised into the study when 


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the investigator notifies the IXRS that the subject meets eligibility criteria and the IXRS 
provides the assignment of investigational product kit numbers for the subject.
4.6.2
Methods to Ensure Blinding
This is a double-blind study in which MEDI0382 and placebo are not identical in the prefilled 
syringe titration volumes. Neither the subject nor any of the investigator or sponsor staff who 
are involved in the treatment or clinical evaluation of the subjects will be aware of the 
treatment received (ICH E9).
The different fill volumes of investigational product (MEDI0382 and placebo) and the relative 
position of the plunger rods will be visually distinct during administration. Neither the 
subject/legal representative nor any of the investigator or sponsor staff who are involved in the 
treatment or clinical evaluation of the subjects will be aware of the treatment received 
(ICH E9). The blinding mechanism will be implemented through the IXRS to ensure that 
treatment groups are not revealed to the site. In the event that treatment allocation for a subject 
becomes known to the investigator or other study staff involved in the management of study 
subjects, the sponsor must be notified immediately. If the treatment allocation for a subject 
needs to be known to treat an individual subject for an AE, the investigator must notify the 
sponsor immediately and, if possible, before unblinding the treatment allocation.
In addition, to maintain the blind, investigational product (MEDI0382 and placebo) prefilled 
syringes will be handled by an unblinded investigational product manager or unblinded study 
personnel who will not be involved in the treatment or clinical evaluation of subjects. An 
unblinded site monitor will perform investigational product accountability, and this will be a 
different person to the blinded site monitor who will oversee other aspects of the study at the 
clinical site. The site will maintain a written plan detailing which staff members are 
blinded/unblinded and the process of investigational product administration used to maintain 
the blind.
4.6.3
Methods for Unblinding
4.6.3.1
Unblinding in the Event of a Medical Emergency
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation using emergency unblinding envelopes which will be held 
securely at the study site. In general, unblinding should only occur if management of the 
medical emergency would be different based on the subject having received investigational 
product. In the majority of cases, the management of a medical emergency would be the same 
whether or not investigational product was received by the subject. If this was the case, the 
investigational product allocation should not be unblinded. 


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MedImmune retains the right to unblind the treatment allocation for SAEs that are unexpected 
and are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities.
Instructions for unblinding an individual subject’s investigational product allocation are 
contained in the IXRS manual.
4.6.3.2
Unblinding for Pharmacokinetic Analysis
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as ‘excluded’ as 
listed in Section 4.7.2. Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, 
anti-emetics, anti-diarrhoeals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines.
4.7.2
Prohibited Concomitant Medications
Other than the medications described above, use of concomitant medications or herbal 
supplements at the times specified in the list below is not permitted. Subjects must be 
instructed not to take any medications, including over-the-counter products, without first 
consulting with the investigator.

Concurrent or previous use of a GLP-1 analogue containing preparation within the last 
30 days or 5 half-lives of the drug, whichever is longest, prior to the start of screening 
(Visit 1)

Concurrent use of any herbal preparations or medicinal products licensed for control of 
body weight or appetite and within 1 week prior to the start of the single-blind placebo 
treatment period (Visit 2)

Concurrent or previous use of drugs approved for weight loss (eg, orlistat, bupropion 
naltrexone, phentermine-topiramate, phentermine, lorcaserin) and within the last 30 days 
or 5 half-lives of the drug, whichever is longest, prior to the start of the single-blind 
placebo treatment period (Visit 2)


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
Concurrent use of opiates, domperidone, metoclopramide, or other drugs known to alter 
gastric emptying within 2 weeks prior to the start of Visit 2
4.8
Statistical Evaluation
4.8.1
General Considerations
Data will be provided in listings sorted by treatment group and subject number. Tabular 
summaries will be presented by treatment group and visit. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous variables 
will be summarized by descriptive statistics, including mean, standard deviation, median, 
minimum, and maximum. Baseline values will be defined as the last valid assessment prior to 
the first administration of investigational product unless otherwise specified. Additional 
details of statistical analyses will be described in the statistical analysis plan.
4.8.2
Analysis Populations
The Intent-to-treat population will include all subjects who receive any investigational product 
analysed according to randomised treatment group.
The Modified Intent-to-treat (mITT) population will include all subjects who receive at least 
one dose of investigational product in the double-blind treatment period analysed according to 
randomised treatment group.
The As-treated population will include all subjects who receive any investigational product 
analysed according to the treatment they actually receive.
The Per-protocol population will include all subjects in the mITT population who complete 
treatment with investigational product up to Day 58.
The PK population will include all subjects in the As-treated population and have at least one 
PK sample taken that is above the lower limit of quantitation.
The Immunogenicity population will include all subjects in the As-treated population who 
have at least one serum sample for immunogenicity testing.
4.8.3
Sample Size
 
 


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4.8.4
Efficacy
4.8.4.1
Primary Efficacy Analysis
The efficacy analysis will be based on the mITT population. The primary efficacy endpoint of 
percentage change in body weight from Day 17 to 59 will be compared between MEDI0382 
and placebo groups using an analysis of covariance (ANCOVA) model adjusting for treatment 
group and measurement at baseline. Last observation carried forward will be used for missing 
data imputation for post-baseline values when applicable.
4.8.4.2
Secondary Efficacy Analyses
The secondary efficacy endpoints will be based on the mITT population and analysed by an 
ANCOVA model similar to that used for the primary efficacy analysis. Selected secondary 
endpoints will also be analysed using the Per-protocol population.
4.8.4.3
Exploratory Efficacy and Pharmacodynamic Analyses
 
 
4.8.5
Safety
4.8.5.1
Analysis of Adverse Events
The safety analysis will be based on the As-treated population. Adverse events and SAEs will 
be coded by the most updated version of the Medical Dictionary for Regulatory Activities 
(MedDRA) and the type, incidence, severity, and relationship to investigational product by 
will be summarized by MedDRA System Organ Class (SOC) and Preferred Term (PT).
Specific AEs will be counted once for each subject for calculating percentages. In addition, if 
the same AE occurs multiple times within a particular subject, the highest severity and level of 
relationship observed will be reported. All TEAEs will be summarized overall, by MedDRA 
SOC and PT, and by severity and relationship to investigational product. In addition, 
summaries of deaths, SAEs, and treatment discontinuations due to AEs will be provided.
4.8.5.2
Analysis of Clinical Laboratory Parameters
Additional safety data including vital signs, safety laboratory analysis, and ECGs will be 
summarised descriptively at each time point by treatment group.
4.8.6
Analysis of Immunogenicity
 
 
 


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4.8.7
Analysis of Pharmacokinetics
 
4.8.8
Patient Reported Outcomes
Analysis of patient reported outcomes (PROs) will be based on the mITT population. The 
exploratory PRO endpoints including change in self-reported hunger and satiety scores from, 
Day 15 to 58 and the change in total energy intake in kilojoules (kJ) as recorded in a food 
diary from Day 16 to 32 and from Day 16 to 59 will be analysed by an ANCOVA model 
similar to that used for the primary efficacy analysis.
4.8.9
Interim Analysis
No interim analyses are planned.
5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The ICH Guideline for Good Clinical Practice E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. An abnormal laboratory finding (including ECG finding) that requires 
medical intervention by the investigator, or a finding judged by the investigator as medically 
significant should be reported as an AE. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
haematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cell 
increased). Abnormal laboratory values that are not, in the investigator's opinion, medically 
significant and do not require intervention should not be reported as AEs.
AEs may be treatment emergent (ie, occurring after initial receipt of investigational product) 
or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, disease, 
or other untoward medical event that begins after written informed consent has been obtained 
but before the subject has received investigational product. 


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Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or serious adverse event (SAE).
5.2
Definition of Serious Adverse Events
An SAE is any AE that:

Results in death

Is immediately life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability/incapacity 

Is a congenital anomaly/birth defect in offspring of the subject

Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
5.3
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the investigator for severity, relationship 
to the investigational product, possible etiologies, and whether the event meets criteria of an 
SAE and therefore requires immediate notification to the sponsor (Section 5.4). See 
Section 5.2 for the definition of SAEs and Section 10.3 for guidelines for assessment of 
severity and relationship. 
If an AE evolves into a condition that meets the regulatory definition of ‘serious’, it will be 
reported on the SAE Report Form.
5.3.1
Time Period for Collection of Adverse Events
AEs and SAEs will be collected from time of signature of informed consent throughout the 
study including the follow-up period as described above.


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5.3.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
MedImmune retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary. Updates regarding SAEs that were 
ongoing at the time of the subject’s completion of study participation should be submitted to 
the study representative using a paper SAE follow-up form.
5.3.3
Deaths
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:
•
An AE causing the death must be reported as an SAE within 24 hours. The report should 
assign main and contributory causes of death.
•
Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) may be helpful in the assessment of the cause of death, and if performed a copy 
of the post-mortem results should be forwarded to the sponsor representative(s) within the 
usual timeframes (refer to Section 5.4 for additional information).
5.4
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 CRF.
If any SAE occurs in the course of the study, then investigators or other site personnel must
inform the appropriate sponsor representative(s) within 1 day, ie, immediately but no later 
than 24 hours after becoming aware of the event.
The designated sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor’s patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform sponsor 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to inform the designated sponsor 
representative(s).


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If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed. 
5.5
Other Events Requiring Immediate Reporting
5.5.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the IB, unless otherwise specified in this protocol.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on a MedImmune investigational product occurs during the course of the study, 
then the investigator or other site personnel inform appropriate sponsor representatives 
immediately, or no later than 24 hours after becoming aware of the event.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.4. 
For other overdoses, reporting must occur within 30 days.
5.5.2
Hepatic Function Abnormality
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need 
to be reported as SAEs. Please refer to Section 10.5 for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law. 
5.5.3
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor except for:
•
Pregnancies discovered before the study subject has received any investigational product
•
Pregnancies in the partner of male subjects
5.5.3.1
Maternal Exposure
If a subject becomes pregnant during the course of the study, the investigational product 
should be discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 


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Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
subject was discontinued from the study.
If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel will inform the appropriate sponsor representatives within 1 day, i.e., immediately 
but no later than 24 hours after becoming aware of the event.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site within 1 or 5 
calendar days for SAEs (Section 5.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy.
6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review and 
discuss the requirements of the protocol and related documents with the investigational staff 
and also train them in any study-specific procedures and system(s) utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 


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accordance with the Laboratory Manual and that study drug accountability checks are 
being performed

Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts)

Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this protocol and the Clinical Study Agreement, the terms of protocol 
shall prevail with respect to the conduct of the study and the treatment of subjects and in all 
other respects, not relating to study conduct or treatment of subjects, the terms of the Clinical 
Study Agreement shall prevail.
Agreements between MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through their last protocol-specified visit/assessment at Visit 10, regardless of the 
number of doses of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (Section 4.1.5 and Section 4.1.6).
The end of the study (‘study completion’) is defined as the date of the last protocol-specified 
visit/assessment (Visit 10) for the last subject in the study. 


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6.4
Data Management 
Data management will be performed by MedImmune Data Management staff or other party
according to the Data Management Plan.
An electronic data capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded in the eCRFs as specified in the study protocol 
and in accordance with the eCRF instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the Principal Investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc. will only be collected with the subject’s informed consent. The Informed Consent 
Form will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that describes how subject data will be collected, used, and distributed 
in compliance with relevant data protection and privacy legislation.
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. MedImmune will not provide individual genotype results 
to subjects, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law.


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7.2
Ethics and Regulatory Review
The IEC responsible for each site must review and approve the final study protocol, including 
the final version of the Informed Consent Form and any other written information and/or 
materials to be provided to the subjects. The IEC must also approve all advertising used to 
recruit subjects for the study. The investigator is responsible for submitting these documents 
to the applicable IEC and distributing them to the study site staff.
The opinion of the IEC must be given in writing. The investigator must provide a copy of the 
written approval to MedImmune before enrolment of any subject into the study. 
MedImmune should approve any substantive modifications to the Informed Consent Form that 
are needed to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IEC annually.
Before the study is initiated, MedImmune will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. MedImmune 
will provide safety updates/reports according to local requirements, including suspected 
unexpected serious adverse reactions where relevant, to regulatory authorities, IEC, and 
Principal Investigator (s).
Each Principal Investigator is responsible for providing reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product to the 
IEC. MedImmune will provide this information to the Principal Investigator so that he/she can 
meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. MedImmune will develop a core 
informed consent form for use by all investigators in the clinical study. MedImmune must 
approve any modifications to the informed consent form that are needed to meet local 
requirements.
The Principal Investigator(s) at each centre will:

Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study

Ensure each subject is notified that they are free to discontinue from the study at any time

Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided

Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study


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
Ensure the original, signed ICF (s) is/are stored in the Investigator’s Study File

Ensure a copy of the signed ICF is given to the subject

Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the IFC that is approved by an IEC
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune.
Substantial changes must be documented in a study protocol amendment. MedImmune will 
distribute amended versions of the protocol to the principle investigator(s). Before 
implementation, amended protocols must be approved by relevant IRB/IEC (Section 7.2) and 
according to local requirements, the national regulatory authority approval. The IRB/IEC must 
also approve revisions to the informed consent form, advertising, and any other written 
information and/or materials resulting from the change to the protocol.
If local regulations require, any unsubstantial changes will be communicated to or approved 
by each IEC.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the centre, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analysed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the ICH, and any applicable regulatory requirements. The investigator 
will contact MedImmune immediately if contacted by a regulatory agency about an inspection 
at the site.


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8
REFERENCES
Bagger et al 2015
Bagger JI, Holst JJ, Hartmann B, Andersen B, Knop FK, Vilsbøll T. Effect of oxyntomodulin, 
glucagon, GLP-1, and combined glucagon +GLP-1 infusion on food intake, appetite, and 
resting energy expenditure. J Clin Endocrinol Metab. 2015;100(12):4541-52.
Carneiro et al 2016
Carneiro IP, Elliott SA, Siervo M, et al. Is Obesity Associated with Altered Energy 
Expenditure? Advances in Nutrition. 2016;7(3):476-487. doi:10.3945/an.115.008755.
Caron et al 2016
Caron N, Peyrot N, Caderby T, Verkindt C, Dalleau G. Energy Expenditure in People with 
Diabetes Mellitus: A Review. Frontiers in Nutrition. 2016;3:56. doi:10.3389/fnut.2016.00056.
Chakravarthy et al 2017
Chakravarthy M, Parsons S, Lassman ME, Butterfield K, Lee Anita YH, Previs S, et al. 
Effects of 13-Hour Hyperglucagonemia on Energy Expenditure and Hepatic Glucose 
Production in Humans. Diabetes Jan 2017, 66 (1) 36-44; DOI: 10.2337/db16-0746.
Farr et al 2016
Farr OM, Tsoukas MA, Triantafyllou G, et al. Short-term administration of the GLP-1 analog 
liraglutide decreases circulating leptin and increases GIP levels and these changes are 
associated with alterations in CNS responses to food cues: A randomized, placebo-controlled, 
crossover study. Metabolism: clinical and experimental. 2016;65(7):945-953. 
doi:10.1016/j.metabol.2016.03.009.
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.
Horowitz et al 2012
Horowitz MI, Flint A, Jones KL, Hindsberger C, Rasmussen MF, Kapitza C, et al. Effect of 
the once-daily human GLP-1 analogue liraglutide on appetite, energy intake, energy 
expenditure and gastric emptying in type 2 diabetes. Diabetes Res Clin Pract. 2012 
Aug;97(2):258-66. doi: 10.1016/j.diabres.2012.02.016. Epub 2012 Mar 24.
Hill et al 2014
Hills AP, Mokhtar N, Byrne NM. Assessment of Physical Activity and Energy Expenditure: 
An Overview of Objective Measures. Frontiers in Nutrition. 2014;1:5. 
doi:10.3389/fnut.2014.00005.


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Kuo et al, 2008
Kuo B, Mcallum RW, Koc, KL, Sitrin MD, Wo JM, Chey WD, et al 2008. Comparison of 
gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and 
gastroparetic subjects. Aliment Pharmacol Ther.2008;27:186-96.
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.
Petersen et al 2005
Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of non-
alcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight 
reduction in patients with type 2 diabetes. Diabetes. 2005 Mar;54(3):603-8.
Salem et al 2016
Salem V, Izzi-Engbeaya C, Coello C, et al. Glucagon increases energy expenditure 
independently of brown adipose tissue activation in humans. Diabetes, Obesity & Metabolism. 
2016;18(1):72-81. doi:10.1111/dom.12585.
Skyder et al 2017
Skyder JS, Bakris GL, Bonifacio E, Darsow T, Eckel RH, Groop L, et al. Differentiation of 
diabetes by pathophysiology, natural history, and prognosis. Diabetes. 2017 Feb;66(2):241-55.
Van Strien et al 1986
Van Strien T, Frijters JER, Bergers GPA, and Defares PB, The Dutch Eating Behavior 
Questionnaire (DEBQ) for assessment of restrained, emotional, and external eating behavior. 
Eating Disorders. 1986 Feb;5(2): 295–315.
Wynne et al 2006
Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS. Oxyntomodulin increases 
energy expenditure in addition to decreasing energy intake in overweight and obese humans: a 
randomized controlled trial. Int J Obes. 2006;30(12):1729-36.


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9
CHANGES TO THE PROTOCOL
9.1
Protocol Amendment 5, 20Mar2019
The changes to text summarised below have been incorporated in the body of Protocol 
Amendment 5.
Table 9
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
Protocol Synopsis (Objectives and Endpoints; 
Statistical Methods), Section 2.2 (Secondary
Objectives and Endpoints, Table 2, Secondary
Objectives and Endpoints), Section 2.3 (Exploratory
Objectives and Endpoints, Table 3, Exploratory
Objectives and Endpoints), Section 3.2.3.2 
(Secondary Endpoints), Section 4.8.1 (General 
Considerations), Section 4.8.2 (Analysis 
Populations), Section 4.8.4 (Efficacy), and 
Section 4.8.8 (Patient Reported Outcomes)
To correct errors identified in the planned statistical 
analyses:
•
The objectives and endpoints were updated.
•
The secondary objective and related endpoint 
pertaining to the effect of placebo treatment on 
ad libitum lunchtime energy intake was 
removed.
•
The rationale for the single-group crossover 
analyses was removed.
•
Text describing which subjects were to be 
included in the treatment groups for certain 
endpoints was removed.
•
Analysis populations were added and revised.
•
The analysis populations were changed for the 
efficacy and PRO analyses.
Protocol Synopsis (Treatment Groups and Regimens) 
and Section 3.1.2 (Treatment Regimen)
The text was revised:
•
To correct a typographic error in the treatment 
groups and regimens section of the protocol 
synopsis.
•
To better clarify the regimen for the single-blind 
placebo treatment group.
 
 
 
 
 
 
Protocol Synopsis (Statistical Methods) and 
Section 4.8.5.1 (Analysis of Adverse Events)
The terminology for AEs was reconciled to improve 
consistency and correct typographic errors.
Section 3.1.3 (Dose Escalation)
The text was revised to better clarify how dose 
escalation will occur from Day 17 onwards.
 
 
 


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Table 9
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
Section 4.2.2 (Randomised Treatment Period, Table 6 
Treatment Period Study Procedures), Section 4.3.2.7 
(Muscle Biopsy), and Section 4.3.2.9 (Intravenous 
Glucose Tolerance Test)
Minor procedural changes were made:
•
To align with the capabilities of the study site in 
completing procedures.
•
To correct typographic errors.
Section 4.3.8 (Biomarker Evaluation and Methods)
Upon further consideration after authoring the 
original protocol, the text was revised to clarify the 
biomarker evaluation.
Section 4.5.1.3 (Treatment Administration)
Text describing the type of treatment to be 
administered on Day 1 was deleted to correct 
typographic error.
Section 10.5 Appendix 5 (Actions Required in Cases 
of Increases in Liver Biochemistry and Evaluation of 
Hy’s Law)
The processes for the evaluation of Hy’s Law were 
updated to reflect changes in the sponsor’s standard 
operating procedures.
ADA = anti-drug antibodies; AE = adverse event; PRO = patient reported outcome.
9.2
Protocol Amendment 4, 31Aug2018
The changes to text summarised below have been incorporated in the body of Protocol 
Amendment 4.
Table 10
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
Protocol Synopsis (Objectives and Endpoints) and 
Section 2.3 (Exploratory Objectives and Endpoints)
Correction of typographic error: CO2 consumption to 
production
Section 4.2.2 (Randomized Treatment Period, Table 6 
Treatment Period Study Procedures)
Clarification: Change to time of DLW urine 
collection from 1 hour to 3 hours in footnote f
Correction of typographic error: Removal of 
instruction relating to investigational product as not 
relevant at either time-point; footnote j.
9.3
Protocol Amendment 3, 20Aug2018
The changes to text summarised below have been incorporated in the body of Protocol 
Amendment 3.
Table 11
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
Protocol Synopsis (Objectives and Endpoints) and 
Section 2.2 (Secondary Objectives and Endpoints, 
Table 2, Secondary Objectives and Endpoints)
Typographic error: Corrected DLW assessment in 
text from Day 16 to 17.


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Table 11
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
Section 1.6 (Benefit-risk and Ethical Assessment)
Typographic error: Removed reference to IB version 
to ensure this remains the most up to date version for 
the duration of the study in case of future IB updates.
Section 4.2.2 (Randomized Treatment Period, Table 6 
Treatment Period Study Procedures)
•
Typographic error: Inserted footnote “b” in table 
next to the abbreviated physical examination on 
Day 58 and added text to footnote “b” to state 
that the physical examination can occur at any 
time on Day 58 or 59. Table footnotes beginning 
with “b” reordered).
•
Typographic error: Corrected DLW assessment 
in table and footnote “f” from Day 16 to 17.
•
Typographic error: Activity monitor charging 
corrected in table from Day 17 to 16.
•
Typographical error: Corrected day of 
double-blind investigational product 
administration from Day 59 to 58 in table and 
footnote “v.” 
•
Typographical error: Corrected investigational 
product dispensing visit from Visit 7 to 8 in 
table.
•
Accidental omission: Added definition for 
“VAS = Visual Analog Scale” to list of 
abbreviations used in the table.
•
Typographical error: Corrected text in footnote 
“a” to include fasting on Day 59 and corrected 
the timing for subjects to be fasted for an 
additional 4 hours to Day 17 with 
cross-reference to footnote “s.”
•
Accidental omission: Added C peptide to the 
metabolism panel in table footnote “j.”
•
Clarification: Deleted portion of text in table 
footnote “m” to simplify/provide better 
consistency as details already provided in 
referenced section. 
•
Clarification: Updated exercise times whilst 
inside the whole room calorimeter from 
“1000 ± 15 min and 1200 ± 15 min, 
1400 ± 15 min and 1600 ± 15 min,” to 
“1130 ± 15 min and 1430 ± 15 min, 1730 ± 15 
min and 2030 ± 15 min,” respectively, in table 
footnote “o.”
•
Clarification: Amended table footnote “p” to 
remove sentence around pre- and post meal and 
to clarify that it is the VAS questionnaire that is 
to be repeated during the day. 
Section 4.3.1 (Screening/Enrolment, Treatment, and 
Follow-up)
•
Clarification: Added Day 15/16 to text to clarify 
timing of collection of urine for protein 
estimation.
•
Typographic error: Changed DLW assessment 
in text from Day 16 to 17.


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Table 11
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
 
 
Section 4.6.2 (Methods to Ensure Blinding)
Clarification: Additional paragraph added to describe 
measures that will be taken to ensure the blind.
DLW = doubly labelled water; IB = Investigators Brochure; MMTT = mixed-meal tolerance test; VAS = Visual 
Analog Scale.
9.4
Protocol Amendment 2, 17Jul2018
The changes to text summarised below have been incorporated in the body of Protocol 
Amendment 2.
Table 12
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
Section 3.1.4.3 (Hyperglycaemia)
All changes were made at the request of the MHRA.
Section 4.1.3 (Exclusion Criteria)
Section 4.2.1 (Enrolment/Screening Period) Table 5 
(Schedule of Screening Procedures)
Section 4.2.2 (Randomized Treatment Period) 
Table 6 Treatment Period Study Procedures
Section 4.2.3 (Follow-up Period) Table 7 (Schedule 
of Follow-up Procedures)
Section 4.2.4 (Early Discontinuation Visit or 
Unscheduled Study Visit)
Section 4.3.5 (Clinical Laboratory Tests)
Section 5.3.1 (Time Period for Collection of Adverse 
Events)
MHRA = Medicines and Healthcare products Regulatory Agency.
9.5
Protocol Amendment 1, 23May2018
The changes to text summarised below have been incorporated in the body of Protocol 
Amendment 1.


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Table 13
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
Section 3.2.2 (Rationale for Study Population), 
Section 4.1.2 (Inclusion Criteria), and Section 4.2.1 
(Enrolment/Screening Period) Table 5 (Schedule of 
Screening Procedures)
Inclusion criterion 5 and additional text sections were 
revised to widen enrolment by allowing inclusion of 
subjects using SGLT2i.
Section 4.1.3 (Exclusion Criteria)
Text was added to exclusion criterion 13 to allow the 
study site flexibility in employing an alternative 
estimation of eGFR.
Section 4.1.4 (Subject Enrolment and 
Randomisation), Section 4.6.1 (Methods for 
Assigning Treatment Groups), Section 4.6.2 
(Methods to Ensure Blinding), and Section 4.6.3.1 
(Unblinding in the Event of a Medical Emergency)
Text describing manual randomisation procedures 
was amended to use an IXRS, as upon further 
consideration after authoring the original protocol, it 
was decided that it would be complex and time 
consuming for the study site to employ manual 
randomisation. Using an IXRS will help avoid 
manual randomisation errors.
Section 4.2.2 (Randomised Treatment Period) Table 6 
(Treatment Period Study Procedures)
Added row for double-blind investigational product 
administration to clarify when investigational product 
will be administered. Two additional time points for 
in clinic administration of investigational product 
were added for Visit 4 as these were inadvertently not 
included in the original protocol. Footnote j was 
amended to correct a typographic error. Text was 
added to footnote u to clarify investigational product 
administration procedures. The letter w linking to 
footnote v was changed to v to correct a typographic 
error.
Section 4.2.2 (Randomized Treatment Period) 
Table 6 (Treatment Period Study Procedures) and 
Section 4.3.2.9 (Intravenous Glucose Tolerance Test)
Text was amended (including footnote g in Table 6) 
to correct and clarify the timing of samples for the 
IVGTT.
Section 4.2.3 (Follow-up Period) Table 7 (Schedule 
of Follow-up Procedures)
Revised footnotes to make consistent with Table 6.
Section 4.2.4 (Early Discontinuation Visit or 
Unscheduled Study Visit)
New section allowing for and describing procedures 
for early discontinuation or unscheduled study visits 
was added upon further consideration after authoring 
the original protocol, as some subjects could 
potentially withdraw from the study due to intensive 
study procedures or require additional visits.
Section 4.3.1 (Screening/Enrolment, Treatment, and 
Follow-up)
Text describing the administration of investigational 
product procedures was updated in accordance with 
the amendment described above for Table 6.
Section 4.3.10 (Estimate of Volume of Blood to Be 
Collected)
Blood volume estimations were updated in 
accordance with amendment in the IVGTT schedule 
described above for Table 6 and Section 4.3.2.9.


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Table 13
Summary of Revisions to the Protocol
Section of the Protocol Affected
Reason for Amendment
Section 4.6.3.1 (Unblinding in the Event of a Medical 
Emergency)
Text describing discontinuation of investigational 
product in the event of unblinding of investigational 
product allocation was removed as this procedure was 
deemed unnecessary for this study.
eGFR = estimated glomerular filtration rate; IVGTT = intravenous glucose tolerance test; IXRS = interactive 
voice/web response system; SGLT2i = sodium-glucose co-transporter inhibitor(s).


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10
APPENDICES
10.1
Appendix 1 – Signatures
Sponsor Signature(s)
An Exploratory Phase 2, Randomised, Double-blind, Placebo-controlled Study to Evaluate the 
Effect of MEDI0382 on Energy Balance in Overweight and Obese Subjects with 
Type 2 Diabetes Mellitus
I agree to the terms of this protocol and protocol amendment(s).
Signature and date: 
Electronic signature attached
Boaz Hirshberg, MD
Clinical Therapy Area Head
One MedImmune Way, Gaithersburg MD, 20878, USA
Telephone number: 1-301-398-0645


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10.2
Appendix 2 - Contraception Guidance
For females of childbearing potential:

Females of childbearing potential are defined as those who are not surgically sterile (ie, 
surgical sterilisation includes bilateral tubal ligation, bilateral oophorectomy, or complete 
hysterectomy) or those who are not postmenopausal (defined as at least 1 year since last 
menses and/or having an elevated follicle-stimulating hormone level in the 
postmenopausal range in previous laboratory test results).

A highly effective method of contraception is defined as one that results in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly. The acceptable 
methods of contraception are described in Table 14.

Female subjects must refrain from egg cell donation and breastfeeding while on study and 
for 28 days after the final dose of investigational product.
Table 14
Highly Effective Methods of Contraception
•
Tubal occlusion
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system (eg, Mirena®)
•
Medroxyprogesterone injections (eg, Depo-Provera®)
•
Etonogestrel implants (eg, Implanon®, Norplan®)
•
Norelgestromin/ethinyl estradiol transdermal system
•
Intravaginal device (eg, NuvaRing®)


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10.3
Appendix 3 - Additional Safety Guidance
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from an adverse event 
(AE) as it occurred or it is suspected that use or continued use of the product would result in 
the subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion) or convulsions 
that do not result in hospitalization

Development of drug dependency or drug abuse
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below.


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Grade 1
An event of mild intensity that is usually transient and may 
require only minimal treatment or therapeutic intervention. The 
event does not generally interfere with usual activities of daily 
living.
Grade 2
An event of moderate intensity that is usually alleviated with 
additional specific therapeutic intervention. The event interferes 
with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject.
Grade 3
A severe event that requires intensive therapeutic intervention. 
The event interrupts usual activities of daily living, or 
significantly affects the clinical status of the subject.
Grade 4
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental disabilities.
Grade 5
Death as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.
Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. The following factors should be considered when deciding if there is a 
‘reasonable possibility’ that an AE may have been caused by the investigational product.

Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product?

Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or products of the same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties? 

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect investigational product?


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


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10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases
and Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and 
Anaphylaxis Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in 
onset and may cause death. They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for 
all 3 categories). 
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia)
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that patient (minutes to several hours):
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP
(b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline


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10.5
Appendix 5 - Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
10.5.1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s law cases and Hy’s Law cases. It is not intended to be a comprehensive 
guide to the management of elevated liver biochemistries.
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of potential Hy’s Law and 
Hy’s Law events; this includes samples taken at scheduled study visits and other visits 
including all local laboratory evaluations even if collected outside of the study visits.
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible potential Hy’s Law events.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than drug-induced liver injury (DILI) caused by the 
investigational product. 
The investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law
cases and for reporting AEs and SAEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
10.5.2
Definitions
10.5.2.1
Potential Hy’s Law
AST or alanine transaminase (ALT) ≥3 × ULN together with total 
bilirubin (TBL) ≥2 × upper limit of normal (ULN) at any point during the study following the 
start of investigational product irrespective of an increase in alkaline phosphatase (ALP).
10.5.2.2
Hy’s Law
Aspartate transaminase (AST) or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no 
other reason, other than the investigational product, can be found to explain the combination 
of increases; eg, elevated ALP indicating cholestasis, viral hepatitis, or another drug.


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For potential Hy’s Law and Hy’s Law, the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur.
10.5.3
Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any subject who meets any of the following identification criteria 
in isolation or in combination:

ALT ≥3 × ULN

AST ≥3 × ULN

TBL ≥2 × ULN
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will:

Notify the sponsor study representative

Determine whether the subject meets potential Hy’s Law criteria (Section 10.5.2) by 
reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
10.5.4
Follow-up
10.5.4.1
Potential Hy’s Law Criteria Are Not Met
If the subject does not meet potential Hy’s Law criteria the investigator will:

Inform the study representative that the subject has not met potential Hy’s Law criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the study protocol.
10.5.4.2
Potential Hy’s Law Criteria Are Met
If the subject does meet potential Hy’s Law criteria the investigator will:

Determine whether potential Hy’s Law criteria were met at any study visit prior to 
starting study treatment (Section 10.5.2.1)

Notify the sponsor study representative who will then inform the study team

Within 1 day of potential Hy’s Law criteria being met, the investigator will report the 
case as an SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and 
causality assessment ‘yes/related’ according to clinical study protocol process for SAE 
reporting


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The medical monitor contacts the investigator, to provide guidance, discuss and agree on an 
approach for the study subjects’ follow-up (including any further laboratory testing) 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. 
Complete follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the medical monitor. 

Complete the relevant eCRF Modules as information becomes available
10.5.5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law
criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the medical 
monitor will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting potential Hy’s Law criteria other than DILI 
caused by the investigational product, to ensure timely analysis and reporting to health 
authorities per local requirements from the date potential Hy’s Law criteria were met. The 
medical monitor and Global Safety Physician will also be involved in this review together 
with other subject matter experts as appropriate.
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE, update the previously submitted potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the sponsor’s standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:

Send the updated SAE (report term ‘Hy’s Law’) according to the sponsor’s standard 
processes.


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
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the Hy’s Law case, a causality assessment 
of ‘related’ should be assigned
If, there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for Hy’s Law, then it is assumed 
that there is no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of Potential Hy’s Law (report 
term now ‘Hy’s Law case’), ensuring causality assessment is related to the investigational 
product and seriousness criteria are medically important, according to the clinical study 
protocol process for SAE reporting

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are still met. Update the previously submitted potential Hy’s 
Law SAE report following clinical study protocol process for SAE reporting, according to 
the outcome of the review and amend the reported term if an alternative explanation for 
the liver biochemistry elevations is determined
10.5.6
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgement. If required, for additional 
assistance on which tests could be used to evaluate other potential causes of liver dysfunction,
consult with the Hepatic Safety Knowledge Group. Any test results need to be recorded.
Hy’s Law Lab Kit for Central Laboratories
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgM and IgG anti-HCV
HCV RNA
IgM anti-HEV


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HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
REFERENCES
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) 'Drug-induced liver injury: Premarketing 
clinical evaluation'


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10.6
Appendix 6 - Biological Samples
10.6.1
Storage, Re-use and Destruction of Biological Samples
Biological samples will be stored for a maximum of 15 years from the date of the Last 
Subject’s Last Visit, after which they will be destroyed. 
The results of biomarker and muscle biopsy research will be reported either in the CSR itself 
or as an addendum, or separately in a scientific report or publication. The results of this 
research may be pooled with biomarker data from other studies with the study drug to 
generate hypotheses to be tested in future research. ADA samples and other residual samples 
will be stored for up to 2 years after marketing approval. 
10.6.2
Labelling and Shipment of Biological Samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria).
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the subject unless agreed with MedImmune and appropriate 
labelling, shipment and containment provisions are approved.
10.6.3
Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each study site keeps full traceability of collected biological 
samples from the subjects while in storage at the study site until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival. The sample receiver keeps full 
traceability of the samples while in storage and during use until used or disposed of or until 
further shipment and keeps documentation of receipt of arrival.
MedImmune keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the Translational Sciences Biorepository 
during the entire life cycle.
10.7
Appendix 7 – Genetic Research
Rationale and Objectives
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 


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the drug; disease aetiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, blood samples will be collected for DNA analysis 
from consenting subjects.
MedImmune intends to collect and store DNA for genetic research to explore how genetic 
variations and gene expression 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 clinical study report (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
Genetic Research Plan and Procedures
Selection of Genetic Research Population and Study Selection Record
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit. The subject will 
not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, subjects must 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:


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
Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection
Discontinuation of Subjects from this Genetic Research
Specific reasons for discontinuing a subject from this genetic research are:
Withdrawal of consent for genetic research: Subjects may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study. Voluntary discontinuation will not prejudice further treatment. Procedures for 
discontinuation are outlined in Section 4.1.6 of the main Protocol.
Collection of Samples for Genetic Research
The blood samples for genetic research will be obtained from the subjects at Visit 2 provided 
that the subject has given explicit consent for this. Although deoxyribonucleic acid (DNA)
variants are a stable parameter, early sample collection is preferred to avoid introducing bias 
through excluding subjects who may withdraw due to an AE, such subjects would be 
important to include in any genetic analysis. If for any reason the sample is not drawn at 
Visit 2, it may be taken at any visit until the last study visit. Only 1 sample should be collected 
per subject for genetic research during the study. Samples will be collected, labelled, stored 
and shipped as detailed in the Laboratory Manual.
Coding and Storage of DNA Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last subject last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable by the second, unique number only. This number is used to identify the sample 
and corresponding data at the MedImmune genetics laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(MedImmune employee or designated organisations working with the DNA).
The link between the subject randomisation code and the second number will be maintained 
and stored in a secure environment, with restricted access at MedImmune or 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 trace 
samples for destruction in the case of withdrawal of consent.


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Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 4.1.6 of the main Protocol.
Informed Consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely discontinue from the genetic aspect of the study at 
any time.
Subject Data Protection
MedImmune will not provide individual genotype/gene expression results to subjects, any 
insurance company, any employer, their family members, or general physician unless required 
to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, a MedImmune physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data. 
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/gene expression data generated in this study will be stored at a secure system at 
MedImmune and/or designated organisations to analyse the samples.
The results from this genetic research may be reported in a separate report from the clinical 
study report or published in scientific journals.
MedImmune and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as Hospitals, Academic Organisations, or Health Insurance Companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 


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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 will be prepared where appropriate.


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10.8
Appendix 8 - Patient-Reported Outcome Questionnaires


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10.8.1
Dutch Eating Questionnaire (DEBQ)
Example of Dutch Eating Questionnaire (DEBQ)
Volunteer Name:
Date:
Volunteer No. 
Please place an () in the box which applies best to each of the numbered statements. All of the results will be 
strictly confidential. Most of the questions directly relate to food or eating, although other types of questions have 
been included. Please answer each question carefully. Thank you.
1.  If you have put on weight, do you eat less than you usually do?
Never
Seldom
Sometimes
Often
Very Often
Not Relevant
2. Do you try to eat less at mealtimes than you would like to eat?
Never
Seldom 
Sometimes
Often
Very Often
3.
How often do you refuse food or drink offered because you are concerned about your weight?
Never
Seldom 
Sometimes
Often
Very Often
4.
Do you watch exactly what you eat?
Never
Seldom 
Sometimes
Often
Very Often
5.
Do you deliberately eat foods that are slimming?
Never
Seldom 
Sometimes
Often
Very Often
6.
When you have eaten too much, do you eat less than usual the following days? 
Never
Seldom 
Sometimes
Often
Very Often
Not Relevant
7. Do you deliberately eat less in order not to become heavier? 
Never
Seldom 
Sometimes
Often
Very Often
8. How often do you try not to eat between meals because you are watching your weight?


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Never
Seldom 
Sometimes
Often
Very Often
9.
How often in the evening do you try not to eat because you are watching your weight?
Never
Seldom 
Sometimes
Often
Very Often
10. Do you take into account your weight with what you eat?
Never
Seldom 
Sometimes
Often
Very Often
11. Do you have the desire to eat when you are irritated?
Never
Seldom 
Sometimes
Often
Very Often
Not Relevant
12. Do you have a desire to eat when you have nothing to do? 
Never
Seldom 
Sometimes
Often
Very Often
Not Relevant
13. Do you have a desire to eat when you are depressed or discouraged?
Never
Seldom 
Sometimes
Often
Very Often
Not Relevant
14.  Do you have a desire to eat when you are feeling lonely?
Never
Seldom 
Sometimes
Often
Very Often
Not Relevant
15.  Do you have a desire to eat when somebody lets you down?
Never
Seldom 
Sometimes
Often
Very Often
Not Relevant
16.  Do you have a desire to eat when you are cross?
Never
Seldom 
Sometimes
Often
Very Often
Not Relevant
17. Do you have a desire to eat when you are approaching something unpleasant to happen?
Never
Seldom 
Sometimes
Often
Very Often
18. Do you get the desire to eat when you are anxious, worried or tense?
Never
Seldom 
Sometimes
Often
Very Often
19. Do you have a desire to eat when things are going against you or when things have gone wrong?
Never
Seldom 
Sometimes
Often
Very Often


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20. Do you have a desire to eat when you are frightened?
Never
Seldom 
Sometimes
Often
Very Often
Not Relevant
21. Do you have a desire to eat when you are disappointed?
Never
Seldom 
Sometimes Often
Very Often
Not Relevant
22. Do you have a desire to eat when you are bore or restless?
Never
Seldom 
Sometimes Often
Very Often
Not Relevant
23. Do you have a desire to eat when you are emotionally upset?
Never
Seldom 
Sometimes Often
Very Often
Not Relevant
24. If food tastes good to you, do you eat more than usual?
Never
Seldom 
Sometimes
Often
Very Often
25. If food smells and looks good do you eat more than usual?
Never
Seldom 
Sometimes
Often
Very Often
26. If you see or smell something delicious, do you have the desire to eat it?
Never
Seldom 
Sometimes
Often
Very Often
27. If you have something delicious to eat, do you eat it straight away? 
Never
Seldom 
Sometimes
Often
Very Often
28. If you walk past the baker do you have the desire to buy something delicious?
Never
Seldom 
Sometimes
Often
Very Often
29. If you walk past a snack bar or a café, do you have the desire to buy something delicious?
Never
Seldom 
Sometimes
Often
Very Often
30. If you see others eating, do you also have the desire to eat?
Never
Seldom 
Sometimes
Often
Very Often


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31. Can you resist eating delicious foods?
Never
Seldom 
Sometimes
Often
Very Often
32. Do you eat more than usual, when you see others eating?
Never
Seldom 
Sometime
s
Often
Very Often
33. When preparing a meal are you inclined to eat something?
Never
Seldom 
Sometimes
Often
Very Often
10.8.2
Appendix 8 - Visual Analogue Scale
Example of Visual Analogue Scale
HOW HUNGRY DO YOU FEEL RIGHT NOW?
NOT AT ALL
EXTREMELY
HOW SICK DO YOU FEEL RIGHT NOW?
NOT AT ALL
EXTREMELY
HOW PLEASANT WOULD IT BE TO EAT RIGHT NOW?
NOT AT ALL
EXTREMELY
HOW MUCH DO YOU THINK YOU COULD EAT RIGHT NOW?
NOTHING
A LARGE AMOUNT


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10.9
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


SIGNATURE PAGE
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Document Name: D5670C00021-clinical-protocol-amendment-5-clean
Document Title:
D5670C00021-clinical-protocol-amendment-5-clean
Document ID:
Doc ID-004024583
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
20-Mar-2019 22:57 UTC
Boaz hirshberg
Management Approval
20-Mar-2019 14:59 UTC
Christina Watson
Content Approval
20-Mar-2019 15:01 UTC
Lan-Feng Tsai
Content Approval
20-Mar-2019 15:44 UTC
Rosalin Arends
Content Approval
20-Mar-2019 15:02 UTC
Victoria Parker
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_003.pdf: 
Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
1 of 1 6  
S A P te m plate versi o n 3. 0  
St atistic al A n al ysis Pl a n  
A n E x pl or at or y P h ase 2 a, R a n d o mise d, D o u ble -bli n d, Pl ace b o -
c o ntr olle d St u d y t o E v al u ate t he Effect of M E DI 0 3 8 2 o n E ner g y 
B al a nce i n O ver wei g ht a n d O bese S u bjects wit h Ty pe 2 Di a betes 
Mellit us 
 
Pr ot oc ol N u m ber:  D 5 6 7 0 C 0 0 0 2 1 
 
 




Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
3 of 1 6  
S A P te m plate versi o n 3. 0  
3. 7. 3  
Deat hs a n d Tr eat me nt Disc o nti n uati o ns d ue t o A d verse E ve nts .......................... 1 5  
3. 7. 4  
Cli nical La b orat or y E val uati o n ............................................................................. 1 5 
3. 7. 5  
Ot her Safet y E v al uati o ns  ...................................................................................... 1 5 
3. 7. 5. 1  
Vital Si g ns  ............................................................................................................. 1 5 
3. 7. 5. 2  
Electr ocar di o gra m  ................................................................................................. 1 5 
3. 8  
I m m u n o ge nicit y .................................................................................................... 1 6 
3. 9  
 .................................................................................................. 1 6 
3. 1 0  
Pr ot oc ol De viati o ns ............................................................................................... 1 6 
4  
I N T E RI M A N A L Y SI S ......................................................................................... 1 6 
5  
R E F E R E N C E S ...................................................................................................... 1 6 
6  
V E R SI O N HI S T O R Y  ........................................................................................... 1 6 
 
LI S T O F  T A B L E S 
Ta ble  1 
A nal ysis P o p ulati o ns ................................................................................... 1 0 
 
 


Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
4 of 1 6  
S A P te m plate versi o n 3. 0  
List of A b bre vi ati o ns  
A b bre vi ati o n or 
S peci alize d Ter m  
Defi niti o n  
A D A  
A nti -dr u g a nti b o d y/a nti b o dies  
A E  
A d verse e ve nt  
A E E  
acti vit y e ner g y e x pe n dit ure  
AI R g  
Ac ute i ns uli n res p o nse  
A L T  
ala ni ne a mi n otra nsferase  
A N C O V A  
A nal ysis of c o varia nce  
A S T  
as partate a mi n otra nsferase  
A T C  
a nat o mical t hera pe utic c he mical class  
B MI  
B o d y mass i n de x 
D E B Q  
D utc h Eati n g Be ha vi or Q uesti o n naire  
D X A  
D ual X -ra y a bs or pti o metr y 
E C G  
Electr ocar di o gra m  
E E  
e ner g y e x pe n dit ure 
E x E E  
e xercise e ner g y e x pe n dit ure  
GI P  
Gl uc ose -de pe n de nt i ns uli n otr o pic p ol y pe pti de  
G L P - 1 
Gl uca g o n -li ke pe pti de- 1 
I P D 
i m p orta nt pr ot oc ol de viati o ns 
I V G T T 
I ntra ve n o us gl uc ose t olera nce test 
I WR S  
I nteracti ve we b res p o nse s yste m 
Me d D R A  
M e dical D icti o nar y f or R e g ulat or y A cti vities 
M M T T  
Mi xe d -meal t olera nce test  
P K  
P har mac o ki netics  
P R O  
Patie nt re p orte d o utc o me  
P T  
preferre d ter m  
R E E  
resti n g e ner g y e x pe n dit ure 
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S C  
S u bc uta ne o us  
S O C  
s yste m or ga n class 
S P P  
Statistical pr o gra m mi n g pla n  
T 2 D M  
t y pe 2 dia betes mellit us 
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt 


Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
5 of 1 6  
S A P te m plate versi o n 3. 0  
A b bre vi ati o n or 
S peci alize d Ter m  
Defi niti o n  
T E E  
t otal e ner g y e x pe n dit ure 
T E S A E  
Treat me nt -e mer ge nt seri o us a d verse e ve nt  
U L N  
U p per li mit of refere nce ra n ge  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  e n ha nce d 
 








Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
9 of 1 6  
S A P te m plate versi o n 3. 0  
2. 4  
S a m ple Size  
Si xtee n s u bjects i n t he M E DI 0 3 8 2 gr o u p a n d 8 s u bjects i n t he place b o gr o u p will pr o vi de 
> 9 0 % p o wer t o detect a 2. 5 % wei g ht c ha n g e fr o m baseli ne differe nce bet wee n  
 
 a n d place b o at D a y 5 9, ass u mi n g a sta n dar d de viati o n of 2. 0 %, a 2-si de d 0. 1 al p ha. 
3  
S T A TI S TI C A L M E T H O D S  
3. 1  
Ge ner al C o nsi der ati o ns  
Data will be pres e nte d i n data listi n gs s orte d b y t reat me nt, s u bject n u m ber a n d date c ollecte d, 
w here a p pr o priat e. Ta b ul ar s u m maries will be prese nte d f or eac h treat me nt. Cate g orical data 
will be s u m marize d b y tr eat me nt wit h t he n u m ber a n d perce nta ge of s u bjects wit hi n eac h 
cate g or y. C o nti n u o us varia bles w ill be s u m marize d b y treat me nt wit h descri pti ve statistics 
i ncl u di n g mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m. F or s o me varia bles, 
t he ge o metric mea n a n d 9 5 % CI will be prese nte d. Baseli ne val ues will be defi ne d as t he l ast 
vali d assess me nt p ri or t o t he first a d mi nistrati o n of i n vesti gati o nal pr o d uct u nless ot her wise 
s pecifie d.  
All a vaila ble data will be i ncl u de d i n t he a nal yses a n d missi n g data will n ot be i m p ute d , 
e xce pt i n a last o bser vati o n carri e d f or w ar d ( L O C F) a n al ysis a n d as s pecifie d i n t he 
calc ulati o n of t he A U C val ues. W he n last o bser vati o n carrie d f or w ar d ( L O C F) is use d t o 
i m p ute f or missi n g p ost- baseli ne data, o nl y p ost-b aseli ne data will be carrie d f or war d (e . g., 
ba seli ne data will n ot be carri e d f or w ar d). 
All statistical tests will be 2 -si de d at a n al p ha = 0. 1 0 si g nifica nce le v el u nless state d 
ot her wise.  T here will be n o a dj ust me nt f or m ulti plicit y.  
Data a n al yses will be perf or me d usi n g S A S
® versi o n 9. 4 or hi g her ( S A S I nstit ute I nc., Car y, 
N C). T he a nal ytical res ults ge nerate d fr o m S A S pr o gra ms will f oll o w Me dI m m u ne S A S 
pr o gra m mi n g sta n dar ds a n d will be vali date d acc or di n g t o Me dI m m u ne S A S vali dati o n 
pr oce d ur es. 
3. 2  
A n al ysis P o p ul ati o ns  
T he a nal ysis  p o p ulati o ns are defi ne d  i n Ta ble  1. 


Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 0  of 1 6  
S A P te m plate versi o n 3. 0  
T a ble  1  
A n al ysis  P o p ul ati o ns  
P o p ul ati o n  
Descri pti o n  
I nte nt-t o-treat 
(I T T) p o p ulati o n  
S u bjects w h o recei ve a n y st u d y i n vesti gati o nal pr o d uct will be i ncl u de d i n t he I T T 
p o p ulati o n a n d s u bjects will be a nal yze d acc or di n g t o t heir ra n d o mize d treat me nt gr o u p.  
M o difie d I nte nt -t o-
treat ( mI T T) 
p o p ulati o n  
S u bjects i n t he I T T p o p ulati o n w h o recei ve at least o ne d ose of t he i n vesti gati o nal pr o d uct 
i n t he d o u ble-bli n d treat me nt peri o d, a n d s u bjects will be a nal yze d acc or di n g t o t heir 
ra n d o mize d treat me nt gr o u p. 
As -treate d 
p o p ulati o n  
S u bjects w h o recei ve a n y st u d y i n vesti gati o nal pr o d uct will be i ncl u de d i n t he as-treate d 
p o p ulati o n a n d will be a nal yze d acc or di n g t o  t he treat me nt t he y act uall y recei ve. 
Per -pr ot oc ol 
p o p ulati o n  
S u bjects  i n t he mI T T p o p ulati o n (recei ve at least o ne d ose of t he i nvesti gati o nal pr o d uct 
i n t he d o u ble-bli n d treat me nt peri o d ) w h o c o m plete treat me nt u p t o Da y 5 8.  
P K p o p ulati o n  
S u bjects i n t he A s-treate d p o p ulati o n w h o  ha ve at least o ne  P K sa m ple ta ke n wit h a val ue 
t hat is a b o ve t he l o wer li mit of q ua ntitati o n.  
I m m u n o ge nicit y 
p o p ulati o n  
S u bjects i n t he A s-treate d p o p ulati o n w h o ha ve at least o ne ser u m sa m ple f or 
i m m u n o ge nicit y testi n g. 
 
3. 3  
St u d y S u bjects  
3. 3. 1  
S u bject Dis p ositi o n a n d C o m pleti o n St at us 
A s u m mar y of s u bject eli gi bilit y a n d ra n d o mizati o n (i ncl u di n g a s u m mar y of s u bjects 
ra n d o mise d b ut n ot treate d wit h d o u ble- bli n d i n vesti gati o nal pr o d uct) as w ell as treat me nt 
a d mi nistered will be pr o vi de d. I n a d diti o n, dis p ositi o n of s u bjects t hr o u g h o ut t he st u d y wit h 
res pect t o c o m pleti o n of treat me nt a n d e n d of st u d y will be pr o vi de d. 
3. 3. 2  
De m o gr a p hics a n d B aseli ne C h ar acteristics 
De m o gra p hic i nf or mati o n relate d t o se x, a ge, race, wei g ht, hei g ht, a n d b o d y mass i n de x 
( B MI) will be pres e nte d b y treat me nt gr o u p a n d f or all s u bjects c o m bi ne d. A s u m mar y of 
baseli ne disease c haracteristics ma y i ncl u de  d urati o n of dia betes, s pecifie d dia betes 
c o m plicati o ns , a n d s m o ki n g a n d alc o h ol hist or y. 
3. 3. 3  
St u d y Dr u g E x p os ure 
T he n u m ber of d os es a n d t otal d ose recei ve d will be s u m marize d f or eac h i n vesti gati o nal 
pr o d uct ( M E DI 0 3 8 2 or p lace b o) b y d escri pti ve statistics a n d fre q ue n cies. 
3. 3. 4  
C o nc o mit a nt Me dic ati o ns 
C o nc o mita nt me dicati o ns will be c o de d usi n g t he c urre nt W H O Dr u g Dicti o nar y e n ha n ce d 
( W H O-D D).  T h e n u m ber a n d perce nta ge of s u bjects w h o t o o k c o nc o mita nt me dicati o ns f or 
t he hi g hest a nat o mical t h era pe utic c he mical ( A T C) class a n d preferre d t er m will be 
s u m marize d b y st u d y part a n d treat me nt f or t h e As-treate d p o p ulati o n. T h e s u m mar y of 
c o nc o mita nt me dicati o ns will i ncl u de all c o nc o mita nt me dicati o ns ta ke n o n or after t h e date 
of first d ose of i n vesti gati o nal pr o d uct or a n y c o nc o mita nt me dicati o n starte d pri or t o first 
d ose of i n vesti gati o nal pr o d uct t hat c o nti n ue d be y o n d t he date of first d ose of i n vesti gati o nal 


Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 1  of 1 6  
S A P te m plate versi o n 3. 0  
pr o d uct. C o nc o mita nt me dicati o ns will be s u m marize d se paratel y f or t he d o u ble - bli n de d 
treat me nt peri o d a n d f or t he si n gle- bli n de d treat me nt peri o d. 
3. 4  
Effic ac y A n al yses  
3. 4. 1  
Pri m ar y Effic ac y E n d p oi nt(s) a n d A n al yses 
3. 4. 1. 1  
Pri m ar y Eff ic ac y E n d p oi nt(s) 
Perce nta g e c ha n g e i n b o d y wei g ht i n k g fr o m Da y 1 7 t o 5 9 
3. 4. 1. 2  
H a n dli n g of Dr o p o uts a n d Missi n g D at a 
If a s u bject h as a missi n g Da y 1 7 ( bas eli ne) w ei g ht val ue, t he last wei g ht val ue pri or t o Da y 
1 7 will be use d as t he bas eli ne i n t he a nal ysis.  If a su bject has  a missi n g wei g ht val ue o n 
D a y 5 9, t he s u bject will be i ncl u de d i n t he a n al ysis usi n g t he last val ue after t he start of t he 
d o u ble- bli n d peri o d, ie, l ast o bser vati o n carrie d f or war d ( L O C F). 
3. 4. 1. 3  
Pri m ar y Effic ac y A n al ysis 
T he a nal ysis of t he pri mar y efficac y e n d p oi nt will be perf or me d usi n g t he mI T T  p o p ulati o n. 
T he pri mar y efficac y e n d p oi nt of perce nt a ge c h a n ge i n b o d y wei g ht fr o m Da y 1 7 t o 5 9 will 
be c o m par e d bet wee n M E DI 0 3 8 2 a n d place b o gr o u ps usi n g a n a nal ysis of c o varia n ce 
( A N C O V A) m o d el a dj usti n g f or treat me nt gr o u p a n d baseli ne w ei g ht. L O C F wil l be use d f or 
missi n g data i m p utati o n if t he Da y 5 9 e val uati o n is missi n g. 
3. 4. 2  
Sec o n d ar y Effic ac y E n d p oi nt(s) a n d A n al yses 
3. 4. 2. 1  
Sec o n d ar y Effic ac y E n d p oi nt(s)  
•  
Perce nta g e a n d a bs ol ute c ha n ge i n t otal  e n er g y i nta ke i n kJ fr o m t he a d li bit u m l u nc h 
fr o m Da y 1 6 t o 3 2 a n d D a y 1 6 t o 5 9 
•  
Perce nta g e a n d a bs ol ute c ha n ge  i n t otal e n er g y i nta ke i n kJ d uri n g t he a d li bit u m l u nc h 
fr o m Da y - 1 t o 1 6 
•  
Perce nta g e a n d a bs ol ute c ha n ge i n T E E,  A E E, a n d R E E as meas ure d b y w h ole r o o m 
i n direct cal ori metr y i n kJ per k g of fat b o d y mass fr o m D a y 1 5 t o 5 8 
•  
Perce nta g e a n d a bs ol ute c ha n ge  i n R E E as meas ure d b y h o o d i n direct cal ori metr y i n kJ 
per k g of f at b o d y mass i n kJ fr o m Da y  1 6 t o 3 2 
•  
Perce nta g e a n d a bs ol ute c ha n ge i n t otal  e n er g y e x pe n dit ure as meas ure d b y d o u bl y 
la belle d water i n kJ per k g of fat b o d y mass fr o m baseli ne ( D a y 17) t o t he e n d of 
treat me nt ( D a y 5 8 or 5 9) 
•  
A bs ol ute c ha n ge i n b o d y wei g ht i n k g fr o m Da y 1 7 t o 5 9 
•  
C ha n ge i n a bs ol ute a n d p erce nt a ge c h a n ge i n t otal b o d y fat mass as meas ure d b y D X A 
i n k g fr o m Da y - 1 t o 5 9 
•  
C ha n ge i n a bs ol ute a n d p erce nt a ge  c h a n ge i n t otal b o d y fat mass: lea n  mass rati o as 
meas ure d b y D X A fr o m Da y - 1 t o 5 9 
•  
C ha n ge i n fasti n g gl uc os e d uri n g a M M T T fr o m Da y - 1 t o 5 9 


Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 2  of 1 6  
S A P te m plate versi o n 3. 0  
•  
Perce nta g e c ha n g e i n gl uc ose A U C 4 h d uri n g a M M T T fr o m Da y - 1 t o 5 9 
 
3. 4. 2. 2  
H a n dli n g of Dr o p o uts a n d Missi n g D at a 
Ge ner all y, b ot h a meas ur e me nt at t he baseli ne ti m e p oi nt a n d at t he fi nal ti me p oi nt f or eac h  
e n d p oi nt are nee de d f or a s u bject t o be i ncl u de d i n t he a nal ysis f or c h a n ge or perce nt c ha n g e. 
If t he meas ure me nt at t he fi nal ti me p oi nt f or a n e n d p oi nt is missi n g, L O C F will be use d f or 
missi n g data i m p utati o n if a p plica ble. 
3. 4. 2. 3  
Sec o n d ar y Effic ac y A n al yses 
T he a nal ysis of t he sec o n dar y efficac y e n d p oi nts will be perf or me d usi n g t he mI T T  
p o p ulati o n f or e n d p oi nts c o m pari n g M E DI 0 3 8 2 a n d place b o d uri n g t he d o u ble- bli n d 
treat me nt peri o d. F or sec o n dar y efficac y e n d p oi nts t hat all o w c o m paris o n of M E DI 0 3 8 2 a n d 
place b o, t he e n d p oi nts will be a nal yze d b y a n A N C O V A m o del si milar t o t hat use d f or t he 
pri mar y e fficac y a nal ysis. Selecte d sec o n d ar y e n d p oi nts will als o be a nal yse d usi n g t he Per-
pr ot oc ol p o p ulati o n.  
3. 4. 3  
E x pl or at o r y Effic ac y E n d p oi nt(s) a n d A n al yses 
3. 4. 3. 1  
 
 
 
 
 
 
 
3. 5  
P atie nt Re p orte d O utc o mes  
3. 5. 1  
P R O E n d p oi nts 
•  
C ha n ge i n h u n ger a n d s atie t y sc ores as meas ure d wit h t he D E B Q restrai ne d, e m oti o nal, 
a n d e xter n al eati n g fact ors a n d t he 4- ite m vis ual a nal o g scale fr o m Da y 1 5 t o 5 8 
•  
C ha n ge i n t otal re p orte d e ner g y i nta ke i n kJ as rec or de d i n a f o o d diar y fr o m: 
− 
Da y  1 6 t o 3 2 
− 
Da y  1 6 t o 5 9 
 
3. 5. 2  
P R O A n al yses 
T he a nal ysis of t he P R O e n d p oi nts will be perf or me d usi n g t he mI T T  p o p ulati o n. T he patie nt 
re p orte d o utc o m es ( P R O) e n d p oi nts i ncl u de h u n g er (4 self -re p orte d ite ms) a n d satiet y (3 3 




Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 4  of 1 6  
S A P te m plate versi o n 3. 0  
3. 7  
S afet y A n al yses  
T he a nal yses of t he sec o n dar y saf et y e n d p oi nts will be perf or me d usi n g t h e As- treate d 
p o p ulati o n. 
3. 7. 1  
A d verse E ve nts a n d S eri o us A d verse E ve nts 
A d verse e ve nts will be c o de d wit h Me d D R A versi o n 2 1. 0 or later.  A nal ysis of a d verse 
e ve nts will i ncl u de t he t y pe, i nci de nce, se verit y a n d relati o ns hi p t o st u d y i n vesti gati o nal 
pr o d uct s u m marize d b y Me d D R A S yste m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T), b y 
treat me nt gr o u p as w ell as o verall. T he A Es s u m m aries will i ncl u de o nl y treat me nt-e mer g e nt 
A Es, ie, t h ose starti ng aft er t he first a d mi nistrati o n of d o u ble- bli n d i n vesti gati o nal pr o d uct. 
S u bjects will be c o u nte d o nce f or s p ecific P T or Me d D R A S O C w he n cal c ulati n g i nci de nce 
rates. If t h e sa me A E Pr eferr e d Ter m o cc urs m ulti ple ti mes wit hi n a s u bject, t he hi g hest 
se verit y a n d le v el of rel ati o ns hi p o bser ve d will be re p orte d. N o n-treat me nt-e mer ge nt 
A Es/seri o us a d vers e e v e nts ( S A Es) , ie, t h ose A Es wit h o nset after scree ni n g i ncl u di n g d uri n g 
t he si n gle- bli n d place b o treat me nt b ut bef ore t he st art of d o u ble- bli n d treat me nt wi ll be 
prese nte d i n t he listi n gs. T he per ce nta g e of s u bject wit h n a usea, v o miti n g a n d eit her n a usea 
or v o miti n g o n eac h da y d uri n g t he d ose titrati o n peri o d ( Da ys 1 7 t o 2 8 ) will be s u m marize d 
wit h t he 8 0 % c o nfi de n ce i nter val.  N ote t hat t his is n ot j ust o nse t of a ne w e v e nt b ut i ncl u des 
e ve nts w her e t he da y is i ncl u de d i n t he A E start a n d st o p dates. A si milar a nal ysis i ncl u di n g 
e ve nt rates  will be perf or me d f or eac h of t he 4 - da y d ose titrati o n peri o d (D a ys 1 7- 2 0, 2 1- 2 4, 
a n d 2 5 t o 2 8 ) a n d ot her d osi n g peri o ds. A d verse e ve nts will be s u m marize d se parat el y f or t he 
d o u ble- bli n de d treat me nt peri o d a n d f or t he si n gle- bli n de d treat me nt peri o d. 
3. 7. 2  
Ot her E ve nts 
3. 7. 2. 1  
He p atic F u ncti o n A b n or m alit y  
Cases w her e a s u bject s h o ws ele vati o ns i n li ver bi oc he mistr y ma y re q uire f urt her e v al uati o n 
a n d occ urre n ces of as part ate tra nsa mi nas e  (A S T ) or ala ni ne tra nsa mi nase  (A L T ) ≥ 3 × U L N 
t o get her wit h t otal bilir u bi n ≥ 2 × U L N ma y nee d t o be re p orte d as S A Es. Tes ts f or A S T, 
A L T, a n d t otal bilir u bi n m ust be c o n d ucte d c o n c urre ntl y, defi ne d as deri v i n g fr o m a si n gle 
bl o o d dra w or fr o m se par ate bl o o d dra ws ta k e n wit hi n 8 da ys of eac h ot h er, a n d assesse d 
c o nc urr e ntl y. 
T he cas es of he p atic f u ncti o n a b n or malit y will be s u m marize d o verall, as w ell as cate g orize d 
b y Me d D R A s yste m or g a n class a n d preferre d ter m b y treat me nt  gr o u p. 
3. 7. 2. 2  
I njecti o n Site Re acti o ns 
Treat me nt -e mer ge nt i njecti o n site reacti o ns will be s u m marize d o v erall, as well as 
cate g orize d b y Me d D R A s yste m or ga n cl ass a n d preferre d t er m b y treat me nt  gr o u p. 


Me dI m m u ne   
A nal ysis Pla n f or Pr ot oc ol D 5 6 7 0 C 0 0 0 2 1  
M E DI 0 3 8 2    
2 3 F E B 2 0 1 9; Fi nal  versi o n 2. 0  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
1 5  of 1 6  
S A P te m plate versi o n 3. 0  
3. 7. 2. 3  
N a use a or V o miti n g 
Treat me nt - e mer ge nt n a usea or v o miti n g e ve nts will be s u m marize d o verall, as well as 
cate g orize d b y Me d D R A s yste m or ga n class a n d preferre d t er m b y treat me nt gr o u p. 
3. 7. 3  
De at hs a n d Tre at m e nt Disc o nti n u ati o ns d u e t o A d verse E ve nts 
Deat h a n d A Es res ulti n g i n per ma ne nt disc o nti n uati o n fr o m t he st u d y dr u g will be 
s u m marize d b y treat me nt. T he s u m mar y i ncl u des o verall, cat e g orize d b y Me d D R A s yste m 
or ga n class, a n d preferre d ter m. 
3. 7. 4  
Cli nic al L a b or at or y E v al u ati o n 
He mat ol o g y, ser u m c h e mistr y, a n d uri nal ysis la b orat or y e v al uati o ns will be perf or me d 
d uri n g t he st u d y. T he he mat ol o g y a n d ser u m c he mistr y (i ncl u di n g calcit o ni n, li pase, a n d 
a m ylase) para meters as well as t heir c h a n ges fr o m baseli ne a n d perce nt c ha n ges f r o m 
baseli ne  will be s u m mari ze d wit h descri pti ve statistics ( n u m ber of s u bjects, mea n, a n d 
sta n dar d de viati o n, me di a n, mi ni m u m a n d ma xi m u m) b y treat me nt gr o u p. T he he mat ol o g y 
a n d ser u m c h e mistr y res ults will als o be classifie d as l o w  ( bel o w l o wer li mit of refere nce 
ra n ge), n or mal ( wit hi n refere n ce r a n ge), or hi g h (a b o ve u p per li mit of refere nce ra n ge). T he 
uri nal ysis res ults will be classifie d as n or mal or a b n or mal. T he s hift fr o m b aseli ne 
he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis res ults will be s u m mariz e d b y treat me nt at eac h 
e val uati o n ti me. 
3. 7. 5  
Ot her S afet y E v al u ati o ns 
3. 7. 5. 1  
Vit al Si g ns  
Vital si g ns i ncl u di n g p ulse rate ( b eats/ mi n), s yst olic a n d diast olic bl o o d press ure ( m m H g), 
te m perat ur e (oC), a n d res pirat or y rate ( breat hs/ mi n), as well as t he c ha n ge fr o m base li ne f or 
eac h of t h os e par a meters, will be descri pti vel y s u m marize d b y treat me nt at eac h ti me p oi nt.  
3. 7. 5. 2  
Electr oc a r di o gr a m  
Electr ocar di o gra m para m eters will be assess e d usi n g sta n dar d 1 2-lea d electr ocar di o gra p h y. 
T he f oll o wi n g Electr o car di o gra m ( E C G) para meter s as well as t he c ha n ge fr o m baseli ne f or 
eac h of t h os e par a meters will be re p orte d a n d descri pti vel y s u m marize d b y treat me nt gr o u p 
at eac h of t he s pecifie d ti me p oi nts: Heart rate ( beats/ mi n), R R ( msec), P R ( msec), Q R S 
( msec), a n d Q T ( msec) i nter vals a n d t he Q T c orrecte d i nter val.  
T he n or malit y/a b n or malit y of t he E C G e val uati o n will be s u m marize d usi n g fre q ue n c y ta bles 
of t he n u m ber of s u bjects wit h a n or mal/a b n or mal E C G e val uati o n at eac h s c he d ule d visit.