Clinical trial NCT04019561
Conditions: Non-alcoholic Fatty Liver Disease (NAFLD) Non-alcoholic Steatohepatitis (NASH)
Keywords: Non-alcoholic fatty liver disease NAFLD Non-alcoholic steatohepatitis NASH 0382
Sponsor: MedImmune LLC
Start date: 2019-09-23; Completion date: 2021-05-06
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2 study with 4 treatment groups of two differing doses and matched placebos designed to evaluate the safety (including hepatic safety), tolerability and pharmacodynamic effects of two dose levels of MEDI0382 in obese subjects with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The subjects will have biopsy-confirmed NAFLD/NASH with liver fibrosis stage F1, F2 or F3. Approximately 72 subjects will be randomized

Detailed description:
This is a randomized, double-blind, placebo-controlled, study to evaluate the safety (including hepatic safety), tolerability and pharmacodynamic effects of two dose levels of MEDI0382 in obese subjects with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The subjects will have biopsy-confirmed NAFLD/NASH with liver fibrosis stage F1, F2 or F3. Approximately 72 subjects will be randomized across multiple study sites.

Arms: arm 1: MEDI0382 high dose administered subcutaneously arm 2: Placebo for MEDI0382 high dose administered subcutaneously arm 3: MEDI0382 low dose administered subcutaneoously arm 4: Placebo for MEDI0382 low dose administered subcutaneously
Interventions: intervention 1: MEDI0382 high dose intervention 2: Placebo for MEDI0382 high dose intervention 3: MEDI0382 low dose intervention 4: Placebo for MEDI0382 low dose
Intervention descriptions: intervention 1: MEDI0382 high dose administered subcutaneously intervention 2: Placebo for MEDI0382 high dose administered subcutaneously intervention 3: MEDI0382 low dose administered subcutaneously intervention 4: Placebo for MEDI0382 low dose administered subcutaneously

Protocol documents:
SAP_003.pdf: 
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Statistical Analysis Plan 
Study Code 
D5671C00002 
Edition Number 
V5.0 
Date 
01/06/2021 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate the Safety and Pharmacodynamic Effects of 
MEDI0382 in Obese Subjects With Non-alcoholic Fatty Liver 
Disease (NAFLD)/ Non-alcoholic Steatohepatitis (NASH) 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS .......................................................................................................... 2 
LIST OF ABBREVIATIONS ................................................................................................... 6 
AMENDMENT HISTORY ..................................................................................................... 10 
1 
STUDY DETAILS ............................................................................................... 11 
1.1 
Study objectives .................................................................................................... 11 
1.1.1 
Primary objective and associated endpoint........................................................... 11 
1.1.2 
Secondary objectives and associated endpoints ................................................... 12 
1.1.3 
Exploratory objectives and associated endpoints ................................................. 12 
1.2 
Study design ......................................................................................................... 14 
1.3 
Number of subjects ............................................................................................... 30 
2 
ANALYSIS SETS ................................................................................................ 30 
2.1 
Definition of analysis sets ..................................................................................... 30 
2.2 
Violations and deviations ..................................................................................... 31 
3 
BASELINE, EFFICACY AND SAFETY EVALUATION ................................. 35 
3.1 
General principles ................................................................................................. 35 
3.1.1 
Handling of missing data ...................................................................................... 35 
3.1.1.1 
Imputation of date of first dose of IP .................................................................... 35 
3.1.1.2 
Imputation of date of last dose of IP ..................................................................... 36 
3.1.1.3 
Imputation of AE end date .................................................................................... 36 
3.1.1.4 
Imputation of AE start date................................................................................... 36 
3.1.1.5 
Imputation of concomitant medication end date .................................................. 37 
3.1.1.6 
Imputation of concomitant medication start date ................................................. 37 
3.1.2 
Analysis visit windows ......................................................................................... 37 
3.1.3 
Study phase windows ........................................................................................... 40 
3.2 
Baseline assessments and other subject-specific characteristics .......................... 40 
3.2.1 
Demographic and subject characteristics.............................................................. 41 
3.2.2 
Medical history ..................................................................................................... 41 
3.2.3 
Alcohol use ........................................................................................................... 41 
3.3 
Efficacy and safety variables ................................................................................ 41 
3.3.1 
Primary safety endpoints ...................................................................................... 42 
3.3.1.1 
Adverse events ...................................................................................................... 42 
3.3.1.2 
Laboratory evaluations ......................................................................................... 43 
3.3.1.3 
Vital signs ............................................................................................................. 45 
3.3.1.4 
dECG .................................................................................................................... 47 
3.3.2 
Secondary efficacy endpoints ............................................................................... 48 
3.3.2.1 
Hepatic fat fraction (HFF) as assessed by MRI-PDFF ......................................... 48 
3.3.2.2 
Other related imaging parameters as assessed by MRI ........................................ 48 


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3.3.2.3 
Circulating markers of hepatic inflammation ....................................................... 49 
3.3.2.4 
Immunogenicity .................................................................................................... 49 
3.3.2.5 
Weight, BMI and waist and hip circumference .................................................... 50 
3.3.3 
Exploratory endpoints ........................................................................................... 50 
3.3.3.1 
Biomarkers ............................................................................................................ 50 
3.3.3.2 
Lipid parameters ................................................................................................... 52 
3.3.3.3 
Liver stiffness as assessed by fibroscan................................................................ 52 
3.3.3.4 
Pharmacokinetic parameters ................................................................................. 52 
3.3.3.5 
Patient reported outcomes (PRO) including SF-36 and CLDQ-NASH. .............. 52 
3.4 
Exposure and treatment compliance ..................................................................... 54 
3.4.1 
Exposure ............................................................................................................... 55 
3.4.2 
Compliance ........................................................................................................... 55 
3.5 
Concomitant medications ..................................................................................... 56 
4 
ANALYSIS METHODS ...................................................................................... 56 
4.1 
General principles ................................................................................................. 56 
4.1.1 
Analysis of covariance (ANCOVA) ..................................................................... 57 
4.1.2 
Sensitivity analysis 1 – the mixed model repeated measures (MMRM) .............. 58 
4.1.3 
Sensitivity analysis 2 ............................................................................................ 59 
4.1.4 
Sensitivity analysis 3 ............................................................................................ 59 
4.1.5 
Sensitivity analysis 4 ............................................................................................ 59 
4.2 
Analysis of variables............................................................................................. 60 
4.2.1 
Disposition of subjects .......................................................................................... 60 
4.2.2 
Important protocol deviations ............................................................................... 60 
4.2.3 
Baseline assessment and other subject-specific characteristics ............................ 60 
4.2.3.1 
Demographic and subject-specific characteristics ................................................ 60 
4.2.3.2 
Medical history ..................................................................................................... 61 
4.2.3.3 
Alcohol use ........................................................................................................... 61 
4.2.4 
Primary safety endpoints ...................................................................................... 61 
4.2.4.1 
Adverse events ...................................................................................................... 61 
4.2.4.2 
Laboratory evaluation ........................................................................................... 63 
4.2.4.3 
Vital signs ............................................................................................................. 63 
4.2.4.4 
dECG .................................................................................................................... 64 
4.2.5 
Secondary efficacy endpoints ............................................................................... 65 
4.2.5.1 
Hepatic fat fraction (HFF) as assessed by MRI-PDFF ......................................... 65 
4.2.5.2 
Other related imaging parameters as assessed by MRI ........................................ 65 
4.2.5.3 
Circulating markers of hepatic inflammation ....................................................... 65 
4.2.5.4 
Immunogenicity .................................................................................................... 66 
4.2.5.5 
Weight, BMI and waist and hip circumference .................................................... 67 
4.2.6 
Exploratory endpoints ........................................................................................... 67 
4.2.6.1 
Biomarkers ............................................................................................................ 67 
4.2.6.2 
Lipid parameters ................................................................................................... 68 
4.2.6.3 
Liver stiffness as assessed by fibroscan................................................................ 68 
4.2.6.4 
Pharmacokinetic parameters ................................................................................. 69 


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4.2.6.5 
Patient reported outcomes (PRO) including SF-36 and CLDQ-NASH. .............. 69 
4.2.7 
Treatment compliance .......................................................................................... 69 
4.2.7.1 
Exposure ............................................................................................................... 69 
4.2.7.2 
Compliance ........................................................................................................... 69 
4.2.8 
Concomitant medications ..................................................................................... 70 
5 
INTERIM ANALYSES ........................................................................................ 70 
5.1 
Description of the population ............................................................................... 70 
5.2 
Overview of the effect on safety variables ........................................................... 70 
5.2.1 
Adverse events ...................................................................................................... 70 
5.2.2 
Laboratory evaluation ........................................................................................... 71 
5.2.3 
Vital signs ............................................................................................................. 72 
5.2.4 
dECG .................................................................................................................... 72 
5.3 
Overview of major efficacy parameters ............................................................... 72 
5.3.1 
Hepatic fat fraction (HFF) as assessed by MRI-PDFF ......................................... 72 
5.3.2 
Circulating markers of hepatic inflammation ....................................................... 72 
5.3.3 
Immunogenicity .................................................................................................... 73 
5.3.4 
Weight................................................................................................................... 73 
6 
AD-HOC SAFETY REVIEW .............................................................................. 73 
6.1 
Minimum scope .................................................................................................... 74 
6.1.1 
Description of the population ............................................................................... 74 
6.1.2 
Adverse events ...................................................................................................... 74 
6.2 
Medium scope ....................................................................................................... 74 
6.2.1 
Adverse events ...................................................................................................... 74 
6.2.2 
Vital signs ............................................................................................................. 75 
6.3 
Maximum scope.................................................................................................... 75 
6.3.1 
Laboratory evaluation ........................................................................................... 75 
6.3.2 
Vital signs ............................................................................................................. 75 
6.3.3 
dECG .................................................................................................................... 75 
7 
CHANGES OF ANALYSIS FROM PROTOCOL .............................................. 76 
8 
REFERENCES ..................................................................................................... 77 
9 
APPENDIX .......................................................................................................... 77 
9.1 
Appendix 1 Changes made to the SAP after initial sign-off ................................ 77 
9.1.1 
Version 1.0 ............................................................................................................ 77 
9.1.2 
Version 2.0 ............................................................................................................ 77 
 
LIST OF TABLES 
Table 1 Primary objective and associated endpoint ................................................................ 11 
Table 2 Secondary objectives and associated endpoints ......................................................... 12 


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Table 3 Exploratory objectives and associated endpoints ....................................................... 12 
Table 4 Screening schedule of procedures .............................................................................. 14 
Table 5 MEDI0382/matched placebo 300 μg treatment period schedule of procedures ........ 17 
Table 6 MEDI0382/matched placebo 600 μg treatment period schedule of procedures ........ 22 
Table 7 Schedule of follow-up procedures .............................................................................. 29 
Table 8 Definition of analysis sets .......................................................................................... 30 
Table 9 Analysis visit windows ............................................................................................... 37 
Table 10 Analysis visit windows for unscheduled visits ......................................................... 39 
Table 11 Study phases ............................................................................................................. 40 
Table 12 Vital signs normal reference ranges ......................................................................... 46 
Table 13 ABPM acceptable ranges ......................................................................................... 46 
Table 14 dECG normal reference ranges ................................................................................ 48 
 
LIST OF FIGURES 
No table of figures entries found. 


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LIST OF ABBREVIATIONS 
Abbreviation or special term 
Explanation  
AB 
Abdominal  
ABPM  
Ambulatory blood pressure monitoring 
AC 
Activity  
ADA  
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT  
Alanine aminotransferase 
ANCOVA 
Analysis of covariance  
APRI 
AST platelet ratio index 
AST  
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical  
AUC 
Plasma area under the concentration-time curve  
AUDIT   
Alcohol use disorder identification test 
BARD 
BMI, Ratio, Diabetes Score 
BMI 
Body mass index 
BP  
Blood pressure 
C3M   
Neoepitope of metallopeptidase 9-mediated degraded type III collagen 
C6M   
Neoepitope of matrix metallopeptidase 2-mediated degraded type VI collage 
CAP 
Percentage-controlled attenuation parameter  
CI 
Confidence interval 
CK18 
Cytokeratin 18 
CLDQ-NASH 
Chronic Liver Disease Questionnaire for non-alcoholic steatohepatitis 
CM 
Concomitant medication 
Cmax 
Maximum observed plasma drug concentration  
Covance BM 
Covance biometric 
CS 
Compound symmetry covariance structures 
CSR 
Clinical study report 
D  
Day 
dECG   
Digital electrocardiogram 
E-code 
Subject identification number 
eCRF  
Electronic case report form 
ELF™  
Enhanced liver fibrosis score 
EM 
Emotion  
EOS 
End of study 


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Abbreviation or special term 
Explanation  
EOT 
End of treatment 
FA 
Fatigue  
FIB-4 
Fibrosis-4 score 
FLI 
Fatty liver index 
FSH  
Follicle-stimulating hormone 
FUP 
Follow-up 
GGT 
Gamma glutamyl transferase 
GLP-1 
Glucagon-like peptide-1 
HbA1c 
Haemoglobin A1c 
HDLc 
High density lipoprotein cholesterol 
HFF 
Hepatic fat fraction 
HIV  
Human immunodeficiency virus 
HOMA-IR   
Homeostatic model assessment of insulin resistance 
HR 
Heart rate 
IA 
Interim analysis 
IC 
Informed consent 
IDRP 
Integrated Data Review Plan  
IP  
Investigational product 
IPD 
Important protocol deviation 
ITT 
Intention to treat  
IU 
International units 
LDLc   
Low density lipoprotein cholesterol 
LOCF 
Last observation carried forward  
LSM 
Liver stiffness measurement  
LSmeans 
Least-square means 
MCS 
Mental Component Summary  
MedDRA  
Medical Dictionary for Regulatory Activities  
MMRM  
Mixed model repeated measures  
MRI-PDFF 
Magnetic resonance imaging-proton density fat fraction 
NAFLD  
Non-alcoholic fatty liver disease 
NASH  
Non-alcoholic steatohepatitis 
NHP 
Non-compliance handling plan 
NIS4   
Non-invasive diagnostic score 4 
NFS 
NAFLD fibrosis score 
P4NP7S   
Internal epitope in the 7S domain of type IV collagen 
PCS 
Physical component summary  


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Abbreviation or special term 
Explanation  
PD 
Protocol deviation 
PK 
Pharmacokinetic 
PP 
Per protocol 
PPAR-γ  
Peroxisome proliferator-activated receptor gamma 
PR 
PR wave 
PRO 
Patient reported outcome 
Pro-C3   
Released N-terminal propeptide of type III collagen 
Pro-C5   
Released C-terminal propeptide of type V collagen 
Pro-C6   
Neoepitope in C-terminal of type VI collagen 
PT 
Preferred term 
QRS 
QRS wave 
QT 
QT wave 
QTcB 
Corrected QT Interval using Bazett’s Formula 
QTcF 
Corrected QT Interval using Fridericia’s Formula 
REML 
Restricted maximum likelihood  
RPP 
Rate pressure product  
RR  
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SE 
Standard error 
SF-36  
Short-Form-36 
SGLT-2  
Sodium-glucose co-transporter 2 
SI 
International system of units 
SOC 
System organ class 
SP (POW)  
Power spatial covariance structures 
SY 
Systemic  
T2DM 
Type 2 diabetes mellitus 
TBL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
Tmax 
Time to maximum observed plasma drug concentration  
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
UN 
Unstructured covariance structures 


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Abbreviation or special term 
Explanation  
UNSCH 
Unscheduled 
V 
Visit 
WHO 
World Health Organization 
WHO-DD  
WHO Drug Dictionary  
WO 
Worry  
β-HB 
β-hydroxybutyrate 
 
 


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AMENDMENT HISTORY 
Version 
number 
Date 
Brief description of change 
V1.0 
22/10/2019 
N/A 
V2.0 
05/08/2020 
Amendment due to protocol amendment; changes in statistical 
modelling for exploratory endpoints; additional Safety tables; added 
the ad-hoc safety review; added tables at IA 
V3.0 
28/09/2020 
AVISIT derivation: added range for CRF visits  
V4.0 
11/11/2020 
Added for HFF only: descriptive statistics by T2DM, p-values for 
change from baseline within each group and comparison between all 
active patients versus placebo  
V5.0 
01/06/2021 
Deleted the Disease related medical history page because not recorded 
correctly in the CRF; added COVID tables and other minor changes 
 
 


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1 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objective and associated endpoint 
Table 1 Primary objective and associated endpoint 
Type 
Objective 
Endpoint 
Safety 
To assess the safety 
(including hepatic safety) 
and tolerability of 
MEDI0382 compared with 
placebo 
• 
Incidences of treatment emergent 
adverse events and serious adverse 
events through the end of the follow-
up period. 


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1.1.2 
Secondary objectives and associated endpoints 
Table 2 Secondary objectives and associated endpoints 
Type 
Objective 
Endpoint 
Pharmacodynamic 
effects 
To assess the effect of MEDI0382 
on relative and absolute change in 
hepatic fat as assessed by 
magnetic resonance imaging-
proton density fat fraction (MRI-
PDFF) compared with placebo 
• 
Percent change from baseline in hepatic fat 
fraction (HFF) at Week 19 
• 
Absolute change from baseline to Week 19 in 
HFF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
effects 
To assess the effect of MEDI0382 
on circulating markers of hepatic 
inflammation compared with 
placebo 
Change and percent change from baseline to 
Week 19 in: 
• 
alanine aminotransferase (ALT) 
• 
aspartate aminotransferase (AST) 
• 
gamma glutamyl transferase (GGT) 
Pharmacodynamic 
effects 
To assess the effect of MEDI0382 
on body weight and BMI 
compared with placebo 
• 
Change and percent change from baseline to 
Week 19 in body weight and BMI. 
Dose response 
To assess the dose response of 
MEDI0382 on pharmacodynamic 
parameters 
• 
HFF, body weight, safety, other imaging 
parameters, parameters of hepatic 
inflammation 
Immunogenicity 
To evaluate the immunogenicity 
of MEDI0382 
• 
Development of anti-drug antibodies (ADA) 
and titer (if subjects are ADA positive) during 
treatment and follow-up 
1.1.3 
Exploratory objectives and associated endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI


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Table 3 Exploratory objectives and associated endpoints 
CCI


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Table 3 Exploratory objectives and associated endpoints 
1.2 
Study design 
This is a randomized, double-blind, placebo-controlled, study to evaluate the safety (including 
hepatic safety), tolerability and pharmacodynamic effects of two dose levels of MEDI0382 in 
obese subjects with NAFLD/NASH. The subjects have biopsy-confirmed NAFLD/NASH with 
liver fibrosis stages F1, F2 or F3. Approximately 72 subjects are randomized across multiple 
study sites. 
Subjects are recruited in parallel and randomized using a 2:1:2:1 ratio: 
• 
MEDI0382 300 μg: MEDI0382 SC 50 μg once daily for 1 week, followed by 100 μg daily 
for 2 weeks, 200 μg daily for 2 weeks and 300 μg daily for 14 weeks (n = 24). 
• 
Placebo for MEDI0382 300 μg: matched placebo SC once daily for 19 weeks (n = 12). 
• 
MEDI0382 600 μg: MEDI0382 SC 50 μg once daily for 1 week, followed by 100 μg daily 
for 2 weeks, 200 μg daily for 2 weeks, 300 μg daily for 2 weeks, 400 μg daily for 2 weeks, 
500 μg daily for 2 weeks and 600 μg daily for 8 weeks (n = 24). 
• 
Placebo for MEDI0382 600 μg: matched placebo SC once daily for 19 weeks (n = 12). 
The table below shows all procedures to be conducted at the screening visit.  
Table 4 Screening schedule of procedures 
Study Period 
Screening 
Visit Number 
V1 
V2f 
Procedure/Study Day 
Day -28 to -11 
Day -10 ± 3 
days 
Written informed consent/assignment of E-code number 
x 
  
Informed consent for future genetic research samples (optional) 
x 
  
Informed consent for future non-genetic research samples (optional) 
x 
  
Verify eligibility criteria 
x 
x 
CLDQ-NASH and SF-36 
x 
  
Dispensation/completion of diary (food intake) 
x 
x 
Medical history, including smoking and alcohol history 
x 
  
Demographics 
x 
  
CCI


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Table 4 Screening schedule of procedures 
Study Period 
Screening 
Visit Number 
V1 
V2f 
Procedure/Study Day 
Day -28 to -11 
Day -10 ± 3 
days 
Physical examination (full)a 
x 
  
Weightb, height and BMI calculation 
x 
  
dECGc 
x 
  
Vital signsd (BP, pulse, body temperature, RR) 
x 
  
ABPMe 
  
x 
MRI (including MRI-PDFF)f 
  
x 
Fibroscanf 
  
x 
AUDIT questionnaire 
x 
  
Assessment of SAEs 
x 
x 
Concomitant medications 
x 
x 
SC injection training/demonstration/verify subject’s ability to self-
injectg 
x 
  
Collect blood for: 
Serum chemistry 
x 
  
Hematology 
x 
  
Coagulation parameters 
x 
  
Circulating markers (ALT, AST, GGT) 
x 
  
Calcitonin 
x 
  
HbA1c 
x 
  
Lipase and amylase 
x 
  
TSH 
x 
  
Serum triglycerides 
x 
  
Virology: hepatitis B surface antigen, hepatitis C virus 
antibody; HIV-1 and HIV-2 
x 
  
FSH (postmenopausal females only)h 
x 
  
ADA blood sample 
x 
  
Collect urine for: 
Urinalysis 
x 
  
Pregnancy test 
x 
  
Drug and alcohol screeni 
x 
  
ABPM = ambulatory blood pressure monitoring; ADA = anti-drug antibody; AE = adverse event; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; AUDIT = Alcohol Use Disorder Identification Test; 
BMI = body mass index; BP = blood pressure; CLDQ-NASH = Chronic Liver Disease Questionnaire for non-


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alcoholic steatohepatitis; dECG = digital electrocardiogram; eCRF = electronic case report form; FSH = 
follicle-stimulating hormone; GGT = gamma glutamyl transferase; HbA1c = haemoglobin A1c; HIV = human 
immunodeficiency virus; MRI-PDFF = magnetic resonance imaging-proton density fat fraction; RR = 
respiratory rate; SAE = serious adverse event; SC = subcutaneous; SF-36 = Short-Form-36; E-code = subject 
identification number; TSH = thyroid stimulating hormone; V = visit. 
a Only the screening physical examination will be a full examination. For all time points thereafter, only an 
abbreviated physical examination is required. 
b Body weight should be measured in the morning, after the subject has toileted and removed bulky clothing, 
including shoes. Calibrated scales should be used. 
c A single dECG recording should be performed after the subject has rested in the supine position for at least 10 
minutes. 
d Vital sign measurements should be measured after the subject has rested in the seated position for at least 10 
minutes (rest period for dECG will suffice). Two consecutive BP readings should be taken at intervals of at least 
1 minute, and the average recorded in the eCRF. 
e Subjects will be fitted with the ABPM device while at the clinical unit, which may involve practice inflations. 
The subject will then wear the monitor/cuff for approximately 24 hours (including overnight at home) and will 
remove the device at home at the end of the 24-hour period. 
f Subjects are required to fast for at least 8 hours overnight prior to Visit 2; subjects are permitted to drink water 
during this period of fasting. MRI-PDFF and fibroscan should be performed with the subject in a fasted state. 
Subjects with MRI (including MRI-PDFF) and fibroscan assessments performed within 60 days prior to 
screening do not need to undergo these assessments. If the screening MRI is determined to 
be of inadequate image quality by the MRI analysis vendor the subject may return for repeat MRI 
within the screening visit period. 
g Subject’s ability to administer a SC injection should be verified by undergoing a single SC injection using 
normal saline provided by the site. Willingness to perform this for the duration of the study should be discussed 
with the subject. 
h FSH should only be checked in female subjects who are post-menopausal and have no previous confirmatory 
laboratory FSH result available. 
i An alcohol breath test is an acceptable alternative to an alcohol urine test. If multiple tests are performed and 
conflicting results occur any positive result should be documented. 
The tables below show all procedures to be conducted during the treatment period for 
MEDI0382/Placebo 300 µg and MEDI0382/Placebo 600 µg, respectively.  


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Table 5 MEDI0382/matched placebo 300 μg treatment period schedule of procedures 
Study Period  
Treatment Period 
5-week Up-titration  
14-week Maintenance 
Dose 
50 µg 
100 µg 
200 µg 
300 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 
3, 4, 
5, 6, 
7 
D8 
D22 
D36 
D50 
D64  
D78 
D92 
D106  
D120 
D133 
(± 2 
days) 
(± 2 
days) 
(± 2 
days) 
(± 2 days) 
(± 2 
days) 
(± 2 
days) 
Outpatient visita 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Daily visits for dosingb 
  
x 
  
  
  
  
  
  
  
  
  
  
Dispense glucose meterc 
x 
  
  
  
  
  
  
  
  
  
  
  
Verify eligibility criteriad 
x 
  
  
  
  
  
  
  
  
  
  
  
Verify subject’s ability to 
self-inject 
x 
  
x 
  
  
  
  
  
  
  
  
  
Verify subject fasted for 8 
hours prior to visit 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Randomization 
x 
  
  
  
  
  
  
  
  
  
  
  
Dose initiation or up-
titration 
x 
  
x 
x 
x 
  
  
  
  
  
  
  
Physical examination 
(abbreviated) 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weighte and BMI 
calculation 
x 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
  
  
  
  
  
  
  
  
  
  
  
Waist and hip circumference 
x 
  
  
  
  
  
  
x 
  
  
  
x 


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 18 of 81 
 
Table 5 MEDI0382/matched placebo 300 μg treatment period schedule of procedures 
Study Period  
Treatment Period 
5-week Up-titration  
14-week Maintenance 
Dose 
50 µg 
100 µg 
200 µg 
300 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 
3, 4, 
5, 6, 
7 
D8 
D22 
D36 
D50 
D64  
D78 
D92 
D106  
D120 
D133 
(± 2 
days) 
(± 2 
days) 
(± 2 
days) 
(± 2 days) 
(± 2 
days) 
(± 2 
days) 
dECGf 
x  
  
x 
x 
x 
  
  
  
x 
x 
x 
x 
Vital signsg (BP, pulse, body 
temperature, RR) 
x 
  
x 
x 
x 
  
  
  
x 
x 
x 
x 
MRI (including MRI-
PDFF)h  
x 
  
  
  
  
  
  
x 
  
  
  
x 
Fibroscanh 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Assessments of AEs/SAEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Completion of diary (food 
intake / dosing) 
  
IP dispensation for at home 
self-injection 
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
IP accountability 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Collect bloodi for: 
  
  
  
  
  
  
  
  
  
  
  
  
Serum chemistry 
x 
  
  
  
x 
  
  
x 
  
  
  
x 
Hematology 
x 
  
  
  
x 
  
  
x 
  
  
  
x 
Coagulation parameters 
x 
  
  
  
  
  
  
  
  
  
  
x 


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 19 of 81 
 
Table 5 MEDI0382/matched placebo 300 μg treatment period schedule of procedures 
Study Period  
Treatment Period 
5-week Up-titration  
14-week Maintenance 
Dose 
50 µg 
100 µg 
200 µg 
300 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 
3, 4, 
5, 6, 
7 
D8 
D22 
D36 
D50 
D64  
D78 
D92 
D106  
D120 
D133 
(± 2 
days) 
(± 2 
days) 
(± 2 
days) 
(± 2 days) 
(± 2 
days) 
(± 2 
days) 
MEDI0382 
pharmacokineticsj 
x 
  
x 
x 
x 
x 
x 
x 
  
x 
  
x 
ADAk 
x 
  
x 
  
x 
  
  
x 
  
x 
  
x 
Circulating markers 
(ALT, AST, GGT) 
x 
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
TSH 
x 
  
  
  
  
  
  
  
  
  
  
x 
Lipase and amylase 
x 
  
  
  
  
  
  
  
  
  
  
x 
HbA1c 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Calcitonin 
x 
  
  
  
  
  
  
  
  
  
  
x 
Fasting lipid profilel 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Free fatty acids, β-HB, 
aceto-acetate 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Plasma glucose, 
insulin, glucagon, C-peptide 
and GLP-1 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Serum markers of liver 
fibrosism 
x 
  
  
  
  
  
  
x 
  
  
  
x 
NIS4 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Amino acids panel 
xn 
  
  
  
  
  
  
x 
  
  
  
x 


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 20 of 81 
 
Table 5 MEDI0382/matched placebo 300 μg treatment period schedule of procedures 
Study Period  
Treatment Period 
5-week Up-titration  
14-week Maintenance 
Dose 
50 µg 
100 µg 
200 µg 
300 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 
3, 4, 
5, 6, 
7 
D8 
D22 
D36 
D50 
D64  
D78 
D92 
D106  
D120 
D133 
(± 2 
days) 
(± 2 
days) 
(± 2 
days) 
(± 2 days) 
(± 2 
days) 
(± 2 
days) 
Adiponectin 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Lipidomics 
x 
  
  
  
  
  
  
x 
  
  
  
x 
CK18 and ELF™ 
x 
  
  
  
  
  
  
x 
  
  
  
x 
HOMA-IR calculation 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Sample for future 
genetic testing (optional) 
x 
  
  
  
  
  
  
  
  
  
  
  
Sample for future non-
genetic testing (optional) 
x 
  
  
  
  
  
  
x 
  
  
  
x 
Collect urine for: 
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
x 
  
  
  
x 
  
  
x 
  
  
  
x 
Pregnancy test (females 
of childbearing potential 
only) 
x 
  
  
  
x 
  
  
x 
  
x 
  
x 
ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-HB = β-hydroxybutyrate; BMI = 
body mass index; BP = blood pressure; C3M = neoepitope of metallopeptidase 9-mediated degraded type III collagen; C6M = neoepitope of matrix 
metallopeptidase 2-mediated degraded type VI collage; CK18 = cytokeratin 18; D = day; dECG = digital electrocardiogram; eCRF =electronic case 
report form; ELF™ = enhanced liver fibrosis score; GGT = gamma glutamyl transferase; GLP-1 = glucagon-like peptide-1; HbA1c = haemoglobin 


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 21 of 81 
 
A1c; HDLc = high density lipoprotein cholesterol; HOMA-IR = Homeostatic model assessment of insulin resistance; IP = investigational product; 
LDLc = low density lipoprotein cholesterol; MRI-PDFF = magnetic resonance imaging-proton density fat fraction; NIS4 = non-invasive diagnostic 
score 4; P4NP7S = internal epitope in the 7S domain of type IV collagen; Pro-C3 = released N-terminal propeptide of type III collagen; Pro-C5 = 
released C-terminal propeptide of type V collagen; Pro-C6 = neoepitope in C-terminal of type VI collagen; RR = respiratory rate; T2DM = type 2 
diabetes mellitus; TSH = thyroid stimulating hormone; SAE = serious adverse event. 
Unless stated otherwise, blood samples are to be taken in a fasted state. 
Whenever vital signs, dECGs, and blood draws are scheduled for the same nominal time, the blood draws should occur last. 
a Subjects are required to be dosed at the clinic for the 50 μg dose and on all study day visits when predose procedures are required. Subjects are required to 
fast for at least 8 hours overnight prior to Visits 3 (Day 1), 10 (Day 78) and 14 (Day 133); subjects are permitted to drink water during this period of 
fasting. On days where subjects attend the clinic in a fasted state, blood and urine samples should be obtained prior to administration of IP.  
b Subjects are required to receive their doses at the clinic on Days 1-7, as preparation of the MEDI0382/matched placebo 50 μg dose necessitates dilution 
that must be performed by site staff. Subjects may travel to the site for daily visits during this time or alternatively should be given the option to stay 
overnight locally if this is more convenient. 
c A glucose meter and test strips should be provided to subjects with T2DM. The subjects should be trained in their use and advised to test their capillary 
blood glucose level as per their usual schedule and if they have symptoms of hypoglycemia (hunger, dizziness, shaking, sweating, etc) or feel unwell. 
d Check screening laboratory results and inclusion/exclusion criteria. 
e Body weight should be measured predose in the morning while the subject is fasted (where applicable) and prior to breakfast, after the subject has toileted 
and removed bulky clothing, including shoes. Calibrated scales should be used. 
f Triplicate dECG recording should be collected predose (within 20 minutes) on Visits 3 (Day 1), 5 (Day 8), 6 (Day 22), 7 (Day 36), and 14 (Day 133). At 
other time points, a single dECG recording will be collected predose (within 20 minutes). dECGs may be repeated per site’s local procedure. The dECG 
triplicate recording should be taken prior to the pharmacokinetic samples for MEDI0382. 
g Vital signs schedule:  
• Visits 3 (Day 1), 5 (Day 8), 6 (Day 22), 7 (Day 36), and 14 (Day 133): predose ( within 20 minutes) then 15, 30 and 60 minutes (± 5 minutes) and 
2 hours (± 10 minutes). 
• All other visits: predose (within 20 minutes ± 5 minutes).  
For the predose BP measurements, two consecutive BP readings should be taken at intervals of at least 1 minute, and the average recorded in the eCRF. 
h MRI (including MRI-PDFF) and fibroscan should be performed predose, in the morning with the subjects in a fasted state. The timing of the MRI and 
fibroscan should be kept as consistent as possible at each study visit where these assessments are required. 
i Blood collection to be drawn predose if assessment occurs on a dosing day. Subjects should be in a fasted stated for blood collection drawn on Visits 3 
(Day 1), 10 (Day 78) and 14 (Day 133). For other visits, subject should also be in fasted state for blood collection, whenever possible. 
j MEDI0382 pharmacokinetic sampling schedule: 
• For Visit 3 (Day 1), Visit 5 (Day 8), Visit 6 (Day 22), Visit 7 (Day 36): predose and 6 hours (± 30 minutes) postdose 
• For Visit 8 (Day 50), Visit 9 (Day 64), Visit 10 (Day 78) and Visit 12 (Day 106): predose 
• For Visit 14 (Day 133): predose and at 2, 4, 6, 8, 10, 24, 48, 96 hours (± 30 minutes) postdose. Subjects will be given the option to stay at the clinical 
study site or stay overnight locally, if this is more convenient. 


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 22 of 81 
 
k ADA samples will be collected prior to administration of MEDI0382. 
l Lipid profile includes total cholesterol, LDLc, HDLc, and triglycerides. 
m Markers of liver fibrosis (for collagen turnover) include Pro-C3, Pro-C5, Pro-C6, C3M, C6M and P4NP7S. 
n Predose on Day 1. 
 
Table 6 MEDI0382/matched placebo 600 μg treatment period schedule of procedures 
Study Period 
Treatment Period 
11-week Up-titration  
8-week Maintenance 
Dose 
50 µg 
100 
µg 
200 
µg 
300 
µg 
400 µg 
500 µg 
600 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study 
Day 
D1 
D2, 
3, 
4, 
5, 
6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78  D79 
D80 
D92 
(± 2 
days) 
D106 
D120 
D133 
(± 2 
days) 
(± 2 
days) 
Outpatient visita 
x 
x 
x 
x 
x 
x  
x 
x 
x 
x 
x 
X 
x 
x 
x 
x 
x 
x 
Daily visits for 
dosingb 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dispense glucose 
meterc 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Verify eligibility 
criteriad 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Verify subject’s 
ability to self-inject 
x 
  
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Verify subject fasted 
for 8 hours prior to 
visit 
x 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
x 
Randomization 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dose initiation or up-
titration 
x 
  
x 
x 
x 
x 
  
  
x 
  
  
X 
  
  
  
  
  
  


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 23 of 81 
 
Table 6 MEDI0382/matched placebo 600 μg treatment period schedule of procedures 
Study Period 
Treatment Period 
11-week Up-titration  
8-week Maintenance 
Dose 
50 µg 
100 
µg 
200 
µg 
300 
µg 
400 µg 
500 µg 
600 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study 
Day 
D1 
D2, 
3, 
4, 
5, 
6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78  D79 
D80 
D92 
(± 2 
days) 
D106 
D120 
D133 
(± 2 
days) 
(± 2 
days) 
Physical examination 
(abbreviated) 
x 
  
x 
x 
x 
x 
  
  
x 
  
  
X 
  
  
x 
x 
x 
x 
Weighte and BMI 
calculation 
x 
  
x 
x 
x 
x 
  
  
x 
  
  
X 
  
  
x 
x 
x 
x 
Height 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Waist and hip 
circumference 
x 
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
x 
dECGf 
x 
  
x 
x 
x 
x 
  
  
x 
  
  
X 
  
  
x 
x 
x 
x 
Vital signsg (BP, 
pulse, body 
temperature, RR) 
x 
  
x 
x 
x 
x 
xh  
xh 
x 
xh 
xh 
X 
xh 
xh 
x 
x 
x 
x 
ABPMi 
  
  
  
  
  
x 
  
  
x 
  
  
X 
  
  
  
  
  
x 
MRI-PDFFj 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Fibroscanj 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Assessments of 
AEs/SAEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 24 of 81 
 
Table 6 MEDI0382/matched placebo 600 μg treatment period schedule of procedures 
Study Period 
Treatment Period 
11-week Up-titration  
8-week Maintenance 
Dose 
50 µg 
100 
µg 
200 
µg 
300 
µg 
400 µg 
500 µg 
600 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study 
Day 
D1 
D2, 
3, 
4, 
5, 
6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78  D79 
D80 
D92 
(± 2 
days) 
D106 
D120 
D133 
(± 2 
days) 
(± 2 
days) 
Completion of diary 
(food intake / dosing) 
  
IP dispensation for at 
home self-injection 
  
  
x 
x 
x 
x 
  
  
x 
  
  
x 
  
  
x 
x 
x 
  
IP accountability 
 
 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Collect bloodk for: 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serum chemistry 
x 
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
x 
Hematology 
x 
  
  
  
x 
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Coagulation 
parameters 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
MEDI0382 
pharmacokineticsl 
x 
  
x 
x 
x 
x 
  
  
x 
  
  
x 
  
  
  
x 
  
x 
ADAm 
x 
  
x 
  
x 
  
  
  
  
  
  
x 
  
  
  
x 
  
x 
Circulating 
markers (ALT, AST , 
GGT) 
x 
  
  
  
x 
x 
  
  
x 
  
  
x 
  
  
x 
x 
x 
x 
TSH 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
Lipase and 
amylase 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 25 of 81 
 
Table 6 MEDI0382/matched placebo 600 μg treatment period schedule of procedures 
Study Period 
Treatment Period 
11-week Up-titration  
8-week Maintenance 
Dose 
50 µg 
100 
µg 
200 
µg 
300 
µg 
400 µg 
500 µg 
600 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study 
Day 
D1 
D2, 
3, 
4, 
5, 
6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78  D79 
D80 
D92 
(± 2 
days) 
D106 
D120 
D133 
(± 2 
days) 
(± 2 
days) 
HbA1c 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Calcitonin 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
Fasting lipid 
profilen 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Free fatty acids, 
β-HB, aceto-acetate 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Plasma glucose, 
insulin, glucagon, c-
peptide, and GLP-1 
x 
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
  
  
  
x 
Serum markers 
of liver fibrosiso 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
NIS4 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Amino acids 
panel 
xp 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Adiponectin 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Lipidomics 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
CK18 and 
ELF™  
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
HOMA-IR 
calculation 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 


Statistical Analysis Plan  
AstraZeneca 
D5671C00002 - V5.0 
01/06/2021 
CONFIDENTIAL AND PROPRIETARY 
 26 of 81 
 
Table 6 MEDI0382/matched placebo 600 μg treatment period schedule of procedures 
Study Period 
Treatment Period 
11-week Up-titration  
8-week Maintenance 
Dose 
50 µg 
100 
µg 
200 
µg 
300 
µg 
400 µg 
500 µg 
600 µg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study 
Day 
D1 
D2, 
3, 
4, 
5, 
6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78  D79 
D80 
D92 
(± 2 
days) 
D106 
D120 
D133 
(± 2 
days) 
(± 2 
days) 
Sample for 
future genetic testing 
(optional) 
x 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Sample for 
future non-genetic 
testing (optional) 
x 
  
  
  
  
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Collect urine for: 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
x 
  
  
  
x 
  
  
  
  
  
  
x 
  
  
  
  
  
x 
Pregnancy test 
(females of 
childbearing potential 
only) 
x 
  
  
  
x 
  
  
  
  
  
  
x 
  
  
  
x 
  
x 
ABPM = ambulatory blood pressure monitoring; ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; β-HB = β-hydroxybutyrate; BMI = body mass index; BP = blood pressure; C3M = neoepitope of metallopeptidase 9-mediated 
degraded type III collagen; C6M = neoepitope of matrix metallopeptidase 2-mediated degraded type VI collage; CK18 = cytokeratin 18; D = day; 
dECG = digital electrocardiogram; eCRF = electronic case report form; GGT = gamma glutamyl transferase; GLP-1 = glucagon-like peptide-1; ELF™ 
= enhanced liver fibrosis score; HbA1c = haemoglobin A1c; HDLc = high density lipoprotein cholesterol; HOMA-IR = Homeostatic model assessment 
of insulin resistance; IP = investigational product; LDLc = low density lipoprotein cholesterol; MRI-PDFF = magnetic resonance imaging-proton 
density fat fraction; NIS4 = non-invasive diagnostic score 4; P4NP7S = internal epitope in the 7S domain of type IV collagen; Pro-C3 = released N-
terminal propeptide of type III collagen; Pro-C5 = released C-terminal propeptide of type V collagen; Pro-C6 = neoepitope in C-terminal of type VI 
collagen; RR = respiratory rate; T2DM = type 2 diabetes mellitus; TSH = thyroid stimulating hormone; SAE = serious adverse event. 


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Unless stated otherwise, blood samples are to be taken in a fasted state. 
Whenever vital signs, dECGs, and blood draws are scheduled for the same nominal time, the blood draws should occur last. 
a Subjects are required to be dosed at the clinic for the 50 μg dose and on study day visits when predose procedures are required. Subjects are required to fast 
for at least 8 hours overnight prior to Visits 3 (Day 1), 14 (Day 78) and 20 (Day 133); subjects are permitted to drink water during this period of fasting. 
On days where subjects attend the clinic in a fasted state, blood and urine samples should be obtained prior to administration of IP. Subjects are required 
to visit the clinic on two subsequent days following up-titration to the 400, 500 and 600 μg dose for safety monitoring; subjects may travel to the site 
for daily visits during this time or alternatively should be given the option to stay overnight locally if this is more convenient. 
b Subjects are required to receive their doses at the clinic on Days 1-7, as preparation of the MEDI0382/matched placebo 50-μg dose necessitates dilution 
that must be performed by site staff. Subjects may travel to the site for daily visits during this time or alternatively should be given the option to stay 
overnight locally if this is more convenient. 
c A glucose meter and test strips should be provided to subjects with T2DM. The subjects should be trained in its use and advised to test their capillary blood 
glucose level as per their usual schedule and if they have symptoms of hypoglycaemia (hunger, dizziness, shaking, sweating, etc) or feel unwell. 
d Check screening labs and inclusion/exclusion criteria. 
e Body weight should be measured predose in the morning while the subject is fasted (where applicable) and prior to breakfast, after the subject has toileted 
and removed bulky clothing, including shoes. Calibrated scales should be used. 
f Triplicate dECG recording should be collected predose (within 20 minutes) on Visits 3 (Day 1), 5 (Day 8), 6 (Day 22), 7 (Day 36), 8 (Day 50), 11 (Day 
64), 14 (Day 78), and 20 (Day 133). At other time points, a single dECG recording will be collected predose ( within 20 minutes). dECGs may be 
repeated per site’s local procedure. The dECG triplicate recording should be taken prior to the pharmacokinetic samples of MEDI0382. 
g Vital signs schedule: 
• Visits 3 (Day 1), 5 (Day 8), 6 (Day 22), 7 (Day 36), 8 (Day 50), 11 (Day 64), 14 (Day 78), and 20 (Day 133): predose (within 20 minutes) then 15, 
30 and 60 minutes (± 5 minutes) and 2 hours (± 10 minutes). 
• All other visits: predose (within 20 minutes ± 5 minutes). 
For the predose BP measurement, two consecutive BP readings should be taken at intervals of at least 1 minute, and the average recorded in the eCRF. 
On days when ABPM is due to be checked, a set of vital signs should be performed prior to application of the ABPM cuff. 
h Orthostatic BP is to be taken predose at the timepoints specified above. Measurement of orthostatic BP changes will be performed as follows: 
• After the subject has been supine for a minimum of 5 minutes, BP and pulse rate will be measured in duplicate (at least 1 minute apart). 
• Immediately after supine measurements, a standing BP and pulse rate will be measured in duplicate as follows: 
• First measurement: BP and pulse rate measured after at least 1 minute of standing. 
• Second measurement: BP and pulse rate measured after at least 3 minutes of standing. 
Orthostatic hypotension is defined as a drop of 20 mmHg in systolic BP or a drop of 10 mmHg in diastolic BP within 2 to 5 minutes of standing up, or 
if standing causes signs and symptoms. 
i Subjects will be fitted with the ABPM device while at the clinical unit, which may involve practice inflations. The subject will wear the monitor/cuff for 
approximately 24 hours (including overnight at home) and will remove the device at home at the end of the 24-hour period and return the monitor at 
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j MRI (including MRI-PDFF) and fibroscan should be performed predose in the morning with the subjects in a fasted state. The timing of the MRI (including 
MRIPDFF) and fibroscan should be kept as consistent as possible at each study visit where these assessments are required. 
k Blood collection to be drawn predose if assessment occurs on a dosing day. Subjects should be in a fasted state for blood collection drawn on Visits 3 (Day 
1), 14 (Day 78) and 20 (Day 133). For other visits, subject should also be in fasted state for blood collection, whenever possible. 
l MEDI0382 pharmacokinetic sampling schedule:  
• For Visit 3 (Day 1), Visit 5 (Day 8), Visit 6 (Day 22), Visit 7 (Day 36), Visit 8 (Day 50), Visit 11 (Day 64), and Visit 14 (Day 78): predose and 6 
hours (± 30 minutes) postdose 
• For Visit 18 (Day 106) predose 
• For Visit 20 (Day 133): predose and at 2, 4, 6, 8, 10, 24, 48, 96 hours (± 30 minutes) postdose. Subjects will be given the option to stay at the 
clinical study site or stay overnight locally, if this is more convenient. 
m ADA samples will be collected prior to administration of MEDI0382. 
n Lipid profile includes total cholesterol, LDLc, HDLc, and triglycerides. 
o Markers of liver fibrosis (for collagen turnover) include Pro-C3, Pro-C5, Pro-C6, C3M, C6M, and P4NP7S. 
p Predose on Day 1.  
 
 
During the Coronavirus Disease 19 (COVID-19) Pandemic: 
• 
If a subject is unable to attend clinic visits, and/or receive study intervention due to COVID-19, the site staff should keep in 
close contact with the subject, preferably through telephone calls at the time of the scheduled visit, to maintain awareness of 
their status. Assessments that can be performed over the phone should be completed such as adverse events, study drug 
administration and/or concomitant medications and any additional safety information and recorded in the eCRF and any 
assessments not performed should be recorded as ‘not done’.  
• 
If a subject is not able to attend their scheduled D78 MRI due to COVID-19, the MRI should be performed at the earliest 
opportunity and within 7 days of the original D78 scheduled date. All other subsequent visits should follow the original 
schedule. 
• 
If a subject cannot attend their scheduled D133 visit due to COVID-19, every effort should be made to perform the visit within 
2 days of the original D133 scheduled date, with the exception of the MRI which can be performed within 7 days of the original 
D133 scheduled date. If it is not possible to perform the visit within a 2-day window, then all assessments, excluding 
pharmacokinetic blood, should be performed at the earliest opportunity and within 7 days of the original D133 scheduled date 
where local regulations/public health guidance permit. 
 


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The table below shows all procedures to be conducted during the follow-up period. 
Table 7 Schedule of follow-up procedures 
 
Study Period 
Follow-up Period/Early Discontinuation 
Visit Number 
Visit 15/21 (EoS) 
Study Week 
23 
Procedure/Study Day 
D161 (± 3 days) 
Physical examination (abbreviated) 
x 
Weight and BMI calculation 
x 
dECG 
x 
Vital signsa (BP, pulse, body temperature, RR) 
x 
Assessment of AEs/SAEs 
x 
Concomitant medications 
x 
Completion (food intake) / collection of diary 
x 
Collect blood for: 
Serum chemistry 
x 
Hematology 
x 
Coagulation parameters 
x 
HbA1c 
x 
ADAb 
x 
Circulating markers (ALT, AST, GGT) 
x 
Calcitoninc 
x 
Lipid profiled, free fatty acids, β-HB, aceto-acetate 
x 
Collect urine for: 
Urinalysis 
x 
Pregnancy test (females of childbearing potential 
only) 
x 
For Early discontinuation visit, the following should 
be performed in addition to the abovee: 
  
IP accountability 
x 
MRI-PDFFf 
x 
Fibroscan 
x 
MEDI0382 pharmacokineticsg 
x 
ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate 
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= digital electrocardiogram; EoS = end of study; GGT = gamma glutamyl transferase; HbA1c = haemoglobin 
A1c; HDLc = high-density lipoprotein cholesterol; LDLc = low-density lipoprotein cholesterol; MRI-PDFF 
= magnetic resonance imaging-proton density fat fraction; RR = respiratory rate; SAE = serious adverse event; 
ULN =  
. 
a For BP measurements, two consecutive readings should be taken at intervals of at least 1 minute, and the average 
recorded in the eCRF. 
b If this sample is ADA positive, the subject will be asked to return to provide another sample at approximately 3 
months after the end of study visit. If that sample is ADA positive, additional visit(s) approximately every 3 
months should continue until a sample tests negative for ADA or return to baseline level.  
c Calcitonin need only be re-measured in subjects who had a level > ULN on Day 133. 
d Lipid profile include total cholesterol, LDLc, HDLc, and triglycerides. 
e Subjects are required to fast for at least 8 hours prior to the Early Discontinuation Visit; subjects are permitted to 
drink water during this period of fasting. Subjects should be asked to return within 7 days from last 
investigational product dose, where possible. Subjects should also be asked to return 28 days (±3 days) from 
the last investigational product dose for follow-up assessments unless they are unable or unwilling to return. 
Subjects who discontinue investigational product but wish to continue with study assessments should first 
perform the Early Discontinuation Visit and then continue the assessments as described in Table 5 or Table 
6 as appropriate. Subjects who discontinue from investigational product but continue on the study should not 
have more than 3 MRIs performed within the study treatment period (following randomization). 
f MRI (including MRI-PDFF) and fibroscan should be performed predose in the morning with the subjects in a 
fasted state. Subjects who discontinue from investigational product but continue on the study should not have 
more than 3 MRIs performed within the study treatment period (following randomization). 
g One pharmacokinetic sample should be taken at any time during the visit but should be as close to the ADA 
sample as possible. 
Additional details on study design are provided in the study protocol.  
1.3 
Number of subjects 
The primary objective of the study is safety, but sample size and power are calculated on 
pharmacodynamic endpoint HFF. Assuming 20% treatment difference on percent change in 
HFF with SD = 20%, and assume a 25% dropout rate, 24 subjects per group provide about 83% 
power to detect a treatment difference between a MEDI0382 group and the placebo (alpha = 
0.05, 2-sided). No multiplicity adjustment for alpha is planned. 
2 
ANALYSIS SETS 
2.1 
 Definition of analysis sets 
In Table 8 here below are reported all the analyses sets. 
Table 8 Definition of analysis sets 
Population 
Description 
All enrolled 
subject 
All enrolled subjects include those who have signed the informed consent 
form. All enrolled subject population will be analysed according to the 
randomized treatment group. 


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Table 8 Definition of analysis sets 
Population 
Description 
Intent-to-treat 
(ITT) population 
The ITT population includes all enrolled subjects who are randomized. ITT population 
will be analysed according to the randomized treatment group. The analyses include the 
post IP-discontinuation data for those subjects who discontinue from study treatments 
but are still followed up for their scheduled visits. 
As-treated 
population 
The as-treated population includes all enrolled subjects who are randomized and have 
received at least one dose of study IP. As-treated population will be analysed according 
to the actual treatment received. To determine the actual treatment for a subject, the 
general rule is that if a subject receives placebo as well as active treatments then this 
subject’s actual treatment will be chosen from the active treatments only. 
1. If only placebo kits are delivered to the subject, then the actual arm will be set 
to placebo 
2. If only MEDI0382 kits are delivered to the subject, then 
➢ if the max dose is lower or equal to 300 μg, the actual arm will be set 
to MEDI0382 300 μg 
➢ if the max dose is greater to 300 μg, the actual arm will be set to 
MEDI0382 600 μg 
3. If the subject was provided both with MEDI0382 and placebo kits, then: 
➢ If the subject is randomized to MEDI0382 300 or MEDI0382 600 
groups, the actual arm is assigned as described in point 2 above 
➢ If the subject is randomized to placebo group and received MEDI0382 
kits in more than one delivery visit, the actual arm will be evaluated 
case by case, looking to the reported doses and, in case needed, raising 
queries to the involved personnel. 
➢ If the subject is randomized to placebo group and received MEDI0382 
kits in only one delivery visit, then  
• 
if the first dose following or on the wrong kit delivery date is 
lower or equal to 300 μg, the actual arm will be set to MEDI0382 
300 μg 
• 
if the first dose following or on the wrong kit delivery date is 
greater to 300 μg, the actual arm will be set to MEDI0382 600 μg 
The analyses include the post IP-discontinuation data for those subjects who discontinue 
from study treatments but are still followed up for their scheduled visits. 
Per-protocol (PP) 
population 
The PP population includes all enrolled subjects who are randomized and have received 
at least one dose of study IP except for subjects who have discontinued the study IP and 
those with relevant important protocol deviations(IPD). Relevant IPD  are those that 
have the potential to affect the result of the primary efficacy results and are reported 
section 2.2. List of subjects to be excluded from the PP population will be also discussed 
and agreed with the blinded study team in a dedicated meeting prior to database lock. PP 
population is analysed according to the randomized treatment group. 
 
2.2 
Violations and deviations 
The list of important protocol deviations (IPDs) is provided in the AstraZeneca non-compliance 
handling plan (NHP). Relevant IPD that lead to subject exclusion form the PP population are a 
subset of all IPD. More specifically they are: 


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IPD as per NHP v3.0 
Relevant 
IPD  
1 Those who entered the study even though they did not satisfy the entry criteria (ICH3) - 
Inclusion criteria 
 
1.01 
Provision of informed consent (with the exception of consent for future genetic and non 
genetic research) prior to performing any study-specific procedures, including screening 
evaluations 
Y 
1.02 
Subjects aged ≥ 18 years at the time of consent 
Y 
1.03 
BMI ≥ 30 kg/m2 at screening 
Y 
1.04 
Hemoglobin A1c (HbA1c) ≤ 9.5% (inclusive) at screening if T2DM present, managed by 
either diet and/or a stable dose of metformin, sodium-glucose co transporter 2 (SGLT-2) 
inhibitors, sulphonylureas or acarbose (ie, no major dose adjustments in prior 3 months to 
screening) 
Y 
1.05 
Definitive NAFLD/NASH with NAS ≥ 4 with ≥ 1 in each component (ie, steatosis, 
lobular inflammation and ballooning), as diagnosed by liver biopsy within 6 months of 
screening with liver fibrosis stage F1, F2 
Y 
1.06 
Evidence of hepatic steatosis or liver fat (≥ 10%) by MRI-PDFF. Subjects with imaging 
performed within 60 days prior to screening do not need to repeat this assessment at Visit 
2 (Day -10) 
Y 
1.07 
Women of childbearing potential: 
(a) Who are sexually active with a non-sterilized male partner must have used at least one 
highly effective method of contraception (see Section Appendix A 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 
through to the end of the study. It is strongly recommended for the male partner of a 
female subject to also use male condom plus spermicide throughout this period. 
Cessation of contraception after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. 
(b) Must have a negative urine pregnancy test within 72 hours prior to the first dose of 
investigational product; and not be breastfeeding 
Y 
2 Those who entered the study even though they did not satisfy the entry criteria (ICH3) - 
Exclusion criteria 
 
2.01 
History of, or any existing condition that, in the opinion of the investigator, would 
interfere with evaluation of the investigational product, put the subject at risk, influence 
the subject’s ability to participate or affect the interpretation of the results of the study 
Y 
2.02 
Liver disease of other etiologies (eg, alcoholic steatohepatitis; drug-induced, viral, or 
autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; 
hemochromatosis; alpha 1 antitrypsin deficiency; Wilson’s disease) including positive 
results for hepatitis B surface antigen (HBsAg) or hepatitis C antibody tests (anti-HCV) 
Y 
2.03 
History of cirrhosis and/or hepatic decompensation, including ascites, hepatic 
encephalopathy or variceal bleeding 
Y 
2.04 
Prior or planned liver transplantation 
Y 
2.05 
Alcohol consumption > 21 units of alcohol per week for males and > 14 units per week 
for females on average over a two-year time frame prior to baseline biopsy 
Y 
2.06 
Evidence of alcohol dependence as assessed by the Alcohol Use Disorder Identification 
Test (AUDIT) questionnaire at screening 
Y 
2.07 
A history of type 1 diabetes mellitus (T1DM), a history of diabetic ketoacidosis or 
current use of insulin-based therapies 
Y 


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2.08 
Clinically significant inflammatory bowel disease or other severe disease or surgery 
affecting the upper gastrointestinal tract (including bariatric surgery) which may affect 
gastric emptying or could affect the interpretation of safety and tolerability data 
Y 
2.09 
Physician-diagnosed diabetic subjects with clinically significant gastroparesis (as judged 
by the investigator) or those treated for gastroparesis within 6 months prior to screening 
Y 
2.10 
History of > 5 kg weight loss in the last 6 months prior to screening or recent (within 3 
months of screening) use of drugs approved for weight loss (eg, orlistat, 
bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as those 
drugs used off-label 
Y 
2.11 
Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, 
including but not limited to, myocardial infarction, acute coronary syndrome or stroke, 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 
Y 
2.12 
Severe congestive heart failure (New York Heart Association Class IV) 
Y 
2.13 
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 
Y 
2.14 
History of substance dependence likely to impact subject safety or compliance with study 
procedures, or positive screen for drugs of abuse at screening (CSP 1.0. 2.0 & 3.0) 
Y 
2.15 
History of psychosis or bipolar disorder. History of major depressive disorder within the 
past year with the subject being clinically unstable, or any history of suicide attempt or 
history of suicidal ideation within the past year 
Y 
2.16 
Recent (within 3 months of baseline biopsy) use of therapies associated with 
development of NAFLD (eg, systemic corticosteroids, methotrexate, tamoxifen, 
amiodarone, or long-term use of tetracyclines) 
Y 
2.17 
Recent (within 3 months of baseline biopsy) use of obeticholic acid or other therapy 
under investigation for NASH 
Y 
2.18 
High dose vitamin E (> 400 IU) unless on a stable dose for at least 1 year prior to the 
baseline biopsy, and not initiated after the biopsy was taken 
Y 
2.19 
Recent (within 3 months of baseline biopsy) use of GLP-1 receptor agonist or GLP-1 
receptor agonist containing therapies 
Y 
2.20 
Any subject who has received another investigational product as part of a clinical study 
within the last 30 days or 5 half-lives of the therapy (whichever is longer) at the time of 
screening. Any prior exposure to MEDI0382 is not permitted 
Y 
2.21 
Concurrent participation in another interventional study of any kind or repeat 
randomization in this study 
Y 
2.22 
Severe allergy/hypersensitivity to any of the proposed study treatments or excipients 
Y 
2.23 
Contra-indication to MRI: such as subjects with pacemakers, metallic cardiac valves, 
magnetic material such as surgical clips, implanted electronic infusion pumps or other 
conditions that would preclude proximity to a strong magnetic field; subjects with history 
of extreme claustrophobia or subject cannot fit inside the MR scanner cavity 
Y 
2.24 
History of acute pancreatitis or current chronic pancreatitis. Subjects with serum 
triglyceride concentrations above 1000 mg/dL (11 mmol/L) at screening, as this can 
precipitate acute pancreatitis 
Y 


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2.25 
Abnormal laboratory values including any of the following: 
(a) AST or ALT > 5 × upper limit of normal (ULN). (b) Impaired renal function defined 
as estimated glomerular filtration rate (eGFR) ≤ 30 mL/minute/1.73 m2 at screening 
(estimated according to chronic kidney disease epidemiology collaboration [CKD-EPI]). 
(c) Albumin < 35 g/L. 
(d) International normalized ratio (INR) > 1.3. 
(e) Total Bilirubin (TBL) > 25 μmol/L in the absence of known Gilbert’s disease. 
(f) Platelets < 140-150,000/mm3. 
(g) Any other clinically significant abnormalities in clinical chemistry, hematology, or 
urinalysis results as judged by the investigator 
Y 
2.26 
Severely uncontrolled hypertension defined as systolic blood pressure ≥ 180 mmHg 
and/or diastolic blood pressure ≥ 110 mmHg on the average of 2 seated measurements 
after being at rest for at least 10 minutes at screening or randomization 
Y 
2.27 
Basal calcitonin level > 50 ng/L at screening, or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2) 
Y 
2.28 
Hemoglobinopathy, hemolytic anemia, or chronic anemia (hemoglobin concentration < 
11.5 g/dL [115 g/L] for male subjects or < 10.5 g/dL [105 g/L] for female subjects) at 
screening, or any other condition known to interfere with interpretation of HbA1c 
measurements 
Y 
2.29 
Any positive results for human immunodeficiency virus (HIV) infection 
Y 
2.30 
Any AstraZeneca, MedImmune, or study site employee, or close relatives of any of the 
aforementioned employees 
Y 
2.31 
Females who are pregnant or lactating 
Y 
2.32 
History of substance dependence or a positive screen for drugs of abuse, likely to impact 
subject safety or compliance with study procedures, or positive screen for drugs of abuse 
at screening, at the discretion of the Investigator (CSP 4.0 and onward) 
Y 
3 Those who developed discontinuation/ withdrawal criteria during the study but were not withdrawn 
from treatment (ICH3) 
3.01 
An adverse event that, in the opinion of the Investigator or AstraZeneca, warrants 
discontinuation from further dosing 
Y 
3.02 
Patient noncompliance that, in the opinion of the Investigator or sponsor, warrants 
withdrawal (e.g. refusal to adhere to scheduled visits) 
Y 
3.03 
Pregnancy in a female subject. 
Y 
3.04 
Liver function tests meeting any of the following criteria: 
(a) ALT and/or AST are > 3 × ULN and TBL > 2 × ULN 
(b) ALT and/or AST are > 5 × ULN for ≥ 4 consecutive days, at any time after the initial 
confirmatory result in subjects with normal baseline values. 
 
(c) ALT and/or AST > 8 × ULN 
(d) New onset jaundice that is not explained by Gilbert’s irrespective of other liver 
biochemistries 
(e) Albumin < 28 g/L 
(f) INR > 2 
Y 
3.05 
Acute viral hepatitis 
Y 
3.06 
Symptoms or signs of cirrhosis and/or hepatic decompensation (e.g., ascites, variceal 
bleeding, hepatic encephalopathy). 
Y 
3.07 
Acute pancreatitis. 
Y 


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4 Those who developed discontinuation/ withdrawal criteria during the study but were not withdrawn 
from Study (ICH3) 
4.01 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not 
be initiated on treatment, and must be withdrawn from the study 
Y 
5 Subject received the wrong treatment or incorrect dose. (ICH3) 
 
5.08 
Subject missed IP dose for ≥7 contiguous days or less than 80% compliance overall. 
Note: the first 7 days of dosing (D1-D7) are mandatory and if any single doses are missed 
during this period then it would constitute an IPD. 
If a subject misses a dose due to an AE is not considered an IPD,  in this case it would be 
a non important protocol deviation. It would also be considered NIPD if a dose was 
missed due to an AE during the first 7 days of dosing. 
Y 
5.10 
Subjects with 5.01 - 5.05 for more than 2 weeks 
Y 
6 Subject received prohibited medications (ICH3) 
 
6.02 
Subject received prohibited procedures, see exclusion criteria: liver transplantation. 
Y 
6.03 
Subjects with 6.01 for more than 2 weeks  
Y 
 
 
 
3 
BASELINE, EFFICACY AND SAFETY EVALUATION 
3.1 
General principles 
3.1.1 
Handling of missing data  
Missing data are not replaced unless otherwise specified for statistical modelling. Only date of 
first and last dose of IP, AE start and end date and concomitant medications (CMs) end date are 
imputed. Imputation rules are reported below.  
3.1.1.1 
Imputation of date of first dose of IP 
Date and time of first dose of IP are mandatory eCRF fields. No Imputations are expected. In 
the rare cases of missing date, the date of first dose of IP will be imputed if all the following 
criteria are met: 
• 
There is a completely missing or partial missing date for the first dose of IP, and 
• 
There is at least one kit for which the amount of drug dispensed does not equal the amount 
of drug returned, and 
• 
The kits for which the amount of drug dispensed does not equal the amount of drug returned 
have complete non-missing dispensed date 
If that is the case, the date of first dose of IP is imputed with the earliest dispensed date from 
kits for which amount of drug dispensed does not equal the amount of drug returned. Completely 
missing time and time where only hour is missing is imputed to 00:00. If only minutes are 
missing, then it will be imputed to HH:00.  


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3.1.1.2 
Imputation of date of last dose of IP 
Last dose date and time are mandatory eCRF fields. No Imputations are expected. In the rare 
cases of missing date, the last dose date of study drug is imputed if all the following criteria are 
met: 
• 
There is a completely missing or partial missing date for the last dose of study drug, and 
• 
There is at least one kit for which the amount of drug dispensed does not equal the amount 
of drug returned, and 
• 
The kits for which the amount of drug dispensed does not equal the amount of drug returned 
have complete non-missing returned date. 
If that is the case, last dose date of study drug is imputed with the latest returned date from kits 
for which amount of drug dispensed does not equal the amount of drug returned. Missing time 
is not replaced. 
3.1.1.3 
Imputation of AE end date 
Completely missing AE end dates are not imputed. Partial missing AE end dates are imputed as 
below:  
• 
If the AE is ongoing, the end date is stated to missing.  
• 
If the AE is not ongoing, and if only the day is missing: Assume the last day of the collected 
month. 
• 
If the AE is not ongoing, and both, the day and the month are missing: Assume 31-DEC of 
the collected year. 
After applying these rules, if the imputed AE end date is after the end of study date, the AE is 
set to ongoing and the AE end date to missing. 
3.1.1.4 
Imputation of AE start date 
Before to proceed with the AE start date imputation, the first dose of IP and the AE end date 
are imputed as described in the previous section.  
Only partial AE start dates are imputed; Dates which are completely missing are not imputed. 
Partial dates are imputed as described below:  
If the day is missing and the month and year are different from the month and year of the first 
dose of IP, assume 01-MMM-YYYY. If the month and year are the same as the first dose of IP 
month and year and the end date is on or after (including ongoing / missing) the first dose of IP, 
then assume the date of the first dose of IP. If the month and year are the same as the first dose 
of IP month and year and the end date is prior to the first dose of IP, then assume the end date.  
If the month is missing and the year is different from the year of first dose of IP, assume 01-
JAN-YYYY of the collected year. If the year is the same as the first dose of IP year and the end 
date is on or after (including ongoing / missing) the first dose of IP, then assume the date of the 
first dose of IP. If the year is the same as the first dose of IP and the end date is prior to the first 
dose of IP, then assume the end date.  


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After applying these rules, if the imputed AE start date is after a complete AE end date then 
assume the same date as the complete AE end date; if the end date is missing and the imputed 
AE start date is after the end of study date then assume the same date as the study end date. 
3.1.1.5 
Imputation of concomitant medication end date 
 Completely missing concomitant medication end dates are not imputed. Partial missing 
concomitant medication end dates are imputed as below:  
• 
If the CM is ongoing, the end date is set to missing.  
• 
If the CM is not ongoing, and if only the day is missing: Assume the last day of the of the 
collected month. 
• 
If the CM is not ongoing, and both, the day and the month are missing: Assume 31-DEC of 
the collected year. 
After applying these rules, if the imputed CM is after the end of study date, the CM is set to 
ongoing and the CM end date to missing. 
3.1.1.6 
Imputation of concomitant medication start date 
Both, completely missing and partially missing concomitant medication start dates are not 
imputed. 
3.1.2 
Analysis visit windows 
For the purpose of the statistical analysis primary, secondary and exploratory endpoints, except 
the adverse event, are allocated to the analysis visit as reported in the tables below. The 
allocation to visit windows is performed after the imputation of date of first and last doses of IP 
as in section 3.1.1. Measurements with missing or partially missing dates cannot be imputed to 
any analysis visit. 
Table 9 Analysis visit windows 
Analysis visit (AVISIT) 
Scheduled visit day 
Visit Window (Days) 
Pre-treatment 
From -28 to 1l  
<=1a 
Day 1 
1 
1b 
Week 2 
8 
8 - 9 
Week 4 
22 
20 - 24 
Week 6 
36 
34 - 38 
Week 8 
50 
48 - 52c 
Week 8 
50 
48 - 52d 
Week 8 (D51) 
51 
If in 48 - 53 then CRF Week 8 (D51)e 
Week 8 (D52) 
52 
If in 48 - 54 then CRF Week 8 (D52)e 
Week 10 
64 
62 - 66c 


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Table 9 Analysis visit windows 
Analysis visit (AVISIT) 
Scheduled visit day 
Visit Window (Days) 
Week 10 
64 
62 - 66f 
Week 10 (D65) 
65 
If in 62 - 67 then CRF Week 10 (D65)e 
Week 10 (D66) 
66 
If in 62 - 68 then CRF Week 10 (D66)e 
Week 12h 
78 
76 - 80c 
Week 12 h 
78 
76 - 80g 
Week 12 (D79) 
79 
If in 76 - 81 then CRF Week 12 (D79)e 
Week 12 (D80) 
80 
If in 76 - 82 then CRF Week 12 (D80)e 
Week 14 
92 
88 - 96 
Week 16 
106 
102 - 110 
Week 18 
120 
116 - 124 
Week 19i 
133 
129 - 137 
Week 23 
161 
155 - 166 
a Includes all measurements collected before or on day 1 prior to first dose of IP. If the measurement is collected 
on day 1 but it cannot be determined if it was done before or after the first dose of IP (due to missing time 
and/or planned time point), then it will be considered as collected before the first dose of IP. For height, 
weight, BMI, waist and hip circumference and lipidomics, if the measurement is collected on day 1 is always 
considered collected before the first dose of IP. 
b Includes all measurements collected at day 1 on or after the first dose of IP.  
c Only for subjects in MEDI0382 /placebo 300 μg treatment group.  
d Only for subjects in MEDI0382 /placebo 600 μg treatment group. Excluding Week 8 (D51) and Week 8 (D52). 
e Only for subjects in MEDI0382 /placebo 600 μg treatment group. 
f Only for subjects in MEDI0382 /placebo 600 μg treatment group. Excluding Week 10 (D65) and Week 10 (D66) 
g Only for subjects in MEDI0382 /placebo 600 μg treatment group. Excluding Week 12 (D79) and Week 12 (D80) 
h MRI windows is 76 – 85 
i MRI windows is 129 – 147  
l MRI scheduled visit day is from - 60 days to 1 
After having assigned the visit windows as described above, if there are measurements which 
have not yet the analysis visit assigned, they are labelled as reported in the table below.  


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Table 10 Analysis visit windows for unscheduled visits 
Analysis visit (AVISIT) 
Visit Window (Days) 
UNSCH Early Discontinuation 
1 day to 9 days (included) after last dose of IP a 
UNSCH Follow-up 
23 days to 33 days (included) after last dose of IPb 
UNSCH 1.x 
2 - 7 
UNSCH 2.x 
10 - 19 
UNSCH 4.x 
25 - 33 
UNSCH 6.x 
39 - 47 
UNSCH 8.x 
53 - 61 
UNSCH 10.x 
67 – 75  
UNSCH 12.x 
81 – 87 d 
UNSCH 14.x 
97 - 101 
UNSCH 16.x 
111 - 115 
UNSCH 18.x 
125 – 128 
UNSCH 19.x 
138 – 154f 
UNSCH 23.x 
>166 
a Unscheduled early discontinuation visit (UNSCH Early Discontinuation) is used only for subjects who 
discontinue the study IP before visit at week 19. If a measurement falls within the UNSCH Early 
Discontinuation then cannot be assigned to any other unscheduled analysis visit.  
b Unscheduled follow up visit (UNSCH Follow-up) is used only for subjects who discontinue the study before 
week 19. If a measurement falls within the UNSCH Follow-up analysis visit then cannot be assigned to any 
other unscheduled analysis visit.  
d  MRI windows is 86 – 87 
f MRI windows is 141 – 154 
The unscheduled visits will be numbered sequentially with an increment of 0.1. For example, 
if two measurements are done in the unscheduled visits that occur between visit Week 4 and 
visit Week 6, then these unscheduled visits will be numbered UNSCH 4.1 and UNSCH 4.2 in 
the order they occurred. The unscheduled visits are not summarized in tables but only 
presented in listing. 
For the purpose of the statistical analysis: 
• 
the baseline value used for statistical analyses is the last available value among those in the 
pre-treatment visit window. If several measurements are collected during the selected day, 
the average (for numeric values)/worst (for categorical values) of the measurements is 
taken. If there are several categorical values corresponding to the worst case, then the last 
measurement registered in CRF will be taken.   
• 
all the other post baseline visit values, except vital signs:  


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- 
If more than one measurement falls in the same visit window but in different days, the 
nearest to the scheduled visit day is taken.  If several measurements are collected within 
the same distance from the scheduled study day, the data of the latest visit after the 
scheduled study day within that window is used. 
- 
If several measurements are collected during the selected day, the average (for numeric 
values)/worst (for categorical values) of the measurements is taken. If there are several 
categorical values corresponding to the worst case, then the last measurement registered 
in CRF will be taken.  
• 
 post-baseline visit values for vital signs: 
- 
all eCRF planned timepoints within the same day are kept separately for the statistical 
analysis. If more than one measurement falls in the same visit window but in different 
days, the nearest to the scheduled visit day is taken. If several measurements are 
collected within the same distance from the scheduled study day, the data of the latest 
visit after the scheduled study day within that window is used. Except for Week 23, if 
the selected day has no timepoints, it cannot be considered for the statistical analysis 
and the subsequent nearest day needs to be considered. For Week 23, if several 
measurements are collected during the selected day, the average of the measurements is 
taken. 
 
3.1.3 
Study phase windows 
For the purpose of the statistical analysis primary, secondary and exploratory endpoints are 
allocated to the study phase in which they are collected as reported below. The allocation to the 
study phases (Table 11) is performed after the imputation of date of first and last doses of IP as 
in section 3.1.1. The allocation of the AEs to the study phases is performed after the imputation 
of AE start and AE end dates as reported in section 3.1.1.  
Table 11 Study phases 
Study phase 
Phase Window for Analysis (Days) 
Pre-treatment  
before first dose of study IP (day <1a) 
On-treatment  
from day 1b to day of last dose of IP (included) 
Follow-up 
> day of last dose of IP (not included) 
a Includes all measurements collected before first dose of IP. If the measurement is collected on the day of first 
dose of IP but the time of collection (or the planned timepoint) cannot determine if the measurement was 
before or after first dose of IP, then it will be considered as collected before first dose of IP. 
b Includes all measurements collected on the day of first dose of IP, at the time of IP intake and after. 
3.2 
Baseline assessments and other subject-specific characteristics 
Demographic and subject characteristics, medical history and nicotine and alcohol use are 
collected pre-treatment as per section 1.2.  


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3.2.1 
Demographic and subject characteristics 
Demographic and subject characteristics include age,  age group (<50; >=50 -<65; >=65), sex, 
race, ethnic group, country, height (cm), weight (kg), body mass index (BMI) (kg/m2), liver 
fibrosis stage (F1, F2 and F3) and type 2 diabetes mellitus. Age is the age at screening as 
reported in the eCRF. BMI (kg/m2) is calculated as: weight (kg) divided by the square of height 
(cm)/100.  
Height, weight and BMI are allocated to the concerning analysis visits as per section 3.1.2. 
Evaluations with missing or partially missing dates cannot be imputed to any analysis visit. 
Only baseline values are included in the demographic and subject characteristics. 
3.2.2 
Medical history 
Medical history  is coded in Medical Dictionary for Regulatory Activities (MedDRA) version 
21.0 or higher. Diet and exercise history are also collected.  
3.2.3 
Alcohol use  
The AUDIT questionnaire to assess detailed alcohol use habits is completed at screening. 
Alcohol use (never-current-former) including consumption frequency and unit, is also collected. 
3.3 
Efficacy and safety variables 
The primary objective of the study is the safety of MEDI0382 compared with placebo. Safety 
endpoints are the adverse events (AE) including serious adverse events (SAEs). Other safety 
endpoints included in the study are laboratory evaluations, vital signs and dECG.  
The secondary objective of the study is the efficacy of MEDI0382 compared with placebo.  
Secondary efficacy endpoints are: 
• 
Hepatic fat fraction (HFF) as assessed by magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF); 
• 
Other related imaging parameters as assessed by MRI; 
• 
Circulating markers of hepatic inflammation - ALT, AST and GGT; 
• 
Immunogenicity 
• 
Weight, BMI and waist and hip circumference 
 
 
 
 
 
 
 
 
 
 
 
Efficacy and safety endpoints are collected as reported in section 1.2. 
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3.3.1 
Primary safety endpoints  
3.3.1.1 
Adverse events 
An adverse event is the development of any untoward medical occurrence in a subject or clinical 
study subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. The term AE is used to include both serious and non-serious AEs and can 
include a deterioration of a pre-existing medical occurrence. An AE may occur at any time, 
including run-in or washout periods, even if no study treatment has been administered. SAEs 
will be collected from time of signature of informed consent, throughout the treatment period 
and including the follow-up period. All non-serious AEs will be recorded from time of first dose 
of IP, throughout the treatment period and including the follow-up period. Adverse events (AEs) 
will be coded with MedDRA version 21.0 or later. For any additional details on AE reporting 
please refer to the study protocol.  
The AEs are assigned to the study phases described in section 3.1.3, based on the AE start date 
and time as follows: 
If both the start date and start time of an AE are known, then: 
• If the AE start datetime is before the first dose of IP datetime, then the AE is assigned 
to the pre-treatment phase.  
• If the AE start datetime is on or after the first dose of IP datetime through the day of last 
dose of IP (inclusive), then the AE is assigned to the on-treatment phase, 
• If the AE start day is after the day of last dose of IP , then the AE is assigned to the 
follow-up phase. 
If only the start date of an AE is known, and the start time of the AE is unknown, then: 
• If the AE start date is before the first dose of IP date, then the AE is assigned to the pre-
treatment phase, 
• If the AE start date is on or after the first dose of IP date through the day of last dose of 
IP (inclusive), then the AE is assigned to the on-treatment phase, 
• If the AE start date if after the day of last dose of IP , then the AE is assigned to the 
follow-up phase. 
If the start date of an AE is completely missing, the AE is assigned as follow:  
• If the AE end date is known and is before the first dose of IP date, then the AE is assigned 
to the pre-treatment phase, 
• If the AE end date is completely missing or if the AE end date is on or after the first dose 
of IP date no assignation can be done. 
The study day of start of the AE is calculated as the start date of the AE - date of the first dose 
of IP +1 for AE started on or after day 1 and as the start date of the AE - date of the first dose 
of IP for AE started before day 1. Study day of start of AE is calculated for complete date only. 


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Imputed dates should not be used. If one of the dates is missing or partially missing, the study 
day of start of the AE is missing.  
All the AE in the on-treatment phase are considered treatment emergent adverse events 
(TEAEs).  
The duration of AE is calculated as the end date of the AE – start date of the AE +1. Duration 
is calculated for complete date only. Imputed dates should not be used. If one of the dates is 
missing or partially missing, the duration is missing.  
3.3.1.2 
Laboratory evaluations 
Clinical laboratory safety tests are performed in a central clinical laboratory.  
Clinical laboratory safety tests are: 
Serum chemistry 
• blood urea nitrogen  
• creatinine  
• total protein  
• albumin  
• total bilirubin (TBL)  
• alkaline phosphatase (ALP) 
• alanine aminotransferase (ALT) 
• aspartate aminotransferase (AST)  
• calcium 
• glucose (fasting where required) 
• sodium 
• potassium 
• chloride 
• bicarbonate 
• phosphorus 
• gamma glutamyl transferase (GGT) 
• calcitonin 
• thyroid stimulation hormone (TSH) 
• amylase and lipase 
Haematology 
• red blood cell count  
• haemoglobin  
• haematocrit  
• absolute white blood cell count 
• white blood cell count with percent differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
• platelet count 
• mean cell volume 
• mean corpuscular haemoglobin concentration 
• mean corpuscular haemoglobin 


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Coagulation parameters 
• prothrombin time  
• activated partial thromboplastin time 
• thrombin time 
• international normalized ratio 
Urinalysis 
• pH (quantitative) 
• specific gravity (quantitative) 
• glucose (qualitative) 
• blood (qualitative) 
• colour (qualitative) 
• appearance (qualitative) 
• Ketones (qualitative) 
• Nitrites (qualitative) 
• Protein (qualitative) 
• Bilirubin (qualitative) 
• Leukocytes (qualitative) 
• Urobilinogen (qualitative) 
Laboratory data are assigned to the analysis visits and the study phases as described in section 
3.1.2 and section 3.1.3 respectively. Evaluations with missing or partially missing dates cannot 
be imputed to any study phase and analysis visit.  
Laboratory test results for haematology, coagulation, clinical chemistry and urinalysis 
quantitative parameters below the lower limit of quantification (LLOQ) for which the exact 
value cannot be determined, will be replaced with the LLOQ divided by the squared root of 2. 
After the LLOQ replacement, change from baseline to each post-baseline visit for haematology, 
coagulation, clinical chemistry and urinalysis quantitative parameters is defined as the post-
baseline visit value minus the baseline visit value. 
After the LLOQ replacement, haematology, coagulation, clinical chemistry and urinalysis 
quantitative parameters are also classified as normal (if value is within normal reference range), 
low (if value is below the normal reference range), and high (if value is above the normal 
reference range) based on the reference range indicator.  
After the LLOQ replacement, AST, ALT and total Bilirubin are also classified as below: 
AST and ALT: 
• <3xULN (or below the LLOQ) 
• ≥3 - <5xULN 
• ≥5 - < 8xULN 
• ≥8xULN 
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• <1xULN (or below the LLOQ, only for measurements at baseline) 
• <2xULN (or below the LLOQ, for all the other non-baseline value) 
• ≥2xULN (for all the other non-baseline value) 
Occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN are reported as 
SAE (Potential Hy´s law) as described in the study protocol. 
3.3.1.3 
Vital signs 
Vital signs include: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Heart rate (bpm) 
• Respiratory rate (breaths per minute) 
• Temperature (C) 
• Rate pressure product - RPP (mmHg*bpm) – derived variable 
The rate pressure product (RPP) is calculated as heart rate * systolic blood pressure.  Heart rate 
and systolic blood pressure should come from the same day, same timepoint.  
Vital signs parameters are assigned to the analysis visits as described in section 3.1.2. 
Evaluations with missing or partially missing dates cannot be imputed to any analysis visit. 
Vital signs parameters are also allocated to timepoints within visit based on eCRF timepoints. 
eCRF timepoints at day 1 are: 
• 15 min 
• 30 min 
• 60 min 
• 2 hours 
eCRF timepoints at day 8, 22, 36, 50, 64, 78 and 133 are: 
• Pre-dose  
• 15 min 
• 30 min 
• 60 min 
• 2 hours 
eCRF timepoints at day 92, 106, 120 is 
• Pre-dose  
eCRF timepoints at day 51, 52, 65, 66, 79 and 80 are: 
• Pre-Dose mean of supine measurements 
• Pre-Dose mean of standing measurements 
Change from baseline is defined as the post-baseline visit value minus the baseline value.  


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Additionally, vital signs values will be classified as normal (if value is within normal reference 
range), low (if value is below the normal reference range), and high (if value is above the normal 
reference range) according to the normal reference ranges (Table 12): 
Table 12 Vital signs normal reference ranges 
Parameter 
Normal Reference Ranges 
Systolic blood pressure 
80 - 130 mmHg 
Diastolic blood pressure 
50 -80 mmHg 
Heart rate 
50 - 100 bpm 
Respiratory rate 
12 - 24 breaths per minute 
Temperature 
 <=37ºC 
 
Systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate (bpm) and Rate 
pressure product - RPP (mmHg*bpm) are also measured using the ambulatory blood pressure 
monitoring (ABPM) device. The subject wears the monitor/cuff for approximately 24 hours 
(including overnight at home). The 24-hour window is based on the start of the recording, which 
will begin with the first valid inflation. Any data collected after the 24-hour window will be 
excluded from the analysis. 2 inflations per hours are performed during day hours (from 6:00:00 
to 22:00:00). 1 inflation per hours is performed during night hours (from 22:00:00 to 6:00:00).  
ABPM parameters are calculated as below: 
Complete ABPM systolic blood pressure, diastolic blood pressure and heart rate are derived as 
the arithmetic means of the single measurements in the 24h.  
Day ABPM systolic blood pressure, diastolic blood pressure and heart rate are derived as the 
arithmetic means of the single measurements considering only the day hours. Day hours from 
6:00:00 to 22:00:00 are included. 
Night ABPM systolic blood pressure, diastolic blood pressure and heart rate are derived as the 
arithmetic means of the single measurements considering only the night hours. Night hours from 
22:00:01 to 05:59:59 are included. 
Single measurements with missing or zero numeric values or out of acceptable range values (as 
per table below) or for which the visit status is set to not done should not be used in the 
calculation.  
 
Table 13 ABPM acceptable ranges 
Parameter 
ABPM acceptable ranges 
Systolic blood pressure 
10 - 250 mmHg 
Diastolic blood pressure 
5 - 200 mmHg 
Heart rate 
1 – 200 bpm 


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The ABPM rate pressure product (RPP) is calculated as heart rate * systolic blood pressure. 
Heart rate and systolic blood pressure should come from the same day, same timepoint 
(complete-night and day).   
Additionally, the entire visit, for all the parameters, should be considered of poor quality and so 
discarded from the analysis if any of the following is true: 
• there are less than 18 valid hours out of the total 24 hours (a valid hour is when there is 
at least one valid measurement during that hour) for at least one of the parameters.  
• there are more than 3 consecutive missing hours out of the 24 total hours (missing hour 
is when there are not valid measurements during that hour) for at least one of the 
parameters.  
• there are less than the 70% of successful measurements out of the total measurement 
recorded for at least one of the parameters. 
ABPM parameters are then assigned to the analysis visits as described in section 3.1.2. 
Evaluations with missing or partially missing dates cannot be imputed to any analysis visit. 
3.3.1.4 
dECG 
dECG evaluation includes: 
• PR interval (msec) 
• QRS duration (msec) 
• QT interval (msec) 
• Heart rate (beats/min) 
• QTcB interval (msec) 
• QTcF interval (msec) 
• Overall evaluation (normal, abnormal, borderline). If abnormal also reason and 
clinically significance is collected 
 
dECG parameters are assigned to analysis visits and study phases as described in section 3.1.2 
and section 3.1.3 respectively. Evaluations with missing or partially missing dates cannot be 
imputed to any study phase and analysis visit. 
dECG last observation on treatment is defined as last available value among those in the on-
treatment study phase. 
Change from baseline is defined as the post-baseline visit value minus the baseline value. 
Additionally, dECG values will be classified as normal (if value is within normal reference 
range), low (if value is below the normal reference range), and high (if value is above the normal 
reference range) according to the below normal reference ranges: 


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Table 14 dECG normal reference ranges 
Parameter 
Normal Reference Ranges 
PR interval 
110 – 220 msec 
QRS duration 
75 – 115 msec 
QT interval 
320 – 450 msec 
Heart rate 
50 – 100 beats/min 
QTcB interval 
320 – 450 msec 
QTcF interval 
320 – 450 msec 
 
QTcF intervals are classified also as: 
• >=450 msec 
• >=480 msec 
• >=500 msec 
QTcF increases respect to baseline are classified as: 
• >=30 msec 
• >=60 msec 
• >=90 msec 
3.3.2 
Secondary efficacy endpoints  
Secondary efficacy endpoints are: 
• Hepatic fat fraction (HFF) as assessed by MRI-PDFF  
• Other related imaging parameters as assessed by MRI  
• Circulating markers of hepatic inflammation  
• Immunogenicity 
• Weight, BMI and waist and hip circumference 
3.3.2.1 
Hepatic fat fraction (HFF) as assessed by MRI-PDFF  
Hepatic fat fraction (HFF) is assessed by MRI-PDFF in a central external laboratory. HFF is 
assigned to the analysis visits as described in section 3.1.2. Measurements with missing or 
partial missing dates are not assigned to any analysis visit.  Change from baseline is defined as 
the post-baseline visit value minus the baseline value; percent change from baseline is 
calculated as the visit value minus the baseline value dived by the baseline value *100. 
 
  
 
 
 
 
 
 
 
 
 
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3.3.2.3 
Circulating markers of hepatic inflammation  
Circulating markers of hepatic inflammation are: 
• alanine aminotransferase (ALT) 
• aspartate aminotransferase (AST) 
• gamma glutamyl transferase (GGT) 
These parameters are tested in a central external laboratory. All these parameters are assigned 
to the analysis visits as described in section 3.1.2. Measurements with missing or partial missing 
dates are not assigned to any analysis visit.   
ALT, AST and GGT below the LLOQ for which the exact value cannot be determined, will be 
replaced with the LLOQ divided by the squared root of 2. 
After the LLOQ replacement, change from baseline is defined as the post-baseline visit value 
minus the baseline value; percent change from baseline is calculated as the visit value minus 
the baseline value dived by the baseline value *100. 
3.3.2.4 
Immunogenicity 
Immunogenicity parameters are: 
• Anti-drug antibody (ADA) 
• Immunogenicity titer 
• ADA cross-reactivity to GLP-1 
• ADA cross-reactivity to glucagon 
These parameters are tested in an external laboratory. A validated screening assay will be used 
to determine ADA positive samples. Any positive samples will be tested in a confirmatory assay 
whereby the specificity of the ADA response will be confirmed as either positive or negative 
with respect to MEDI0382. Titer evaluation and cross-reactivity to GLP-1 and glucagon may 
be performed on samples that are confirmed positive for ADA. All these parameters are assigned 
to the analysis visits as described in section 3.1.2. Measurements with missing or partial missing 
dates are not assigned to any analysis visit.  
ADA positive sample with titers below the LLOQ (<=15) will be replaced with the LLOQ (15). 
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3.3.2.5 
Weight, BMI and waist and hip circumference 
Waist to hip ratio is calculated as waist measurement divided by hip measurement. 
Measurements should be done the same day.  Weight (kg), BMI (kg/m2) , waist and hip 
circumference (cm) and waist to hip ratio are assigned to analysis visits as described in section 
3.1.2. Measurements with missing or partial missing dates are not assigned to any analysis 
visit.  Change from baseline is defined as the post-baseline visit value minus the baseline 
value; percent change from baseline is calculated as the visit value minus the baseline value 
dived by the baseline value *100. 
3.3.3 
Exploratory endpoints  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
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3.4 
Exposure and treatment compliance 
As per study protocol, subjects start the subcutaneous (SC) injections of the study IP at day 1. 
From day 1 to day 7 (included) the injections are performed at site. Starting from day 8, study 
IP is dispensed to the subject for self-administration at home. Dispensation visits are: 
• 
Day 8 
• 
Day 22 
• 
Day 36 
• 
Day 50 
• 
Day 64 
• 
Day 78 
• 
Day 92 
• 
Day 106 
• 
Day 120 
At the dispensation visits the site provide the subject with the number of vials required from the 
current visit (included) and up to the next visits (excluded) considering that the Subjects should 
self-inject 1 vial per day. Subjects must return any unused investigational product, and the 
sharps bin, at their next visit to the clinical site. Number of dispensed vials and number of 
returned vials are collected in CRF at each dispensation visits. 
Except for the first week, for all the other in-site visits the study IP is administered by site 
personnel taken the kit from the kit stock of vials dispensed.  
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3.4.1 
Exposure 
Exposure (days) is calculated only for subjects in the as-treated population as the total number 
of days on study drug (i.e., gaps in dosing due to study drug interruption will not be taken-out 
from the calculation).  Exposure is calculated as the study drug dose last date minus study drug 
dose first date plus one. If any of the first or last dates are missing or partially missing, then 
imputed dates will not be used, and study drug exposure is set to missing.  
Actual exposure (days) is calculated as the total number of days of effective study drug intake 
(i.e., gaps in dosing due to study drug interruption will be taken-out from the calculation). In 
this way, the subject’s dosing can be reduced to a series of unbroken intervals within each, the 
exposure is calculated as study drug dose stop date minus the study drug dose start date plus 
one. Actual exposure is then derived as the sum of exposures over all the unbroken intervals.  
If any of the start or stop dates are missing or partially missing for an interval, study drug 
exposure for that interval is set to missing. Actual exposure is the sum over only the intervals 
where drug exposure was not set to missing.  
Cumulative exposure and cumulative actual exposure (day) is also computed based on exposure, 
using the following duration (days) categories: 
• 
>=8 
• 
>=22 
• 
>=36 
• 
>=50 
• 
>=64 
• 
>=78 
• 
>=92 
• 
>=106 
• 
>=120  
3.4.2 
Compliance 
Overall compliance to the IP is calculated only for subjects in the as-treated population. 
The percent compliance is defined as the total number of vials consumed divided by the total 
number of vials that should have been taken where, total number of vials consumed will be 
calculated as: Total number of vials dispensed – Total number of vials returned and the total 
number of vials that should have been taken is the exposure in days. 
No replacement of missing data is performed. Therefore, if one of the total number of vials 
dispensed, total number of vials returned, or duration of exposure is missing the resulting 
compliance is missing.  
Compliance is also categorized as: 
• 
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• 
≥ 80% to < 120% 
• 
≥ 120% 
3.5 
Concomitant medications 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as restricted and 
prohibited as listed in the study protocol and detailed (coding and indication wherever 
applicable) in the in the Integrated Data Review Plan (IDRP) 
The WHO-DD March 2019 B3 Global or higher is used to classify medications by WHO 
Anatomical Therapeutic Chemical (ATC) classification of ingredients.  
The imputation method described in section 3.1.1.5 is used in case of medication stop date 
partially missing. Completely missing stop date are not be imputed. Both, completely missing 
and partially missing concomitant medication start dates are not imputed. 
After the end date imputation, the medications will be classified as either prior or concomitant 
(but not both) according to its stop date. Prior medication is defined as any medication with a 
stop date prior to the first dose of study drug (exclusive). Concomitant medication is defined as 
any medication with a stop date on or after the first dose of study drug, or any medication that 
is ongoing at study end. Medications with completely missing stop date are classified as 
concomitant. 
Prohibited and restricted concomitant medications are confirmed and flagged by the study 
physician in accordance with the study protocol. 
4 
ANALYSIS METHODS 
4.1 
General principles 
Data will be summarized using descriptive statistics, by treatment group which consist of 
MEDI0382 300 μg, MEDI0382 600 μg and placebo, where the placebo group includes the 2 
doses of 300 μg and 600 μg of placebo. Data will be summarized at each visit. 
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
SD, median, minimum and maximum. 
For categorical variables and unless otherwise specified, the number and percentages of subjects 
by categories will be tabulated. Percentages will be calculated based on the number of subjects 
with no missing data, i.e., will add up to 100%. Categories with count of zero will be not 
displayed. 
All efficacy, exploratory and safety endpoints will be summarized by treatment group and at 
each visit as appropriate using descriptive statistics as above. Unscheduled visits will be only 
listed. For continuous variables, descriptive statistics will be summarized for the observed 
values, the changes from baseline and the percent change from baseline.  


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Changes from baseline, in certain categorical variables will be summarized using shift tables. 
The number and percent of subjects within each treatment group will be generated for each 
category post-baseline by baseline category.  
If not otherwise specified, all the analyses will include the post IP-discontinuation data for those 
subjects who discontinue from study treatments but are still followed up for their scheduled 
visits. 
The following statistical models will be used to compare MEDI0382 300 μg versus placebo and 
MEDI0382 600 μg versus placebo for some of the study endpoints: 
4.1.1 
Analysis of covariance (ANCOVA)  
The ANCOVA model will be used to fit change and percent change at week 12 and week 19.  
Data used in the model are data from baseline and the scheduled tested visit. The group of 
treatment will be considered as a fixed effect of the model while the baseline value as covariate. 
Comparisons of MEDI0382 300 μg versus placebo and MEDI0382 600 μg versus placebo will 
be assessed within the same model. The restricted maximum likelihood (REML) approach will 
be used for the estimation of the variance and covariance parameters of the linear mixed model; 
two-sided difference test, with alpha level at 5% will be used for the comparisons and for the t-
type confidence interval calculation.  
Unless otherwise specified, last observation carried forward (LOCF) method will be applied to 
handle missing data, that is, a missing endpoint will be replaced with the last available post-
baseline measurement prior to the missing endpoint. 
The residual errors on the model will be evaluated for Normality using residual panel plots in 
order to validate the model results. 
The reportable results from the model will be: 
• 
The least-square means (LSmeans) and their standard errors for each group  
• 
The difference between active groups and placebo (LSmean difference) together with its 
confidence interval (CI)  
• 
The p-value for the difference between active groups and placebo 
For exploratory endpoints, if the parameter results to be normally distributed, the variable fitted 
in the model will be the change from baseline; the ANCOVA model and the reportable results 
will be those described above.  
On the other hand, if the parameter results to be log-normally distributed, the variable fitted in 
the model will be the change from baseline in logarithmical scale. Change from baseline in 
logarithmical scale is defined as the log-transformation of the post-baseline visit value minus 
the log-transformation of the baseline value. 
The ANCOVA model will be as described above but the reportable results from the model will 
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• 
Back transformed LSmeans for each group, which correspond to the estimated percent 
change from baseline; back transformed LSmeans is derived as [EXP( LSMean)-1]*100,  
• 
95%CI of the back transformed LSmeans for each group; 95%CI of the back transformed 
LSmeans is derived as [EXP(Lower)-1]*100; [EXP(Upper)-1]*100. 
• 
The ratio between active groups and placebo; the ratio is calculated as EXP( LSMean 
differnce )*100 
• 
The 95%CI of the ratio; the 95%CI of the ratio is calculated as [EXP(Lower)]*100; 
[EXP(Upper)]*100. 
• 
P-value 
 
To be noted that a ratio lower than 1 means that the active group shows a higher decrease (or a 
lower increase) compared to the placebo group. On the other hand, a ratio greater than 1 means 
that the active group shows a lower decrease (or a higher increase) compared to the placebo 
group. 
4.1.2 
Sensitivity analysis 1 – the mixed model repeated measures (MMRM)  
The sensitivity analysis 1 will be used only at final analysis and will consists on fitting a MMRM 
to percent change from baseline. Tested visits within the MMRM model are week 12 and week 
19. Data used in the model come from all previous available scheduled visits. Fixed factors of 
the model will be treatment, visit and treatment*visit interaction. The baseline value will be 
used as covariate. Visit within subject will be considered as repeated measurements. 
Comparisons of MEDI0382 300 μg versus placebo and MEDI0382 600 μg versus placebo will 
be assessed within the same model. The restricted maximum likelihood (REML) approach will 
be used for the estimation of the variance and covariance parameters of the linear mixed model; 
two-sided difference test, with alpha level at 5% will be used for the comparisons and for the t-
type confidence interval calculation. 
The model will use the SP (POW) structure for unequally spaced data variance-covariance 
matrix as default. Visit will be expressed as planned days to accomplish the variance-covariance 
matrix estimation.  
In case the model will not converge for any reasons, the following back-up solutions will be 
adopted sequentially: 
1. The compound symmetry (CS) will be used instead of the SP (POW) 
2. The unstructured (UN) will be used instead of the CS 
The residual errors on the model will be evaluated for Normality using residual panel plots in 
order to validate the model results. 
The reportable results from the model will be: 
• 
The least-square means (LSmeans) and their standard errors for each group  
• 
The difference between active groups and placebo (LSmean difference) together with its 
confidence interval (CI)  
• 
The p-value of the difference 


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4.1.3 
Sensitivity analysis 2 - the Wilcoxon Sum Rank test 
Th sensitivity analysis 2 will consist on calculating the Wilcoxon Sum Rank test on percent 
change at week 12 and week 19. Data used in the model are data from baseline and the scheduled 
tested visit. Comparisons of MEDI0382 300 μg versus placebo and MEDI0382 600 μg versus 
placebo will be both assessed using this test.  
Unless otherwise specified, last observation carried forward (LOCF) method will be applied to 
handle missing data, that is, a missing endpoint will be replaced with the last available post-
baseline measurement prior to the missing endpoint. 
The reportable results will be: 
• 
Median, interquartile range, minimum and maximum of the percent change from baseline 
for each group  
• 
The p-value for the difference between active groups and placebo 
 
4.1.4 
Sensitivity analysis 3 
The sensitivity analysis 3 will consist of repeating the descriptive analysis and the ANCOVA 
model on the same population used for the main analysis but including only data in the on-
treatment phase.  Sensitivity analysis 3 will be performed at Interim analysis and at final analysis 
only for HFF and ALT. Data in the on-treatment phase are: 
• 
For HFF all data done before or on the day of last IP + 14 days 
• 
For ALT all data done before or on the day of last IP + 4 days  
 
4.1.5 
Sensitivity analysis 4 
The sensitivity analysis 4 will consist of repeating the descriptive analysis and the ANCOVA 
model on the PP population. It will be performed at Interim analysis and at final analysis only 
for HFF and ALT.  
4.1.6 
Logistic model 
The logistic model will be used to fit proportion of subjects with post-treatment HFF (absolute) 
< 5% and proportion of subjects with percent decrease from baseline in HFF ≥ 30% at week 12 
and at week 19. Data used in the model are data from baseline and the scheduled tested visit. 
The group of treatment will be considered as a fixed effect of the model while the baseline value 
as covariate. Comparisons of MEDI0382 300 μg versus placebo and MEDI0382 600 μg versus 
placebo will be assessed within the same model. Two-sided difference test, with alpha level at 
5% will be used for the comparisons and for the Wald confidence interval calculation.  
Unless otherwise specified, last observation carried forward (LOCF) method will be applied to 
handle missing data, that is, a missing endpoint will be replaced with the last available post-
baseline measurement prior to the missing endpoint. 


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The reportable results from the model will be: 
• 
The odds ratio between active groups and placebo together with its confidence interval (CI) 
by the exact method 
• 
The p-value for the odds ratio between active groups and placebo 
4.2 
Analysis of variables 
4.2.1 
Disposition of subjects 
Subject dispositions (number and percentage of subjects enrolled, subjects randomized, subjects 
who received at least one dose of study IP, subjects who completed the treatment and subjects 
who completed the study) will be presented in a summary table for each treatment group and 
overall.  A listing including all standardized disposition terms will be also provided for all 
discontinued subjects. Both, the table and the listing will be based on all enrolled subjects 
population. 
A Summary of COVID-19 study disruptions will be also presented. Listings of subjects affected 
by pandemic situation and the CTMS issues due to pandemic are also included.  
The number of subjects belonging to each analysis population will be presented in a separate 
summary table for each treatment group. The table will be based on all enrolled subjects 
population. Listings of all subjects excluded from the ITT population and from the as-treated 
population will be also provided. The listings will include reason for exclusion from respective 
population and will be based on all enrolled subjects population. 
Randomization code and actual kit are also listed. 
4.2.2 
Important protocol deviations 
The number and percentage of subjects with at least one IPD will be summarized following the 
NHP categories, for each treatment group and overall.  
All IPD will be also listed for all subjects included in the ITT population. 
4.2.3 
Baseline assessment and other subject-specific characteristics 
4.2.3.1 
Demographic and subject-specific characteristics 
All demographic and subject-specific characteristics reported in section 3.2.1 will be presented 
in summary tables for each treatment group and overall; Age, height, weight and BMI will be 
summarized descriptively as continuous variable with n, mean, median, SD, minimum, and 
maximum; all the other demographic and subject-specific characteristics will be summarized as 
categorical variables with the number and percentages of subjects by categories. Only the 
baseline measurement for height, weight and BMI will be considered. 
All demographic and subject-specific characteristics will be also provided in listings.  


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The tables and the listings will be based on the ITT population. Baseline and post-baseline 
definitions are detailed in section 3.1.2. 
4.2.3.2 
Medical history 
Relevant medical history as described in section 3.2.2 will be presented in summary tables as 
number and percentages of subjects by System Organ Class (SOC) and Preferred Term (PT) for 
each treatment group and overall.  Subjects with multiple events in the same SOC/PT will be 
counted only once in that SOC/PT. Subjects with events in more than one SOC/PT will be 
counted once in each of those SOC/PT. The table will be sorted alphabetically by SOC and PT 
and will be based on the ITT population.  
Diet and exercise history will be presented in summary table for each treatment group and 
overall. The table will be based on the ITT population. 
4.2.3.3 
Alcohol use 
Alcohol use as described in section 3.2.3 will be presented in summary table as number and 
percentages of subjects for each treatment group and overall. AUDIT questionnaire as described 
in section 3.2.3 will be also summarized together with alcohol use, as number and percentages 
of subjects for each question in the questionnaire. The table will be based on the ITT population. 
4.2.4 
Primary safety endpoints  
4.2.4.1 
Adverse events 
After having assigned the AEs to the corresponding study phase as described in section 3.3.1.1, 
the AEs will be summarized for each treatment group. The AEs tables will be based on the as-
treated population. Summary tables will include AEs in the on-treatment phase and AEs in the 
follow-up phase.  
Summary tables are listed below. 
An overview table containing: 
• 
Number and percentage of subjects with any AEs 
• 
Number and percentage of subjects with any AEs leading to death 
• 
Number and percentage of subjects with any SAEs 
• 
Number and percentage of subjects with any AEs leading to discontinuation of IP 
• 
Number and percentage of subjects with any AEs leading to withdrawal from study 
The following summary tables will be presented by SOC and PT: 
• 
The number and percentage of subjects with any AEs 
• 
The number of AEs 
• 
The number and percentage of subjects with AEs with outcome of death,  
• 
The number and percentage of subjects with SAEs  
• 
The number of SAEs 


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• 
The number and percentage of subjects with AEs leading to discontinuation.  
• 
The number and percentage of subjects with any AEs by maximum reported intensity.  
• 
The number and percentage of subjects with any AEs and investigator’s causality 
assessment. If a subject has multiple events in the same PT, the event with the strongest 
relationship will be counted. 
The number and percentage of subjects with most common AEs (frequency of >5%) will be 
presented by PT. 
Where number of subjects with AEs are summarized by system organ class (SOC) and/or 
preferred term (PT) , subjects with multiple events in the same SOC/PT are counted only once 
in that SOC/PT. Subjects with events in more than 1 SOC/PT are counted once in each of those 
SOCs/PTs.  
Additionally, the following tables will be presented: 
• 
the number of subjects with serious adverse events, by seriousness criteria. 
• 
the number and percentage of subjects with non-serious AEs occurring with a frequency > 
5.0% in any treatment group for each SOC and PT. This table will be produced as a separate 
pdf output to meet clinical trial transparency requirements and not for inclusion in the 
clinical study report (CSR). It will be delivered at the same time as the CSR outputs. 
• 
the number of subjects with injection site reactions by high level term (HLT) and PT. 
A list of key subject information for subjects with AEs with outcome of death, subjects with 
SAEs, and subjects with AEs leading to discontinuation of IP will be provided. The durations 
reported in these tables, will be derived only for fully completed dates as below: 
• 
Time from first dose of IP to AE (in days) will be calculated as the AE start date minus date 
of dose +1.  
• 
Time from first dose to death (in days) will be calculated as the date of death minus date of 
dose +1.  
• 
The same approach will be used for deriving time from start of treatment to AE becoming 
serious or discontinuation. 
• 
Time from last dose prior to AE start and last dose prior to death will be calculates as the 
date of death minus the date of last dose prior to AE/death +1. 
Lastly, a specific table presenting the event rate by period for nausea and vomiting and the 
corresponding bar-charts and line plots will be also provided. The event rate is calculated as: 
Total number of events when subjects are on study IP in the selected period divided by the total 
person-days of exposure to study IP for the whole relevant arm in the selected period. The total 
person-days of exposure is the sum of all the exposures, in days, of all the subjects who are ever 
exposed to study IP within the specific period, in the relevant arm, for the selected period.  
For numerator calculation during a period (e.g. the first 1-week analysis), if an event is onset at 
day 1 and ends at day 3, then it will be counted as one event for this period. For numerator 


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calculation, if an event is onset at day 1 and ends at day 9, then this event will be counted as an 
event for both week 1 analysis and week 2 analysis. Only on-treatment days (from first dose to 
last dose of IP) will be included in the denominator calculation of exposure (person-days); 
consequently, only events on those on-treatment days will be included in the numerator 
calculation. In the rare case in which there is a gap in dosing of more than 7 days, the inclusion 
of the AE which started during the gap period and the exposure days calculation should be 
evaluated case by case.  
All the AEs regardless of the study phases will be also listed for all subjects included in the as-
treated population.  
4.2.4.2 
Laboratory evaluation 
Laboratory evaluation are described in section 3.3.1.2. Baseline and post-baseline definitions 
are detailed in section 3.1.2. All tables and listings for laboratory data will be based on the as-
treated population and presented for each treatment group. 
Laboratory test results for haematology, coagulation, clinical chemistry and urinalysis 
quantitative parameters will be summarized in SI units with n, mean, SD, median, minimum, 
and maximum at each visit and for change from baseline. Shifts from baseline to maximum and 
minimum value during the on-treatment phase will be also presented. 
Shifts from baseline to maximum value during the on-treatment phase will be presented for 
urinalysis qualitative parameters and AST, ALT and total bilirubin in class.  
All laboratory data for haematology, coagulation, clinical chemistry and urinalysis will be also 
presented in listings.  
In addition to the tables above also the maximum on-treatment ALT and AST by maximum 
total bilirubin for assessing Hy’s law criteria, the eDISh plot for ALT and total bilirubin, a list 
of key subject information for subjects with potential Hy’s law as described in the study protocol 
and a list of key subject information for subjects with ALT or AST≥8xULN or total bilirubin 
≥2xULN during the on-treatment phase will be presented.  
4.2.4.3 
Vital signs 
Vital signs and ABPM parameters are described in section 3.3.1.3. Baseline and post-baseline 
definitions are detailed in section 3.1.2. Vital signs tables and listings will be based on the as-
treated population and presented for each treatment group.  
Vital signs will be summarized descriptively as continuous variables with n, mean, median, SD, 
minimum, and maximum, at each visit and timepoint within visit and for change from baseline. 
Orthostatic measures supine are included in this summary table.  
Observed values and change from baseline in systolic blood pressure, diastolic blood pressure, 
heart rate and rate pressure product (RPP) measurements will be also presented in figures with 


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mean and standard error of the mean (SE). Only measurements done pre-dose will be plotted; 
orthostatic measures at day 51, 52, 65, 66, 79 and 80 will be not included. 
The number of subjects in SBP change categories with maximum heart rate change from 
baseline > 20 bpm at concurrent visit will be also summarized. Only measurements done pre-
dose will be considered; measures at day 51, 52, 65, 66, 79 and 80 will be not included. 
All vital signs data, including orthostatic measures at day 51, 52, 65, 66, 79 and 80 will be listed. 
The listing will include reference ranges and classification of vital signs as normal, low and 
high. 
For systolic blood pressure, diastolic blood pressure, heart rate and rate pressure product an 
ANCOVA model as described in section 4.1 for change at week 12 and at week 19 will be also 
presented. Tested visits are the pre-dose measurements at week 12 and at week 19. 
ABPM parameters (complete ABPM SBP, complete ABPM DBP, complete ABPM heart rate, 
complete ABPM RPP, day ABPM SBP, day ABPM DBP, day ABPM heart rate, day ABPM 
RPP, night ABPM SBP and night ABPM DBP, night ABPM heart rate, night ABPMRPP) will 
be summarized descriptively as continuous variables with n, mean, median, SD, minimum, and 
maximum, at each visit and for change from baseline. Summary statistics are calculated 
excluding values = 0 for heart rate, systolic blood pressure and diastolic blood pressure, values 
< 80 mmHg for systolic blood pressure and values < 50 or > 120 mmHg for diastolic blood 
pressure. 
Observed values in complete ABPM systolic blood pressure, diastolic blood pressure, heart rate 
and rate pressure product (RPP) measurements will be also presented in figures with mean and 
standard error of the mean (SE).   
4.2.4.4 
dECG 
dECG parameters are described in section 3.3.1.4. Baseline and post-baseline definitions are 
detailed in section 3.1.2. dECG tables and listings will be based on the as-treated population 
and presented for each treatment group. 
dECG parameters (except for the overall evaluation) will be summarized in SI units with n, 
mean, median, SD, minimum, and maximum, at each visit and for change from baseline.  
Number and percentage of subjects within each QTcF intervals classes at any time during the 
on-treatment phase will be also reported together with number and percentage of subjects within 
QTcF increase classes at any time during the on-treatment phase.  
Overall evaluation will be analysed as shift from baseline to last value in the on-treatment phase.  
dECG parameters will be also listed for all subjects. Overall evaluation will be listed for subjects 
with clinically significant abnormalities.  


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4.2.5 
Secondary efficacy endpoints  
4.2.5.1 
Hepatic fat fraction (HFF) as assessed by MRI-PDFF  
HFF is described in section 3.3.2.1. Baseline and post-baseline definitions are detailed in section 
3.1.2. Tables and listings will be based on the ITT population and presented for each treatment 
group. 
HFF will be summarized descriptively as continuous variable with n, mean, median, SD, 
minimum, and maximum, at each analysis visit and for change and percent change from baseline 
and separately for subjects who have and don’t have type 2 diabetes mellitus. Observed value, 
change and percent change of HFF will be also presented in figure with mean and standard error 
of the mean (SE) by visit.  
An ANCOVA model as described in section 4.1 for change and percent change of HFF, at week 
12 and at week 19 will be also presented. In addition of what reported in section 4.1, also the p-
value of the LSmeans is reported for each group.  
An ANCOVA model as described above for change and percent change of HFF, at week 12 and 
at week 19 will be also presented for subjects in active treatment (MEDI0382 300 μg or 
MEDI0382 600 μg) versus placebo. 
Sensitivity analyses 1, 2, 3 and 4 as described in section 4.1 will be also performed with the aim 
to consolidate the results obtained with the previous ANCOVA model. 
HFF will be also reported in listing. 
4.2.5.2 
Other related imaging parameters as assessed by MRI  
All the other related imaging parameters are described in section 3.3.2.2. Baseline and post-
baseline definitions are detailed in section 3.1.2. Tables and listings will be based on the ITT 
population and presented for each treatment group. 
All parameters will be summarized descriptively as continuous variable with n, mean, median, 
SD, minimum, and maximum, at each analysis visit and for change and percent change from 
baseline.  
An ANCOVA model as described in section 4.1 for change and percent change for each 
parameter, at week 12 and at week 19 will be also presented. 
All parameters will be also reported in listing. 
4.2.5.3 
Circulating markers of hepatic inflammation  
ALT, AST and GGT are described in section 3.3.2.3. Baseline and post-baseline definitions are 
detailed in section 3.1.2. Tables and listings will be based on the ITT population and presented 
for each treatment group. 


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ALT, AST and GGT will be summarized descriptively as continuous variable with n, mean, 
median, SD, minimum, and maximum, at each analysis visit and for change and percent change 
from baseline. Observed value, change and percent change of ALT will be also presented in 
figure with mean and standard error of the mean (SE) by visit. 
An ANCOVA model as described in section 4.1 for change and percent change, at week 12 and 
at week 19 will be also presented. 
All circulating markers will be also reported in listing. 
For the alanine aminotransferase (ALT) the sensitivity analyses 1, 2, 3 and 4 as described in 
section 4.1 will be also performed with the aim to consolidate the results obtained with the 
above ANCOVA model.  
4.2.5.4 
Immunogenicity 
Immunogenicity parameters are described in section 3.3.2.4. Baseline and post-baseline 
definitions are detailed in section 3.1.2. Immunogenicity parameters tables and listings will be 
based on the as-treated population and presented for each treatment group. 
ADA, ADA cross-reactivity to GLP-1 and ADA cross-reactivity to glucagon will be 
summarized as categorical variables with the number and percentages with a positive result at 
the specific visit. ADA titers will be summarized descriptively as continuous variable, only for 
ADA positive tests, with median, interquartile range, minimum, and maximum, at each analysis 
visit. 
ADA, ADA cross-reactivity to GLP-1 and ADA cross-reactivity to glucagon will be also 
summarized including the following: 
• ADA prevalence: subjects who are ADA positive at any visit (including baseline)  
• Subjects who are ADA positive at baseline only  
• Subjects who are ADA positive at baseline and have at least one positive value post 
baseline  
• Subjects who are not ADA positive at baseline and have at least one positive value post-
baseline only (treatment-induced ADA) 
• Subjects who are persistently positive; persistently positive is defined as at least 2 post-
baseline ADA positive measurements (with >=16 weeks apart) or an ADA positive 
result at the last available assessment 
• Proportion of subjects who are transiently positive; transiently positive is defined as at 
least one post-baseline ADA positive measurement and not fulfilling the conditions for 
persistently positive 
• Proportion of subjects who are treatment-boosted ADA; treatment-boosted ADA is 
defined as baseline ADA titer that was boosted to a 4-fold or higher level following drug 
administration   
• ADA incidence (treatment-emergent ADA), defined as the sum of treatment-induced 
ADA (post-baseline positive only) and treatment-boosted ADA 
 
Post baseline includes on-treatment and follow-up phases. 


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All immunogenicity parameters will be also reported in listing. 
4.2.5.5 
Weight, BMI and waist and hip circumference 
Weight, BMI, waist circumference and waist to hip ratio are described in section 3.3.2.5. 
Baseline and post-baseline definitions are detailed in section 3.1.2. Tables and listings will be 
based on the ITT population and presented for each treatment group. 
Weight, BMI, waist circumference and waist to hip ratio will be summarized descriptively as 
continuous variables with n, mean, median, SD, minimum, and maximum, at each analysis visit 
and for change and percent change from baseline.  
Observed value, change and percent change of weight will be also presented in figure with Mean 
and standard error of the mean (SE) by visit.  
An ANCOVA model as described in section 4.1 for change and percent change of weight and 
for change in BMI will be also presented. 
Weight, BMI, waist circumference and waist to hip ratio will be also reported in listing at each 
visit and for change from baseline. 
4.2.6 
Exploratory endpoints  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
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5 
INTERIM ANALYSES 
An unblinded interim analysis (IA) is planned after approximately 39 subjects have completed 
approximately 19 weeks of treatment. The purpose of this interim analysis is to help inform 
further clinical development; no changes will be made to this study unless a safety signal is 
observed. These analyses will not have any impact on the overall type-1 error because no 
changes will be made to the trial based on the outcome of the analyses. The purpose with the 
interim analyses is to trigger external activities not connected to the trial. Additional details on 
the interim analysis procedures (i.e. data cut-off rules, data cleaning, nomination of the 
unblinded biometric team and the unblinding review committee team (URC) and the operational 
procedures used to protect the blinding) are given in the interim analysis charter.  
The interim analysis is focused on: 
• 
Description of the population  
• 
Overview of the safety variables  
• 
Overview of efficacy parameters  
5.1 
Description of the population  
Subject dispositions and demographic and subject-specific characteristics will be presented in 
summary tables as reported in section 4.2.1 and 4.2.3.1 respectively. Overall compliance and 
compliance categories will be presented in a summary table as reported in section 4.2.7.2. 
5.2 
Overview of the safety variables  
5.2.1 
Adverse events 
An overview table will be presented as reported in section 4.2.4.1. 
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The following summary tables will be presented by SOC and PT: 
• 
The number and percentage of subjects with any AEs 
• 
The number and percentage of subjects with AEs with outcome of death,  
• 
The number and percentage of subjects with SAEs  
• 
The number and percentage of subjects with AEs leading to discontinuation.  
 
The following summary tables will be presented by PT: 
• 
The number and percentage of subjects with most common AEs. 
• 
The number and percentage of subjects with any AEs by maximum reported intensity 
• 
Number of subjects with adverse events, by preferred term and relationship as assessed by 
investigator.  
 
Additionally, the following tables will be presented: 
• 
the number of subjects with serious adverse events, by seriousness criteria. 
• 
the number and percentage of subjects with non-serious AEs occurring with a frequency > 
5.0%  
• 
the number of subjects with injection site reactions by high level term (HLT) and PT. 
Lastly, a specific table presenting the event rate by period for nausea and vomiting and the 
corresponding bar-charts will be also provided.  
 
All these tables are described in section 4.2.4.1. 
5.2.2 
Laboratory evaluation 
Laboratory test results for haematology, coagulation, clinical chemistry and urinalysis 
quantitative parameters will be summarized descriptively.  
Shifts from baseline to maximum and minimum value during the on-treatment phase will be 
also presented. 
Shifts from baseline to maximum value during the on-treatment phase will be presented for 
urinalysis qualitative parameters, AST and ALT and total bilirubin in class.  
In addition to the tables above also the maximum on-treatment ALT and AST by maximum 
total bilirubin for assessing Hy’s law criteria, the eDISh plot for ALT and total bilirubin , a list 
of key subject information for subjects with potential Hy’s law as described in the study protocol 
and a list of key subject information for subjects with ALT or AST≥8xULN or total bilirubin 
≥2xULN during the on-treatment phase will be presented.  


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All these tables are described in section 4.2.4.2. 
5.2.3 
Vital signs 
Vital signs will be summarized descriptively.  
Observed values and change from baseline in systolic blood pressure, diastolic blood pressure, 
heart rate and rate pressure product (RPP) measurements will be also presented in figures.  
The number of subjects in SBP change categories with maximum heart rate change from 
baseline > 20 bpm at concurrent visit will be also summarized.  
For systolic blood pressure, diastolic blood pressure, heart rate and rate pressure product the 
ANCOVA model for change will be also presented.  
ABPM parameters will be summarized descriptively. Observed values in complete ABPM 
systolic blood pressure, diastolic blood pressure, heart rate and rate pressure product (RPP) 
measurements will be also presented in figures.   
All these tables are described in section 4.2.4.3. 
5.2.4 
 dECG 
dECG parameters (except for the overall evaluation) will be summarized descriptively as 
reported in section 4.2.4.4.  
5.3 
Overview of efficacy parameters  
5.3.1 
Hepatic fat fraction (HFF) as assessed by MRI-PDFF  
HFF will be summarized descriptively. Observed value, change and percent change of HFF will 
be also presented in figures.  
The ANCOVA model for change and percent change of HFF will be also presented. 
Sensitivity analyses 1, 2, 3 and 4 will be also performed. 
All these tables are described in section 4.2.5.1. 
5.3.2 
Circulating markers of hepatic inflammation  
ALT, AST and GGT will be summarized descriptively. Observed value, change and percent 
change of ALT will be also presented in figures. 
The ANCOVA model for change and percent change will be presented for ALT. The ANCOVA 
model for percent change will be also presented for AST and GGT. 
Sensitivity analyses 1, 2, 3 and 4 will be performed for ALT.  


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All these tables are described in section 4.2.5.3. 
5.3.3 
Immunogenicity 
ADA will be summarized as categorical variables. ADA titer will be summarized descriptively. 
ADA, will be also summarized in an ad-hoc table. All these tables are described in section 
4.2.5.4. 
5.3.4 
Weight 
Weight will be summarized descriptively as continuous variable. Observed value and percent 
change of weight will be also presented in figures. The ANCOVA model for percent change 
from baseline will be also presented. 
All these tables are described in section 4.2.5.5. 
5.3.5 
Biomarkers 
CK18, ELF, Insulin, Plasma glucose, HbA1c, C-peptide, FIB-4, APRI and NFS will be 
summarized descriptively as continuous variable. The ANCOVA model for change from 
baseline will be also presented. 
All these tables are described in section 4.2.6.1.  
5.3.6 
Lipid parameters 
All parameters except Lipidomics - NAFLD will be summarized descriptively as continuous 
variable. The ANCOVA model for change from baseline will be also presented. 
All these tables are described in section 4.2.6.2.  
5.3.7 
Hepatic fat fraction (HFF) as assessed by MRI-PDFF  
Proportion of subjects with post-treatment HFF (absolute) < 5% and proportion of subjects with 
percent decrease from baseline in HFF ≥ 30% will be summarized descriptively as categorical  
variables as described in section 4.2.6.6.  
6 
AD-HOC SAFETY REVIEW 
Upon request from the Sponsor, an unblinded ad-hoc safety review can be performed at any 
time during the study. Aim of this review will be to evaluate product safety only. No changes 
will be made to this study unless a safety signal is observed. The analysis will be carried on 
using the data available at the date of request. No additional external data transfer are planned 
for this analysis.   
Additional details on the Ad-hoc safety procedures (i.e. data cut-off rules, data cleaning, 
nomination of the unblinded biometric team and of the independent monitoring committee 


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team and the operational procedures used to protect the blinding) are given in the interim 
analysis charter. 
Reporting of the results will depend on the scope of the ad-hoc safety review. Pre-specified 
options for the scope (minimum, medium or maximum) are described below. 
6.1 
Minimum scope  
In the minimum scope the following summary tables will be presented. 
6.1.1 
Description of the population 
Subject dispositions and demographic characteristics except height weight, BMI and type 2 
diabetes mellitus will be presented in summary tables as reported in section 4.2.1 and 4.2.3.1 
respectively. 
6.1.2 
Adverse events 
An overview table will be presented as reported in section 4.2.4.1. 
The following summary tables will be presented by SOC and PT: 
• 
The number and percentage of subjects with AEs with outcome of death,  
• 
The number and percentage of subjects with SAEs The number and percentage of subjects 
with AEs leading to discontinuation.  
The following summary tables will be presented by PT: 
• 
The number and percentage of subjects with most common AEs. 
• 
The number and percentage of subjects with any AEs by maximum reported intensity.  
• 
The number and percentage of subjects with any AEs and investigator’s causality 
assessment. 
All these tables are described in section 4.2.4.1. 
6.2 
Medium scope  
In the medium scope, in addition to the summary tables presented for the minimum scope above, 
also the following tables will be presented: 
6.2.1 
Adverse events 
The number of subjects with injection site reactions by high level term (HLT) and PT. 
A specific table presenting the event rate by period for nausea and vomiting and the 
corresponding bar-charts will be also provided.  
All these tables are described in section 4.2.4.1. 


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6.2.2 
Vital signs 
Vital signs will be summarized descriptively as described in section 4.2.4.3. 
6.3 
Maximum scope  
In the maximum scope, in addition to the summary tables presented for the medium scope 
above, also the following tables will be presented: 
6.3.1 
Laboratory evaluation 
 Laboratory test results for haematology, coagulation, clinical chemistry and urinalysis 
quantitative parameters will be summarized descriptively.  
Shifts from baseline to maximum and minimum value during the on-treatment phase will be 
also presented. 
Shifts from baseline to maximum value during the on-treatment phase will be presented for 
urinalysis qualitative parameters, AST and ALT and total bilirubin in class.  
In addition to the tables above also the maximum on-treatment ALT and AST by maximum 
total bilirubin for assessing Hy’s law criteria, the eDISh plot for ALT and total bilirubin , a list 
of key subject information for subjects with potential Hy’s law as described in the study protocol 
and a list of key subject information for subjects with ALT or AST≥8xULN or total bilirubin 
≥2xULN during the on-treatment phase will be presented.  
All these tables are described in section 4.2.4.2.  
6.3.2 
Vital signs 
Observed values and change from baseline in systolic blood pressure, diastolic blood pressure, 
heart rate and rate pressure product (RPP) measurements will be also presented in figures.  
The number of subjects in SBP change categories with maximum heart rate change from 
baseline > 20 bpm at concurrent visit will be also summarized.  
For systolic blood pressure, diastolic blood pressure, heart rate and rate pressure product the 
ANCOVA model for change at week 12 and week 19 will be also presented.  
ABPM parameters will be summarized descriptively. Observed values in complete ABPM 
systolic blood pressure, diastolic blood pressure, heart rate and rate pressure product (RPP) 
measurements will be also presented in figures.   
All these tables are described in section 4.2.4.3. 
6.3.3 
 dECG 
dECG parameters (except for the overall evaluation) will be summarized descriptively as 
reported in section 4.2.4.4.  


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7 
CHANGES OF ANALYSIS FROM PROTOCOL 
This SAP is based on study protocol D5671C00002 Amendment 5 dated 21/04/2020. Any 
further amendment of the study protocol which can have an impact on the SAP will lead to an 
amendment of this document. Changes of analysis from D5671C00002 Amendment 5 dated 
21/04/20120 are listed here below: 
Section 2 – Objectives and endpoints 
• 
In this section is stated that all the endpoints are analyses at week 19. Analyses at week 12 
are also reported. 
Section 2.1 - Primary Objective and Associated Endpoint  
• 
In this section is stated that the primary safety endpoints are the incidences of treatment 
emergent adverse events and serious adverse events. In this SAP it is specified that also 
laboratory data, vital signs and dECG are included in the safety analysis and therefore are 
considered as primary safety endpoints. 
Section 2.2 - Secondary Objectives and Associated Endpoints 
• 
In this section it is stated that one of the objectives is to assess the dose response of 
MEDI0382 on pharmacodynamic parameters. However, pharmacodynamic parameters 
dose-response is already evaluated through the other primary and secondary analyses which 
are performed by treatment group. No additional analyses are included in this report about 
this objective.  
• 
Circumference is considered secondary objectives in this SAP together with body weight 
and BMI while the study protocol mentions only body weight and BMI.  
 
 
 
  
 
 
  
 
 
   
Section 4.3.6 Clinical Laboratory Tests 
• 
Calcitonin, TSH, amylase and lipase are added in the serum chemistry list of parameters. 
Tables 5, 6, 7 and 8 Vital signs 
• 
Rate pressure product (RPP) was not mentioned, however, it is added in the list of vital 
signs parameters and in the statistical analysis. 
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4.8.3.1 Efficacy Analysis 
• 
In this section is stated that percent change from baseline to Week 19 will be analysed using 
analysis of covariance (ANCOVA). However, for all the secondary efficacy parameter for 
which the ANCOVA model is used, both change and percent change are tested and also the 
ANCOVA test at Week 12 is performed.   
• 
Added normality test for all exploratory parameters before to use the ANCOVA model. 
Moreover, for lognormal parameters added that the ANCOVA model is fitted on log-
transformed variable and then the results are transformed back for reportable purpose.  
• 
In this section is stated that the mixed model for repeated measures (MMRM) approach 
should use the unstructured covariance. However, because the visits are not equally spaced, 
the SP (POW) structure is used. In case the model will not converge for any reasons, the 
following back-up solutions will be adopted sequentially: 1 - The compound symmetry 
(CS) will be used instead of the SP (POW); 2 - The unstructured (UN) will be used instead 
of the CS 
4.8.3.2 Additional Analyses of the Efficacy Endpoint 
• 
In this section is stated that additional MMRM analysis is performed only on percent 
change from baseline to Week 19. However, it is performed also on percent change from 
baseline to Week 12. Moreover, the same additional analysis is performed on ALT.  
Section 4.8.4.2 Analysis of Clinical Laboratory Parameters 
• 
This section stated to analyse the Hepatic safety analyses with Mean changes from baseline 
to end of treatment in ALT and AST levels. However, the mean change is reported at al 
visits and not at end of treatment.  
8 
REFERENCES 
N.A. 
9 
APPENDIX 
9.1 
Appendix 1 Changes made to the SAP after initial sign-off 
9.1.1 
Version 1.0 
NA 
9.1.2 
Version 2.0 
Section 2.1 
Specified how to derive actual treatment. 
Section 2.2 


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Added the list of relevant IPD to be used for the derivation of the PP population. 
Section 3.1.2 
Added that lipidomic measurements collected on day 1 are always considered collected before 
the first dose of IP because the time of collection is not reported in CRF but they should 
always be collected pre-dose as per protocol. 
Section 3.3.1.1 Adverse event 
For the sake of clarity, the AEs allocation to the study phases was rephrased. No change in the 
content of the algorithm. 
Section 3.3.1.2 Laboratory evaluation  
Added the complete list of parameters to be included in the white blood cell count with 
percent differential. 
Section 3.3.1.3 Vital signs  
Adjusted normal values for SBP and DSP to reflect common definitions. 
Added the acceptance criteria for ABPM records. 
Added RPP calculation also for ABPM. 
Section 3.3.2.4 Immunogenicity 
Delete description of change and percent change since not used for ADA data 
 
 
Section 4.1 General principles and section 4.2.5 
Added the reportable results in case of log-Normal distributed variables. 
Section 4.1.3 Sensitivity analysis 2 - the Wilcoxon Sum Rank test 
Added IQR to the reportable results 
Section 4.2 Analysis of variables 
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Values below the LLOQ will be replaced with LLOQ/squared root (2). 
Section 4.2.4.1 Adverse event  
Added a table to summarize the number of subjects with injection site reactions.  
Defined most common AE as grater than 5% 
Section 4.2.4.2 Laboratory evaluation 
Added a shift table from baseline for bilirubin, the eDISh plot with ALT vs total bilirubin and 
a list of key subject information for subjects with potential ALT or AST≥8xULN or total 
bilirubin ≥2xULN during the on-treatment phase.  
Section 4.2.4.3 Vital signs 
Added figure on observed values and change from baseline for systolic blood pressure and 
diastolic blood pressure. 
Added a table which summarize the number of subjects in SBP change categories and with 
maximum pulse change from baseline >= 20 bpm. 
For the sake of clarity, the ABPM Summary statistics calculation text was rephrased.  
Added RPP ABPM analysis (descriptive statistics and figures) 
Section 4.2.5.4 Immunogenicity 
Adjusted on ADA AZ standards tables. 
Section 4.2.6 Exploratory endpoints 
 
  
Section 5 Interim analysis 
Modified as per final analysis – section 4 - for the concerning tables. Added tables on number 
and percentage of subjects with any AEs by maximum reported intensity and ABPM 
variables, over time. 
Referenced all repeated details to previous sections. 
Added tables for biomarkers and lipid parameters, sections 5.3.5 and 5.3.6. 
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Section 6 Ad-hoc safety review 
Added the entire section. 
Changes due to protocol amendment 4:  
Added FIB-4, APRI, BARD score, NFS, and FLI in biomarkers exploratory endpoints. 
Deleted adiponectin high in lipid parameters 
Added a sensitivity analysis for HFF and ALT based on the Wilcoxon Sum Rank test. 
Weight and BMI promoted to secondary objectives 
Added proportions related to HFF as exploratory objective (logistic model) 
Changes due to protocol amendment 5:  
Visit windows for MRI at day 78 and at day 133 enlarged 
Interim analysis when approximately 39 subjects will be completed approximately 19 week of 
treatment. 
MRI at screening can be repeated if the first measurements is not adequate.  
9.1.3 
Version 3.0 
Section 3.1.2 Analysis visit windows – table 9: 
AVISIT derivation: added range for AVISIT derived from CRF visits 
9.1.4 
Version 4.0 
Section 4.2.5.1 Hepatic fat fraction (HFF) as assessed by MRI-PDFF: 
Added for HFF only: descriptive statistics by T2DM, p-values for change from baseline 
within each group and comparison between all active patients versus placebo 
9.1.5 
Version 5.0 
Section 3.3.2.4 Immunogenicity 
Specified that also for borderline positive ADA titer values are replaced. 
Sections 3.2.2 and 4.2.3.2 Medical history 


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Deleted the Disease related medical history page because not recorded correctly in the CRF. 
Section 3.3.3.1 Biomarkers 
  
 
 
Section 4.2.1 Disposition of subjects 
Added COVID tables 
Section 4.2.4.1 Adverse events 
Added SOC in table S10 and S11. 
Added line plots for nausea and vomiting. 
Section 4.2.5.4 Immunogenicity 
ADA tables and listing changed the referring population, as-treated population used instead of 
ITT. 
 
 
 
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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5671c00002-sap-v5
Document Title:
Statistical Analysis Plan Version 5
Document ID:
Doc ID-004162346
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
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Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
PPD

Prot_000.pdf: 
MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
CONFIDENTIAL AND PROPRIETARY 
1 of 117 
Template 18.0 
 
 
 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate the Safety and Pharmacodynamic Effects of 
MEDI0382 in Obese Subjects With Non-alcoholic Fatty Liver 
Disease (NAFLD)/ Non-alcoholic Steatohepatitis (NASH) 
Sponsor Protocol Number: D5671C00002 
 
 
Application Number: 
IND number: 139975 
 
Investigational Product: 
MEDI0382 (cotadutide) 
 
Sponsor: 
MedImmune Limited, a wholly owned subsidiary of 
AstraZeneca, PPD 
 Cambridge, CB21 
6GH, UK 
 
Medical Monitor: 
PPD 
 
Medical Monitor, AstraZeneca 
Phone: PPD 
 
 
Protocol History, Date: 
Original Protocol, 15March2019 
Protocol Amendment 1, 17May2019 
Protocol Amendment 2, 19Jul2019 
Protocol Amendment 3, 19Aug2019 
Protocol Amendment 4, 26Feb2020 
Protocol Amendment 5, 20Apr2020 
Protocol Amendment 6, 27Nov2020 
 
 
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from MedImmune. 


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Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
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PROTOCOL SYNOPSIS 
 
TITLE 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Pharmacodynamic 
Effects of MEDI0382 in Obese Subjects With Non-alcoholic Fatty Liver Disease (NAFLD)/Non-alcoholic 
Steatohepatitis (NASH) 
HYPOTHESES 
Primary Hypothesis: 
MEDI0382 will have an acceptable safety (including hepatic safety) and tolerability profile in subjects with 
NAFLD/NASH 
 
Secondary Hypothesis: 
Treatment with any one dose of MEDI0382 tested will lead to a reduction in hepatic fat in subjects with 
NAFLD/NASH 
OBJECTIVES AND ENDPOINTS 
Type 
Primary Objective 
Primary Endpoint 
 
Safety 
To assess the safety (including hepatic 
safety) and tolerability of MEDI0382 
compared with placebo 
• 
Incidences of treatment emergent 
adverse events and serious adverse 
events through the end of the follow-up 
period. 
Type 
Secondary Objectives 
Secondary Endpoints 
 
Pharmacodynamic 
effects 
To assess the effect of MEDI0382 on 
relative and absolute change in hepatic 
fat as assessed by magnetic resonance 
imaging-proton density fat fraction 
(MRI-PDFF) compared with placebo 
• 
Percent change from baseline in hepatic 
fat fraction (HFF) at Week 19 
• 
Absolute change from baseline to 
Week 19 in HFF 
 
 
 
 
 
 
 
 
 
 
 
 CCI 
 
 
Pharmacodynamic 
effects 
 
To assess the effect of MEDI0382 on 
circulating markers of hepatic 
inflammation compared with placebo 
Change and percent change from baseline to 
Week 19 in: 
• 
alanine aminotransferase (ALT) 
• 
aspartate aminotransferase (AST) 
• 
gamma glutamyl transferase (GGT) 
Pharmacodynamic 
effects 
To assess the effect of MEDI0382 on 
body weight and body mass index 
(BMI) compared with placebo 
• 
Change and percent change from 
baseline to Week 19 in body weight and 
BMI. 


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Dose response 
To assess the dose response of 
MEDI0382 on pharmacodynamic 
parameters 
• 
HFF, body weight, safety, other 
imaging parameters, parameters of 
hepatic inflammation 
 
Immunogenicity 
 
To evaluate the immunogenicity of 
MEDI0382 
• 
Development of anti-drug antibodies 
(ADA) and titer (if subjects are ADA 
positive) during treatment and 
follow-up 
Type 
Exploratory Objectives 
Exploratory Endpoints 


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27Nov2020; Final 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, study to evaluate the safety (including hepatic safety), 
tolerability and pharmacodynamic effects of two dose levels of MEDI0382 in obese subjects with 
NAFLD/NASH. The subjects will have biopsy-confirmed NAFLD/NASH with liver fibrosis stage F1, F2 or F3. 
Approximately 72 subjects will be randomized across multiple study sites. 
Subjects will be recruited in parallel and randomized using a 2:1:2:1 ratio: 
• 
MEDI0382 300 μg – once daily subcutaneous (SC) doses of MEDI0382 300 μg (n = 24) 
• 
Placebo for MEDI0382 300 μg – matched placebo (n = 12). 
• 
MEDI0382 600 μg – once daily SC doses of MEDI0382 600 μg (n = 24) 
• 
Placebo for MEDI0382 600 μg – matched placebo (n = 12) 
Subjects will be in the study for approximately 27 weeks (189 days), including a screening period of up to 
4 weeks, a 19-week treatment period, and a 4-week safety follow-up period. 


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TARGET SUBJECT POPULATION 
Subjects will be aged ≥ 18 years with a body mass index ≥ 30 kg/m2, with biopsy-confirmed NAFLD/NASH, 
and liver fibrosis stage F1, F2 or F3. 
TREATMENT GROUPS AND REGIMENS 
• 
MEDI0382 300 μg: MEDI0382 SC 50 μg once daily for 1 week, followed by 100 μg daily for 2 weeks, 
200 μg daily for 2 weeks and 300 μg daily for 14 weeks (n = 24). 
• 
Placebo for MEDI0382 300 μg: matched placebo SC once daily for 19 weeks (n = 12). 
• 
MEDI0382 600 μg: MEDI0382 SC 50 μg once daily for 1 week, followed by 100 μg daily for 2 weeks, 
200 μg daily for 2 weeks, 300 μg daily for 2 weeks, 400 μg daily for 2 weeks, 500 μg daily for 2 weeks 
and 600 μg daily for 8 weeks (n = 24). 
Placebo for MEDI0382 600 μg: matched placebo SC once daily for 19 weeks (n = 12). 
STATISTICAL METHODS 
Sample size: The primary objective of the study is safety, but sample size and power are calculated on efficacy 
endpoint HFF. Assuming 20% treatment difference on relative change in HFF with standard deviation 
(SD) = 20%, and assuming a 25% dropout rate, 24 subjects per group will provide about 83% power to detect a 
treatment difference between a MEDI0382 group and the placebo (alpha = 0.05, 2-sided). No multiplicity 
adjustment for alpha is planned. 
Statistical analyses: The safety analyses will be based on the As-treated population. Treatment emergent 
adverse events will be summarized for incidence with number and percentage. Other safety data, such as vital 
signs, clinical laboratory data, and dECG will be summarized descriptively. 
The pharmacodynamic analyses will be based on the Intent-to-treat population. For pharmacodynamic endpoints 
with continuous distribution, analysis of covariance (ANCOVA) adjusted for baseline value will be conducted. 
Pharmacokinetic and immunogenicity analyses: Pharmacokinetic parameters such as, but not limited to, Cmax, 
tmax, and AUC per group on the last day of dosing, may be estimated from plasma concentration-time data for 
MEDI0382 if data permit. Descriptive statistics will be generated for pharmacokinetic parameters for 
MEDI0382 in group. Additional summary statistics on predose concentrations and specific postdose 
concentrations may be derived, if data permits, from all groups. Subjects who have at least one measurable 
concentration time point of investigational product will be used for this analysis. Samples confirmed positive for 
ADA will be analyzed for antibody titer, ADA incidence rate and titer will be tabulated. 
Interim analysis: An interim analysis is planned after approximately 39 subjects have completed approximately 
19 weeks of treatment. The purpose of this interim analysis is to help inform further clinical development; no 
changes will be made to this study unless a safety signal is observed. The interim analysis results will not be 
provided to the investigator. The interim analysis will be described in the interim analysis charter. 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ............................................................................................................ 2 
LIST OF ABBREVIATIONS.................................................................................................... 11 
1 
INTRODUCTION .................................................................................................. 14 
1.1 
Disease Background ............................................................................................... 14 
1.2 
MEDI0382 Background .......................................................................................... 15 
1.3 
Summary of Nonclinical Experience ...................................................................... 15 
1.4 
Summary of Clinical Experience ........................................................................... 16 
1.5 
Rationale for Conducting the Study ....................................................................... 17 
1.6 
Benefit-risk and Ethical Assessment ...................................................................... 18 
1.7 
Research Hypotheses .............................................................................................. 18 
1.7.1 
Primary Hypothesis ................................................................................................ 18 
1.7.2 
Secondary Hypotheses ............................................................................................. 19 
2 
OBJECTIVES AND ENDPOINTS ....................................................................... 19 
2.1 
Primary Objective and Associated Endpoint ......................................................... 19 
2.2 
Secondary Objectives and Associated Endpoints .................................................. 20 
2.3 
Exploratory Objectives and Associated Endpoints ................................................ 21 
3 
STUDY DESIGN ................................................................................................... 22 
3.1 
Description of the Study ........................................................................................ 22 
3.1.1 
Overview ................................................................................................................ 22 
3.1.2 
Treatment Regimen ................................................................................................ 24 
3.1.3 
Management of Study Medication Related Toxicities ........................................... 25 
3.1.3.1 
Tolerability ............................................................................................................. 25 
3.1.3.2 
Hypoglycemia ......................................................................................................... 25 
3.1.3.3 
Persistent Hyperglycemia ....................................................................................... 26 
3.2 
Rationale for Dose, Population, and Endpoints ...................................................... 26 
3.2.1 
Dose Rationale ....................................................................................................... 26 
3.2.2 
Rationale for Study Population .............................................................................. 28 
3.2.3 
Rationale for Endpoint(s) ....................................................................................... 29 
4 
MATERIALS AND METHODS ........................................................................... 30 
4.1 
Subjects .................................................................................................................. 30 
4.1.1 
Number of Subjects ................................................................................................ 30 
4.1.2 
Inclusion Criteria .................................................................................................... 30 
4.1.3 
Exclusion Criteria ................................................................................................... 31 
4.1.4 
Subject Enrollment and Randomization ................................................................. 33 
4.1.5 
Screen Failures ....................................................................................................... 33 
4.1.6 
Withdrawal from the Study .................................................................................... 34 
4.1.7 
Discontinuation of Investigational Product ............................................................ 34 
4.1.8 
Study Stopping Criteria .......................................................................................... 35 
4.1.9 
Replacement of Subjects ........................................................................................ 36 


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4.1.10 
Withdrawal of Informed Consent for Data and Biological Samples ..................... 36 
4.2 
Schedule of Study Procedures ................................................................................. 37 
4.2.1 
Enrollment/Screening Period ................................................................................. 37 
4.2.2 
Randomized Treatment Period ............................................................................... 40 
4.2.3 
Follow-up Period .................................................................................................... 53 
4.3 
Description of Study Procedures ............................................................................ 54 
4.3.1 
Efficacy................................................................................................................... 54 
4.3.2 
Safety ...................................................................................................................... 54 
4.3.2.1 
Medical History ...................................................................................................... 54 
4.3.2.2 
Physical Examination ............................................................................................. 55 
4.3.2.3 
Digital Electrocardiogram....................................................................................... 55 
4.3.2.4 
Vital Signs .............................................................................................................. 56 
4.3.2.5 
Weight, Height, BMI, Waist and Hip Circumference ............................................ 57 
4.3.3 
Patient Reported Outcomes .................................................................................... 58 
4.3.3.1 
Administration of Patient-Reported Outcome ....................................................... 58 
4.3.4 
Subject Food Intake / Dosing Diary Completion ................................................... 58 
4.3.5 
Pharmacodynamic Evaluation and Methods .......................................................... 59 
4.3.5.1 
Magnetic Resonance Imaging (Including MRI-PDFF) .......................................... 59 
4.3.5.2 
Fibroscan ................................................................................................................ 59 
4.3.6 
Clinical Laboratory Tests ....................................................................................... 59 
4.3.7 
Pharmacokinetic Evaluation and Methods ............................................................. 61 
4.3.8 
Immunogenicity Evaluation and Methods ............................................................. 61 
4.3.9 
Genetic Evaluations and Method ............................................................................ 62 
4.3.10 
Biomarker Evaluation ............................................................................................. 62 
4.3.11 
Storage, Re-use and Destruction of Biological Samples ........................................ 62 
4.3.12 
Estimate of Volume of Blood to be Collected ....................................................... 62 
4.4 
Study or Study Component Suspension or Termination ........................................ 62 
4.5 
Investigational Products ......................................................................................... 63 
4.5.1 
Identity of Investigational Product(s) ..................................................................... 63 
4.5.1.1 
Investigational Product Handling ............................................................................ 64 
4.5.1.2 
Investigational Product Inspection ......................................................................... 64 
4.5.1.3 
Dose Preparation Steps .......................................................................................... 65 
4.5.1.4 
Treatment Administration ...................................................................................... 66 
4.5.1.5 
Monitoring of Dose Administration ....................................................................... 67 
4.5.1.6 
Reporting Product Complaints ............................................................................... 67 
4.5.2 
Additional Study Medications ................................................................................ 68 
4.5.3 
Labeling .................................................................................................................. 68 
4.5.4 
Storage .................................................................................................................... 68 
4.5.5 
Treatment Compliance ............................................................................................ 68 
4.5.6 
Accountability ......................................................................................................... 68 
4.6 
Treatment Assignment and Blinding ...................................................................... 69 
4.6.1 
Methods for Assigning Treatment Groups ............................................................. 69 
4.6.2 
Methods to Ensure Blinding ................................................................................... 69 
4.6.3 
Methods for Unblinding ......................................................................................... 69 
4.6.3.1 
Unblinding in the Event of a Medical Emergency ................................................. 69 


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4.6.3.2 
Unblinding for Interim Analysis Purposes ............................................................. 70 
4.7 
Restrictions During the Study and Concomitant Treatment(s) .............................. 70 
4.7.1 
Permitted Concomitant Medications ...................................................................... 70 
4.7.2 
Prohibited Concomitant Medications ..................................................................... 71 
4.8 
Statistical Evaluation .............................................................................................. 72 
4.8.1 
General Considerations........................................................................................... 72 
4.8.2 
Sample Size ............................................................................................................ 72 
4.8.3 
Efficacy................................................................................................................... 72 
4.8.3.1 
Efficacy Analysis .................................................................................................... 72 
4.8.3.2 
Additional Analyses of the Efficacy Endpoint ....................................................... 73 
4.8.4 
Safety ...................................................................................................................... 73 
4.8.4.1 
Analysis of Adverse Events ................................................................................... 73 
4.8.4.2 
Analysis of Clinical Laboratory Parameters .......................................................... 74 
4.8.5 
Analysis of Immunogenicity/Pharmacokinetics ...................................................... 74 
4.8.6 
Interim Analysis ..................................................................................................... 74 
5 
ASSESSMENT OF SAFETY ................................................................................ 75 
5.1 
Definition of Adverse Events ................................................................................. 75 
5.2 
Definition of Serious Adverse Events .................................................................... 75 
5.3 
Recording of Adverse Events ................................................................................ 75 
5.3.1 
Time Period for Collection of Adverse Events ...................................................... 76 
5.3.2 
Follow-up of Unresolved Adverse Events ............................................................. 76 
5.3.3 
Deaths ..................................................................................................................... 76 
5.3.4 
Adverse Events Based on Signs and Symptoms .................................................... 76 
5.3.5 
Adverse Events Based on Examination and Tests ................................................. 76 
5.3.6 
Potential Hy’s Law and Hy’s Law ......................................................................... 77 
5.4 
Reporting of Serious Adverse Events .................................................................... 77 
5.5 
Other Events Requiring Immediate Reporting ....................................................... 78 
5.5.1 
Overdose ................................................................................................................. 78 
5.5.2 
Pregnancy ............................................................................................................... 78 
5.5.2.1 
Maternal Exposure.................................................................................................. 78 
5.5.3 
Medication Error ..................................................................................................... 79 
6 
STUDY AND DATA MANAGEMENT ............................................................... 80 
6.1 
Training of Study Site Personnel ........................................................................... 80 
6.2 
Monitoring of the Study ......................................................................................... 81 
6.2.1 
Source Data ............................................................................................................ 81 
6.2.2 
Study Agreements ................................................................................................... 81 
6.2.3 
Archiving of Study Documents .............................................................................. 81 
6.3 
Study Timetable and End of Study ........................................................................ 82 
6.4 
Data Management .................................................................................................... 82 
6.5 
Medical Monitor Coverage .................................................................................... 82 
7 
ETHICAL AND REGULATORY REQUIREMENTS ........................................... 82 
7.1 
Subject Data Protection .......................................................................................... 82 


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7.2 
Ethics and Regulatory Review ............................................................................... 83 
7.3 
Informed Consent ................................................................................................... 84 
7.4 
Changes to the Protocol and Informed Consent Form ........................................... 84 
7.5 
Audits and Inspections ........................................................................................... 84 
8 
REFERENCES ....................................................................................................... 86 
9 
CHANGES TO THE PROTOCOL ......................................................................... 88 
9.1 
Protocol Amendment 6 .......................................................................................... 88 
9.2 
Protocol Amendment 5 .......................................................................................... 88 
9.3 
Protocol Amendment 4 .......................................................................................... 89 
9.4 
Protocol Amendment 3 .......................................................................................... 91 
9.5 
Protocol Amendment 2 .......................................................................................... 92 
9.6 
Protocol Amendment 1 .......................................................................................... 95 
 
LIST OF TABLES 
Table 1 
Primary Objective and Associated Endpoint ................................................ 19 
Table 2 
Secondary Objectives and Associated Endpoints ......................................... 20 
Table 3 
Exploratory Objectives and Associated Endpoints ....................................... 21 
Table 4 
Proposed Study Doses and Predicted Safety Margins Based on Safety 
Data From the Cynomolgus Monkey ........................................................... 28 
Table 5 
Screening Schedule of Procedures ............................................................... 38 
Table 6 
 MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of 
Procedures ..................................................................................................... 41 
Table 7 
 MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of 
Procedures ..................................................................................................... 46 
Table 8 
Schedule of Follow-up Procedures ............................................................... 53 
Table 9 
Identification of Investigational Products ..................................................... 63 
Table 10 
MEDI0382 and Placebo Dose Preparation ................................................... 66 
Table 11 
Restricted medications .................................................................................. 71 
Table 12 
Prohibited medications .................................................................................. 72 
Table A1 
Highly Effective Methods of Contraception ................................................. 99 
 
LIST OF FIGURES 
Figure 1 
Study Flow Diagram ..................................................................................... 23 
 
LIST OF APPENDICES 
Appendix A 
Contraception Guidance ............................................................................... 99 


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Appendix B 
Adverse Event Definitions and Additional Safety Information ................. 100 
Appendix C 
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis .............. 104 
Appendix D 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .............................................................................. 105 
Appendix E 
Genetic Research ........................................................................................ 112 
Appendix F 
Alcohol use disorder identification test (AUDIT) ...................................... 115 
Appendix G 
Alcohol use disorder identification test (AUDIT) - Scoring instructions. 117 


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LIST OF ABBREVIATIONS 
 
Abbreviation or 
Specialized Term 
Definition 
ABPM 
ambulatory blood pressure monitoring 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
APRI 
AST platelet ratio index 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUDIT 
Alcohol Use Disorder Identification Test 
BARD score 
BMI, Ratio, Diabetes Score 
BMI 
body mass index 
BP 
blood pressure 
CI 
confidence interval 
CLDQ-NASH 
Chronic Liver Disease Questionnaire for non-alcoholic steatohepatitis 
Cmax 
maximum observed plasma drug concentration 
COVID-19 
Coronavirus disease 19 
CSA 
clinical study agreement 
CSR 
clinical study report 
dECG 
digital electrocardiogram 
DNL 
de novo lipogenesis 
DPP-4i 
dipeptidyl peptidase-4 inhibitor 
eCRF 
electronic case report form 
E-code 
subject identification number 
FAAN 
Food Allergy and Anaphylaxis Network 
FIB-4 
fibrosis-4 score 
FLI 
fatty liver index 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
GGT 
gamma glutamyl transferase 
HbA1c 
hemoglobin A1c 


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Abbreviation or 
Specialized Term 
Definition 
HDLc 
high density lipoprotein cholesterol 
HFF 
hepatic fat fraction 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IWRS 
interactive web response system 
LDLc 
low density lipoprotein cholesterol 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI-PDFF 
magnetic resonance imaging-proton density fat fraction 
NAFLD 
non-alcoholic fatty liver disease 
NAS 
NASH activity score 
NASH 
non-alcoholic steatohepatitis 
NIAID 
National Institute of Allergy and Infectious Diseases 
NFS 
NAFLD fibrosis score 
NOAEL 
no-observed-adverse-effect-level 
PPAR-γ 
peroxisome proliferator-activated receptor gamma 
PRO 
patient reported outcomes 
RR 
relative risk 
SAE 
serious adverse event 
SC 
subcutaneous 
SD 
standard deviation 
SF-36 
Short-Form-36 
SGLT-2 
sodium-glucose co-transporter 2 
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin 
tmax 
time to maximum observed plasma drug concentration 
ULN 
upper limit of normal 
URC 
Unblinded Review Committee 
US FDA 
United States Food and Drug Administration 


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Abbreviation or 
Specialized Term 
Definition 
USA 
United States of America 
w/v 
weight per volume 


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1 
INTRODUCTION 
1.1 
Disease Background 
Non-alcoholic steatohepatitis (NASH) is part of the spectrum of liver diseases known as 
non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis or non-alcoholic 
fatty liver (NAFL) to NASH. NAFLD is the most common cause of chronic liver disease in 
western industrialized countries and has an estimated prevalence of approximately 6% to 35% 
worldwide (Bellentani, 2017; Younossi et al, 2016). NASH is the progressive form of the 
disease with a prevalence of approximately 2% to 3% of the general population, which can 
lead to cirrhosis and its complications, hepatocellular carcinoma, and end-stage liver disease 
(Bellentani et al, 2010). NASH is expected to become the leading cause for liver 
transplantation over the next decade, and is an important etiology driving the burden of 
hepatocellular carcinoma (Cholankeril et al, 2017; Pais et al, 2016; Wong et al, 2014). NASH 
is closely associated with metabolic risk factors including obesity, type 2 diabetes mellitus 
(T2DM), and dyslipidemia. Of particular relevance, epidemiological studies have 
demonstrated the prevalence of co-morbid obesity and T2DM in approximately 80% and 45% 
of patients with NASH, respectively (Younossi et al, 2016). Pathophysiologically, NASH is 
frequently associated with insulin resistance, leading to adipose tissue dysfunction and 
increased hepatic de novo lipogenesis (DNL). Therefore, it is believed that both increased 
adipose tissue lipolysis and hepatic DNL contribute to increased liver fat and formation of 
lipid metabolites causing lipotoxicity. Lipotoxicity, oxidative stress and mitochondrial 
dysfunction are believed to contribute to the hallmarks of NASH including signs of cell death 
or hepatocyte ballooning, lobular or portal inflammation and ultimately in some patients, liver 
fibrosis (Marra and Lotersztajn, 2013; Neuschwander-Tetri, 2017). 
NASH is defined histologically as the combination of hepatic steatosis, inflammation and 
hepatocyte ballooning. Approximately 25% to 35% of patients with NASH develop liver 
fibrosis (Mishra and Younossi, 2012). The fibrosis stage (F1 to F4) is the most important 
prognostic factor in NASH correlating with liver-related outcomes and mortality (Angulo et 
al, 2015; Dulai et al, 2017). A number of factors have been shown to increase the risk of liver 
fibrosis progression to cirrhosis including presence of comorbid T2DM, increasing age, 
hypertension, and high body mass index (BMI) (Angulo, 2007). 
 
There are currently no licensed pharmacological therapies for NASH, with lifestyle 
modifications being the mainstay of treatment. Many patients do not achieve or maintain 
dietary goals and weight loss. Consequently, the development of new therapies for NASH is 
an area of high unmet medical need, particularly given the expected increasing burden of this 
disease in parallel with the rising global epidemics of obesity and T2DM (Estes et al, 2018). 


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1.2 
MEDI0382 Background 
MEDI0382 is briefly described below. A detailed description of the chemistry, pharmacology, 
efficacy, and safety of MEDI0382 is provided in the Investigator’s Brochure (IB). 
 
Glucagon-like peptide-1 (GLP-1) receptor agonists are established treatments for T2DM that 
improve glycemic control, delay gastric emptying, and depress appetite leading to modest 
weight loss (typically 4% to 5.4% placebo-subtracted weight loss at 1 year) (Astrup et al, 
2012). The strong association of NASH with the metabolic syndrome, particularly obesity and 
T2DM, has led to the investigation of GLP-1 agonists in this setting due to their positive 
effects on weight loss and insulin sensitivity. 
In a metabolic sub-study of the multicenter, double-blind, randomized LEAN study, patients 
with NASH who were treated with the GLP-1 receptor agonist liraglutide 1.8 mg (Victoza®) 
for 12 weeks showed increased insulin sensitivity and metabolic improvement such as 
decreased levels of circulating non-esterified fatty acids and markers of adipose inflammation 
(Armstrong et al, 2014). In the main 48-week LEAN study of 52 patients with NASH, 
treatment with liraglutide 1.8 mg led to histological resolution of NASH in 9 (39%) patients 
who underwent end of treatment liver biopsy compared with 2 (9%) patients in the placebo 
group (4.3 relative risk [RR], 95% confidence interval [CI] 1.0, 17.7; p = 0.019) (Armstrong 
et al, 2016). Fewer patients in the liraglutide group versus the placebo group (9% versus 36%, 
respectively) had progression to liver fibrosis (0.2 RR, 95% CI 0.1, 1.0; p = 0.04). 
MEDI0382 is an oxyntomodulin-like peptide with targeted GLP-1 and glucagon receptor 
activity that is under development for the treatment of overweight/obese patients with T2DM. 
The additional glucagon component has similar effects to GLP-1 on gastric emptying and 
appetite and has also been shown to promote increased energy expenditure (Habegger et al, 
2013; Lynch et al, 2014). Oxyntomodulin, a naturally occurring peptide with GLP-1 and 
glucagon receptor co-agonist activity, has been shown to promote weight loss through effects 
on appetite and energy expenditure in obese humans (Wynne et al, 2006). In addition, 
co-infusion of GLP-1 and glucagon has demonstrated synergistic effects on reducing food 
intake and increasing energy expenditure in humans (Cegla et al, 2014). In a rodent model of 
NASH, the synthetic GLP-1 and glucagon receptor co-agonist G49 has been shown to 
improve the histological features of NASH following a methionine and choline-deficient diet 
(Valdecantos et al, 2017). 
MEDI0382, through targeted GLP-1 and glucagon receptor activity, is therefore hypothesized 
to lead to histological resolution of NASH, along with providing beneficial effects on glucose 
and lipid metabolism. 
 
1.3 
Summary of Nonclinical Experience 
Refer to the current MEDI0382 IB for a complete summary of non-clinical information. 


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A series of repeat-dose-toxicity studies that included a 6-month study in rat and a 9-month 
study in the cynomolgus monkey were performed. Consistent with GLP-1 receptor 
mono-agonists, MEDI0382 exposure in both rats and cynomolgus monkeys resulted in the 
anticipated pharmacologic effects on body weight (reduced gain, or loss), food consumption 
(sporadic reductions), water consumption (low throughout dosing periods), gastric emptying 
(delayed in rats), liver (changes indicative of an effect on energy homeostasis in both species), 
pancreas (hypercellularity of the pancreatic islets, acinar degranulation), adrenal glands 
(increased prominence of the zona glomerulosa), and lungs (increased macrophage number, 
rats only). Skin findings (dry scaling, flaky and occasionally reddened) noted in-life in high 
dose group female cynomolgus monkeys only, appeared to be recovering in the treatment-free 
phase of the 9-month toxicology study. Microscopically this correlated with dermal 
inflammation, hyperkeratosis and acanthosis in the affected females and in 1 male not 
previously showing this clinically. The onset of the clinical observations coincided with the 
intensive investigations conducted during Week 26 of the study, which included overnight 
housing of animals in metabolism cages that can be stressful to some animals. The skin 
changes observed are likely to be study conduct- and stress-related, with the secondary effects 
of MEDI0382-induced weight loss (greatest in females) potentially affecting skin condition in 
affected animals. MEDI0382 was not genotoxic and was not considered to be toxic to fertility 
or embryo fetal development in the rat and rabbit, with most findings generally being 
associated with maternal stress. 
In 2 mouse models of NASH, wild type (C57BL6J) or genetically obese (Lepob/Lepob) mice 
fed a diet high in trans-fat, fructose, and cholesterol, had repeated subcutaneous (SC) once 
daily dosing of MEDI0382 (40 μg/kg or 111.84 μg/kg, respectively) for 6 weeks, that resulted 
in improvements in metabolism (reduced body weight, improved glucose tolerance), and liver 
enzymes, hepatic steatosis, and histological features of NASH compared with vehicle 
control(s). Both wild type and genetically obese mice treated with MEDI0382 had a 
statistically significant (p < 0.05) lower NASH activity score (NAS) compared with vehicle. 
The genetically obese mice treated with MEDI0382 had a statistically significant (p < 0.05) 
reduction in liver fibrosis compared with vehicle, which was supported by statistically 
significant reductions (p < 0.05) in plasma levels of the neoepitope of matrix metallopeptidase 
9-mediated degraded type III collagen (C3M) and internal epitope in the 7S domain of type IV 
collagen (P4NP7S) biomarkers (as measured by collagen staining) compared with vehicle. 
1.4 
Summary of Clinical Experience 
This is the first study with MEDI0382 in subjects with non-cirrhotic NAFLD/NASH with 
fibrosis stages F1, F2, or F3, however, seven clinical studies with MEDI0382 are complete 
and six ongoing including two studies with dosing up to 600 μg, one in obese subjects with 
T2DM and the other in subjects with chronic weight management or obesity (see current IB 
for details). Safety assessments for the completed studies show that the administration of 


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MEDI0382 was generally well tolerated, with more frequent, usually mild or moderate, 
gastrointestinal treatment emergent adverse events as expected from this drug class. 
 
In the completed Phase 1/2a (Study D5670C00002) study conducted in 51 overweight and 
obese subjects with T2DM who received 41 days of placebo or MEDI0382 titrated up to a 
dose of 200 μg, a mean reduction from baseline in weight of -4.12% (90% CI -4.88, -3.36) 
was observed in MEDI0382-treated subjects versus -1.78% (90% CI -2.52, -1.03) in placebo, 
and a mean reduction from baseline in glucose area under curve for mixed meal test 4 hours 
(AUCMMT.4 h) of -32.78% (90% CI -36.98, -28.57) versus -10.16% (90% CI -14.10, -6.21) 
in placebo, p < 0.0001. The effects of MEDI0382 (at a dose of 200 μg, dose titrated from 
100 μg) on hepatic fat content as measured by magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF), was measured as an exploratory endpoint in this study, and 
demonstrated a significant reduction versus placebo ([Absolute: least squares [LS] mean 
change (90%CI): -5.98 (-7.67, -4.29) versus -3.17 (-4.68, -1.65), p = 0.017; Relative: LS mean 
change (90%CI): -39.12% (-49.11, -29.14) versus -19.51% (-28.49, -10.53), p = 0.006]) 
(Ambery et al, 2018). 
 
1.5 
Rationale for Conducting the Study 
It has been previously shown that GLP-1 mono-agonists reduce liver fat and improve 
histological features of NASH (Armstrong et al, 2016; Petit et al, 2017). Given MEDI0382 
has additional effects on glucagon that could lead to both a reduction in weight and may 
additionally lead to direct hepatic effects, it is anticipated that MEDI0382 use will lead to 
reduction of liver fat, liver stiffness and circulating markers of hepatocellular injury in this 
subject population. As outlined above, up to 6-week data demonstrating the safety and 
efficacy of MEDI0382 across numerous metabolic endpoints in overweight and obese T2DM 
populations in clinical settings (Study D5670C00002) have been collected. MEDI0382 (at a 
dose of 200 μg) was associated with significant reductions in liver fat, as assessed by 
MRI-PDFF after 41 days of treatment, in a subgroup within a Phase 1/2a study in 
overweight/obese subjects with T2DM (Study D5670C00002). However, we have no data on 
the effect of MEDI0382 on safety and measures of hepatic steatosis and inflammation in the 
target population of NAFLD/NASH with fibrosis (F1, F2, or F3). Furthermore, we have no 
data at doses greater than 200 μg in a population with NAFLD/NASH with fibrosis. Access to 
such data are necessary to support development and design of a longer term pivotal study in 
subjects with NASH with fibrosis, particularly as outlined in the recently released draft 
guidance from the United States Food and Drug Administration (US FDA) on non-cirrhotic 
NASH with fibrosis. 
This will be the first study to investigate the effect of MEDI0382 in subjects with 
non-cirrhotic NAFLD/NASH with fibrosis (F1, F2, or F3). This proof of concept study will 
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biopsy-confirmed non-cirrhotic NAFLD/NASH with fibrosis, enabling us to define the short- 
term effects of MEDI0382 in the target population for this therapy. In turn, it is expected that 
data from the proposed study will support key considerations for safety, study design, dose 
selection, sample size estimation, development of endpoints and even regulatory discussions 
to enable larger longer studies of MEDI0382 in a population with non-cirrhotic 
NAFLD/NASH with fibrosis. 
 
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 (GCP), and applicable regulatory requirements. 
 
This is the first clinical study in which MEDI0382 will be used in subjects with NASH and is 
expected to lead to improvement of NASH based on non-invasive parameters, along with 
significant weight reduction. 
 
Identified and potential risks for MEDI0382 are based on available published data for other 
GLP-1 receptor mono-agonists and glucagon receptor mono-agonists, as well as clinical and 
non-clinical data for MEDI0382. Identified risks/adverse drug reactions for MEDI0382 are 
nausea, vomiting, injection site reactions and increased heart rate. The current IB should be 
consulted for potential risks; for MEDI0382 these include, alterations in blood pressure (BP), 
QT-interval prolongation, anaphylactic-type reactions, skin rash, pancreatitis, pancreatic 
carcinoma, thyroid cancer, hypoglycemia (with sulfonylurea/insulin) and diabetic ketoacidosis 
(following insulin reduction). The study design aims to minimize potential risks to subjects 
participating in this study based on the proposed inclusion/exclusion criteria, safety 
monitoring, and up-titration dosing schedule. Additionally, subjects will be monitored 
throughout the study for signs, symptoms, and/or laboratory analyses suggestive of hepatic 
decompensation. Subjects with hepatic decompensation will be excluded from participation in 
this study (Section 5.2) and will be treated immediately according to standard of care. 
Subjects will be given appropriate training in SC injection administration. 
 
More detailed information about the known and expected benefits and identified and potential 
risks and expected adverse events (AEs) of MEDI0382 may be found in the current IB. 
 
1.7 
Research Hypotheses 
1.7.1 
Primary Hypothesis 
MEDI0382 will have an acceptable safety (including hepatic safety) and tolerability profile in 
subjects with NAFLD/NASH. 


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1.7.2 
Secondary Hypotheses 
Treatment with any one dose of MEDI0382 tested will lead to a reduction in hepatic fat in 
subjects with NAFLD/NASH. 
 
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective and Associated Endpoint 
Table 1 
Primary Objective and Associated Endpoint 
 
Type 
Objective 
Endpoint 
 
Safety 
To assess the safety (including hepatic 
safety) and tolerability of MEDI0382 
compared with placebo 
• 
Incidences of treatment emergent 
adverse events and serious adverse 
events through the end of the follow- 
up period. 


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2.2 
Secondary Objectives and Associated Endpoints 
Table 2 
Secondary Objectives and Associated Endpoints 
 
Type 
Objective 
Endpoint 
Pharmacodynamic 
effects 
To assess the effect of MEDI0382 on 
relative and absolute change in hepatic 
fat as assessed by magnetic resonance 
imaging-proton density fat fraction 
(MRI-PDFF) compared with placebo 
• 
Percent change from baseline in 
hepatic fat fraction (HFF) at Week 19 
• 
Absolute change from baseline to 
Week 19 in HFF 
 
 
 
 
 
 
 
 
 
 
 
 
 CCI 
 
 
Pharmacodynamic 
effects 
 
To assess the effect of MEDI0382 on 
circulating markers of hepatic 
inflammation compared with placebo 
Change and percent change from baseline to 
Week 19 in: 
• 
alanine aminotransferase (ALT) 
• 
aspartate aminotransferase (AST) 
• 
gamma glutamyl transferase (GGT) 
Pharmacodynamic 
effects 
To assess the effect of MEDI0382 on 
body weight and body mass index (BMI) 
compared with placebo 
• 
Change and percent change from 
baseline to Week 19 in body weight 
and BMI. 
 
Dose response 
To assess the dose response of 
MEDI0382 on pharmacodynamic 
parameters 
• 
HFF, body weight, safety, other 
imaging parameters, parameters of 
hepatic inflammation 
 
Immunogenicity 
 
To evaluate the immunogenicity of 
MEDI0382 
• 
Development of anti-drug antibodies 
(ADA) and titer (if subjects are ADA 
positive) during treatment and 
follow-up 


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2.3 
Exploratory Objectives and Associated Endpoints 
Table 3 
Exploratory Objectives and Associated Endpoints 
 


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Table 3 
Exploratory Objectives and Associated Endpoints 
 
3 
STUDY DESIGN 
3.1 
Description of the Study 
3.1.1 
Overview 
This is a randomized, double-blind, placebo-controlled study to evaluate the safety (including 
hepatic safety), tolerability and pharmacodynamic effects of two dose levels of MEDI0382 in 
obese subjects with NAFLD/NASH. The subjects will have biopsy-confirmed NAFLD/NASH 
with liver fibrosis stages F1, F2 or F3. Approximately 72 subjects will be randomized across 
multiple study sites. 
 
Subjects will be recruited in parallel and randomized using a 2:1:2:1 ratio: 
 
 
MEDI0382 300 μg: MEDI0382 SC 50 μg once daily for 1 week, followed by 100 μg 
daily for 2 weeks, 200 μg daily for 2 weeks and 300 μg daily for 14 weeks (n = 24). 
 
Placebo for MEDI0382 300 μg: matched placebo SC once daily for 19 weeks (n = 12). 
 
MEDI0382 600 μg: MEDI0382 SC 50 μg once daily for 1 week, followed by 100 μg 
daily for 2 weeks, 200 μg daily for 2 weeks, 300 μg daily for 2 weeks, 400 μg daily for 
2 weeks, 500 μg daily for 2 weeks and 600 μg daily for 8 weeks (n = 24). 


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 
Placebo for MEDI0382 600 μg: matched placebo SC once daily for 19 weeks (n = 12). 
 
 
Subjects will be in the study for approximately 27 weeks (189 days), including a screening 
period of up to 4 weeks, a 19-week treatment period, and a 4-week safety follow-up period 
(Figure 1). 
 
During the screening period, baseline circulating markers (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], gamma glutamyl transferase [GGT]) will be obtained. 
Subjects will return to site for study procedures at regular intervals, including the collection of 
blood sampling for serum biomarkers and pharmacokinetics, and MRI (including MRI-PDFF) 
when applicable (refer to the schedule of study procedures). 
To help inform further clinical development, once approximately 39 subjects have completed 
approximately 19 weeks of treatment an interim analysis is planned. The interim analysis 
results will not be provided to the investigator. The interim analysis will be described in the 
interim analysis charter. 
 
Figure 1 
Study Flow Diagram 
 
 
MRI = magnetic resonance imaging; PDFF = proton density fat fraction; R = randomization 
a 
Subjects with MRI (including MRI-PDFF) and fibroscan assessments performed within 60 days prior to 
screening do not need to undergo these assessments. 


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3.1.2 
Treatment Regimen 
Subjects randomized to placebo will receive matched placebo for 19 weeks. 
 
Dose Up-titration Period 
 
During the dose up-titration period, subjects randomized to receive MEDI0382 will titrate to 
the top dose in each group as follows: 
 
MEDI0382 300 μg (5 weeks) 
 
 
50 μg for 1 week (7 days) 
 
100 μg for 2 weeks (14 days) 
 
200 μg for 2 weeks (14 days) 
 
MEDI0382 600 μg (11 weeks) 
 
 
50 μg for 1 week (7 days) 
 
100 μg for 2 weeks (14 days) 
 
200 μg for 2 weeks (14 days) 
 
300 μg for 2 weeks (14 days) 
 
400 μg for 2 weeks (14 days) 
 
500 μg for 2 weeks (14 days) 
 
Subjects may travel to the site for daily visits during Week 1 or alternatively should be given 
the option to stay overnight locally, if this is more convenient. 
 
Maintenance Treatment Period 
 
During the maintenance treatment period, subjects randomized to receive MEDI0382 will 
titrate to the maintenance dose and continue with this dose to the end of the period: 
 
MEDI0382 300 μg 
 
 
300 μg for 14 weeks 
 
MEDI0382 600 μg 
 
 
600 μg for 8 weeks 


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3.1.3 
Management of Study Medication Related Toxicities 
3.1.3.1 
Tolerability 
To help prevent the occurrence of nausea and vomiting, prior to receiving investigational 
product, subjects will be counselled about meal size and eating habits. This advice should be 
re-iterated should symptoms occur once investigational product is initiated. In the event that 
symptoms do not improve, subjects should be offered anti-emetic therapy in accordance with 
institutional and local practice guidelines as long as medications that are prokinetic agents 
such as domperidone or metoclopramide are avoided. 
MEDI0382 600 μg group only: in the event that a subject is unable to tolerate the 
investigational product following up-titration to 600 μg at Week 12, down-titration may be 
considered to the 500 μg dose level. If more than two subjects in the first eight subjects 
receiving 600 μg drop out or down-titrate to 500 μg, due to inability to tolerate the 600 μg 
dose, the remaining subjects in MEDI0382 600 μg group will not be up-titrated beyond the 
500 μg dose level. 
Investigators should monitor subjects with vomiting for signs of hypovolemia. Subjects with 
impaired renal function could be extra sensitive to hypovolemia. Such subjects should be 
informed about the importance of adequate hydration in case of nausea and vomiting. These 
subjects should also undergo additional laboratory testing for potential creatinine increases, as 
appropriate. 
 
3.1.3.2 
Hypoglycemia 
Spontaneous and clinically significant hypoglycemia has not been experienced in completed 
studies with MEDI0382 up to a dose of 300 μg alongside metformin treatment. 
 
Self-monitored plasma glucose or blood glucose readings and hypoglycemic events will be 
reviewed and managed by the investigator as per local standards of care. Subjects with T2DM 
will be provided with glucose meters and should be advised to use the glucose meter to check 
their capillary blood glucose level as per their usual schedule and if they have symptoms of 
hypoglycemia (hunger, dizziness, shaking, sweating, etc) or feel unwell. Any blood glucose 
level < 3.0 mmol/L (54 mg/dL) is considered as clinically significant hypoglycemia regardless 
of symptoms or not and should be reported by investigators as an AE. 
 
In the event of a severe hypoglycemic episode in a subject with T2DM taking oral antidiabetic 
agents, dose reduction of such medication should be considered. In the event that no dose 
reduction of oral anti-diabetic agents can be undertaken, the subject may be withdrawn from 
treatment following discussion by the investigator with the medical monitor. Subjects should 
not be discontinued from treatment based on single episodes of hypoglycemia or symptoms of 
hypoglycemia unless clinically indicated. The assessment of a single fingerstick or local 


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laboratory glucose value should not be the sole assessment used to determine subject 
discontinuation due to hypoglycemia. 
 
The definition of a severe hypoglycemic event is as follows: 
 
“Severe hypoglycemia is an event requiring assistance of another person to actively 
administer carbohydrates, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following the 
return of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration” (Seaquist et al, 2013). 
 
3.1.3.3 
Persistent Hyperglycemia 
Rescue therapy will be considered for any subject with persistent hyperglycemia. 
Self-monitored plasma glucose or blood glucose readings will be collected and reviewed by 
the investigator. Rescue therapy with add-on insulin is the preferred option for rescue therapy, 
but additional drug classes are permitted. In addition, the dose of metformin may be increased. 
Any change in anti-diabetic medications must be recorded in the electronic case report form 
(eCRF). It is advisable to avoid dipeptidyl peptidase-4 inhibitor (DPP-4i)-based treatments for 
rescue therapy for hyperglycemia. In the event of a need for rescue therapy for hyperglycemia, 
alternative options should be considered. Rescue therapy with any GLP-1 receptor agonist, or 
peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist-based intervention is 
prohibited. 
3.2 
Rationale for Dose, Population, and Endpoints 
3.2.1 
Dose Rationale 
No clinical studies with MEDI0382 have been performed to date in subjects with non-cirrhotic 
NAFLD/NASH with fibrosis; however, MEDI0382 has been studied in overweight/obese 
subjects with T2DM (Section 1.4). Given the pathophysiological overlap of subjects with 
T2DM and NASH (~80% of NASH patients are obese, and approximately 50% have T2DM 
[Younossi et al, 2016]), the data for subjects with T2DM are relevant for subjects with NASH. 
 
Reductions in weight have been shown to be related to histological changes in NASH and 
liver fibrosis (Vilar-Gomez et al, 2015). Therefore, the effect of body weight change is 
particularly relevant, as it provides a link between the two indications with respect to dose 
response. 
 
Current experience with marketed GLP-1 receptor agonists suggests that higher doses of 
GLP-1 receptor agonist therapy may be associated with greater durability of weight loss, and 
there is a known association between degree of weight loss and improvement in hepatic fat as 
well as histological features of NASH with fibrosis. Furthermore, data from a bariatric surgery 
study indicate that greater weight loss is associated with greater improvements in steatosis and 


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even hepatic inflammation. Taken together, since weight loss is at least in part responsible for 
the anticipated improvements in NAFLD/NASH, it is important to establish whether near 
maximal GLP-1/glucagon dual agonism at higher doses up to and beyond those studied 
exhibits a pharmacodynamic profile that recapitulates or is even perhaps superior to that 
reported with GLP-1 receptor agonists, and to dissect out the weight loss-dependent and 
independent effect on hepatic fat in patients with non-cirrhotic NAFLD/NASH with fibrosis. 
MEDI0382 at 200 μg (Study D5670C00002) was associated with significant reductions in 
liver fat and improvement in transaminase levels in a group of overweight/obese subjects with 
T2DM. Assessment of safety and tolerability of doses of MEDI0382 higher than 300 μg and 
up to 600 μg in an obese population is currently ongoing (Study D5672C00001). Taken 
together, the planned active doses for the current proposed study in subjects with non-cirrhotic 
NAFLD/NASH with fibrosis will include a 600-μg dose arm, determined as the maximal 
tolerated dose in Cohort 1 of the ongoing titration Study D5672C00001 in 12 obese subjects 
treated with MEDI0382 for maximum 2 weeks on stable dose. Review of preliminary safety 
data revealed no new safety concerns with the data supportive of the use of such doses in 
similar settings. Therefore, the current study proposes to assess the effects of MEDI0382 at 
the 600 μg dose in a population with biopsy-confirmed non-cirrhotic NAFLD/NASH with 
fibrosis (F1, F2, F3) (with the opportunity to down-titrate to 500 μg for the entire group based 
on tolerability in the first 8 subjects (see Section 3.1.3). However, there remains a risk that 
doses higher than 300 μg may not be tolerated in this population. In order to mitigate such 
risk, and to be able to gain meaningful information from this critical study, evaluation of the 
effects of MEDI0382 at the 300 μg dose in a second group of subjects with non-cirrhotic 
NAFLD/NASH with fibrosis (F1, F2, or F3) will be performed. Considering the separation 
between the two dose levels in terms of plasma exposure, such a strategy will also add 
considerable value for optimization of dose selection for planned pivotal studies for the 
MEDI0382 NASH program. 
The no-observed-adverse-effect-level (NOAEL) of 90 μg/kg/day was based on findings in the 
9-month, daily repeat-dose SC toxicology study in the cynomolgus monkey. These were 
considered to be consistent with pharmacology-mediated induction of weight loss/lower 
weight gain, reversible changes in the pancreas (acinar degranulation and hypercellularity of 
the pancreatic islets), and changes in energy utilization and associated metabolic stress (minor 
changes in blood chemistry parameters, lower thymus weights). Treatment was also associated 
with changes in the skin (dermal inflammation, acanthosis and hyperkeratosis) in 3 of 
6 female cynomolgus monkeys dosed. 
 
While the NOAEL determined in the rat 6-month, daily repeat-dose SC toxicology study 
(ie, 7.5 μg/kg/day) was lower than that in the cynomolgus monkey, this was driven primarily 
by the findings in the thyroid gland (C-cell hyperplasia, adenoma, and carcinoma) that were 
considered, in this species, to be adverse. This is a known class effect with GLP-1 receptor 
agonists that is considered rodent specific and of unknown relevance to humans (Center for 


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Drug Evaluation and Research, 2005). Therefore, cynomolgus monkey, and the toxicity 
profile of MEDI0382 generated in that species, are the most appropriate non-clinical species 
to use for clinical risk assessment and the setting of safety margins. 
 
Table 4 illustrates the main proposed clinical dose periods and estimated safety margins over 
the predicted maximum observed concentration (Cmax) and AUC in humans for this repeat- 
dose study and the observed Cmax and AUC at the NOAEL in the 9-month repeat-dose toxicity 
study in cynomolgus monkeys. The steady state Cmax and AUC-based safety margins at the 
maximum proposed human dose of 600 μg after up-titration steps based on cynomolgus 
monkey NOAEL (90 μg/kg/day) are 12-fold and 8-fold, respectively, which indicates that the 
exposure is anticipated to be lower in humans to that determined in monkeys at the NOAEL. 
 
Table 4 
Proposed Study Doses and Predicted Safety Margins Based on Safety 
Data From the Cynomolgus Monkey 
 
 
 
Human Dose (μg) 
Predicted Median Human 
Exposure at steady state 
Safety Margin Over Cynomolgus 
Monkey Exposure at NOAELa at 
Day 273 
AUCtau 
(ng•hr/mL) 
Cmax 
(ng/mL) 
AUC 
Cmax 
50 
51 
3.4 
82 
119 
100 
84 
5.5 
50 
74 
200 
160 
10.6 
26 
38 
300 
249 
17 
17 
25 
600 
498 
33 
8 
12 
AUC = area under the concentration-time curve; BMI = body mass index; Cmax = maximum observed 
concentration; NOAEL = no-observed-adverse-effect level. 
Note: The information in this table is based on BMI of 35 kg/m2. 
a 
NOAEL = 90 μg/kg/day 
 
3.2.2 
Rationale for Study Population 
Obese subjects with biopsy-confirmed non-cirrhotic NAFLD/NASH with fibrosis and with or 
without T2DM, will be recruited, as such subjects would gain the most benefit from treatment 
with MEDI0382, rather than healthy subjects who would not see disease benefits. Subjects 
with non-cirrhotic NAFLD/NASH with fibrosis stage F1, F2 or F3 (inclusive) will be 
recruited. In order to ensure a balance of subjects with early and advanced fibrosis, the 
number of subjects with F1 fibrosis will be capped at 25% in the study. Subjects with F4 
fibrosis (cirrhosis) will not be included because histological progression is less relevant in 
these subjects, where the therapeutic emphasis is more on the reduction of the physiological 
abnormalities (e.g., elevated portal pressure). Obese subjects are included because excess 
weight is associated with the development of NASH and MEDI0382 is expected to promote 
weight loss. 


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3.2.3 
Rationale for Endpoint(s) 
Rationale for Primary Endpoint 
 
1 
The current study will evaluate the overall safety (including hepatic safety) and 
tolerability in the setting of multiple dosing of MEDI0382 (up to 600 μg) in a population 
with biopsy-confirmed non-cirrhotic NAFLD/NASH with fibrosis. 
 
Rationale for Secondary Endpoints 
 
1 
Improvements in hepatic steatosis have been associated with a therapeutic response in the 
resolution of NASH. MRI-PDFF has been demonstrated to be as sensitive as histology for 
detecting changes in whole liver fat content in natural history and therapeutic studies 
(Meisamy et al, 2011). Furthermore, MRI-PDFF is a non-invasive assessment with less 
risk to the subject and is less operator-dependent than other methodologies. A relative 
reduction of liver fat content by about 29% has been shown to be associated with 
histologic improvements in NASH (Patel et al, 2016). Use of the GLP-1 and glucagon 
co-agonist MEDI0382 was associated with significant reductions in liver fat in a group of 
overweight/obese subjects with T2DM in the setting of a subgroup within a Phase 1/2a 
study (Study D5670C00002). Therefore, it is reasonable to propose and anticipate a 
clinically relevant and statistically significant reduction of hepatic fat measured by 
MRI-PDFF in a population of biopsy-confirmed non-cirrhotic NAFLD/NASH with 
fibrosis. However, the population proposed for the current study is expected to have an 
admixture of pathologic features of NAFLD, NASH, and fibrosis, with varying degrees of 
improvement in each of these pathophysiologic features and varying time courses for 
such improvement in response to MEDI0382. Since steatosis will be a part of the 
pathophysiologic picture, but may not be the dominant pathologic feature, it is expected 
that we will observe a significant and clinically relevant change in HFF in the current 
study, but of a magnitude that may be less robust than in a population with steatosis 
alone. Furthermore, it is anticipated that prolonged treatment should lead to greater 
reductions in HFF in response to MEDI0382. Taken together, we anticipate a difference 
from placebo in the relative reduction from baseline in HFF in response to at least one 
dose of MEDI0382 tested in the current study. It is reasonable to propose that such a 
change in steatosis along with decreases in inflammation and NASH disease activity 
following prolonged treatment should position MEDI0382 as a viable treatment option for 
subjects with biopsy-confirmed non-cirrhotic NASH with fibrosis. 
2 
Hepatic fat fraction: Improvements in hepatic steatosis have been associated with a 
therapeutic response in the resolution of NASH. MRI-PDFF has been demonstrated to be 
as sensitive as histology for detecting changes in whole liver fat content in natural history 
and therapeutic studies (Meisamy et al, 2011). Furthermore, MRI-PDFF is a non-invasive 
assessment with less risk to the subject and is less operator-dependent than other 
methodologies. A reduction of absolute liver fat content by at least 5% has been shown to 
be associated with histologic improvements in NASH (Patel et al, 2016). Use of the 
GLP-1 and glucagon co-agonist MEDI0382 was associated with significant reductions in 
liver fat in a group of overweight/obese subjects with T2DM in the setting of a subgroup 
within a Phase 1/2a study (Study D5670C00002). Therefore, it is reasonable to propose 


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and anticipate a reduction of absolute hepatic fat measured by MRI-PDFF in a population 
of biopsy-confirmed non-cirrhotic NAFLD/NASH with fibrosis. 
3 
Markers of hepatic inflammation: Changes in circulating levels of transaminases such as 
ALT, AST, and GGT are considered in part to represent changes in hepatic inflammatory 
activity. The current study will measure changes in circulating levels of transaminases as 
indices of hepatic inflammation in a population with non-cirrhotic NASH with fibrosis. 
4 
Body weight and BMI: Excess body weight is associated with the development of NASH. 
Cotadutide is expected to promote weight loss and a reduction in body weight is 
potentially an indicator of therapeutic response. 
 
 
4 
MATERIALS AND METHODS 
4.1 
Subjects 
4.1.1 
Number of Subjects 
In total, 72 subjects are planned for inclusion in this study; 24 subjects will be randomized to 
each of the MEDI0382 groups (300 and 600 μg); and 12 subjects will be randomized to each 
of the corresponding placebo groups. 
 
4.1.2 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
 
1 
Provision of informed consent (with the exception of consent for future genetic and 
non-genetic research) prior to performing any study-specific procedures, including 
screening evaluations. 
2 
Subjects aged ≥ 18 years at the time of consent. 
3 
BMI ≥ 30 kg/m2 at screening. 
4 
Hemoglobin A1c (HbA1c) ≤ 9.5% (inclusive) at screening if T2DM present, managed by 
either diet and/or a stable dose of metformin, sodium-glucose co-transporter 2 (SGLT-2) 
inhibitors, sulphonylureas or acarbose (ie, no major dose adjustments in prior 3 months to 
screening). 
5 
Definitive NAFLD/NASH with NAS ≥ 4 with ≥ 1 in each component (ie, steatosis, 
lobular inflammation and ballooning), as diagnosed by liver biopsy within 6 months of 
screening with liver fibrosis stage F1, F2 or F3. The number of subjects with F1 will be 
capped at 25% in the study. 
6 
Evidence of hepatic steatosis or liver fat (≥ 10%) by MRI-PDFF. Subjects with imaging 
performed within 60 days prior to screening do not need to repeat this assessment at Visit 
2 (Day -10). 
7 
Women of childbearing potential: 
(a) Who are sexually active with a non-sterilized male partner must have used at least 
one highly effective method of contraception (see Section Appendix A for definition 
of females of childbearing potential and for a description of highly effective methods 


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of contraception) from screening, and must agree to continue using such precautions 
through to the end of the study. It is strongly recommended for the male partner of a 
female subject to also use male condom plus spermicide throughout this period. 
Cessation of contraception after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are 
not acceptable methods of contraception. 
(b) Must have a negative urine pregnancy test within 72 hours prior to the first dose of 
investigational product; and not be breastfeeding. 
 
4.1.3 
Exclusion Criteria 
1 
History of, or any existing condition that, in the opinion of the investigator, would 
interfere with evaluation of the investigational product, put the subject at risk, influence 
the subject’s ability to participate or affect the interpretation of the results of the study. 
2 
Liver disease of other etiologies (e.g., alcoholic steatohepatitis; drug-induced, viral, or 
autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; 
hemochromatosis; alpha 1 antitrypsin deficiency; Wilson’s disease) including positive 
results for hepatitis B surface antigen (HBsAg) or hepatitis C antibody tests (anti-HCV). 
3 
History of cirrhosis and/or hepatic decompensation, including ascites, hepatic 
encephalopathy or variceal bleeding. 
4 
Prior or planned liver transplantation. 
5 
Alcohol consumption > 21 units of alcohol per week for males and > 14 units per week 
for females on average over a two-year time frame prior to baseline biopsy. 
6 
Evidence of alcohol dependence as assessed by the Alcohol Use Disorder Identification 
Test (AUDIT) questionnaire at screening (Appendix F and Appendix G). 
7 
A history of type 1 diabetes mellitus (T1DM), a history of diabetic ketoacidosis or current 
use of insulin-based therapies. 
8 
Clinically significant inflammatory bowel disease or other severe disease or surgery 
affecting the upper gastrointestinal tract (including bariatric surgery) which may affect 
gastric emptying or could affect the interpretation of safety and tolerability data. 
9 
Physician-diagnosed diabetic subjects with clinically significant gastroparesis (as judged 
by the investigator) or those treated for gastroparesis within 6 months prior to screening. 
10 History of > 5 kg weight loss in the last 6 months prior to screening or recent (within 
3 months of screening) use of drugs approved for weight loss (e.g., orlistat, 
bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well as those 
drugs used off-label. 
11 Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, 
including but not limited to, myocardial infarction, acute coronary syndrome or stroke, or 
subjects who have undergone percutaneous coronary intervention or a coronary artery 
bypass graft within the past 6 months or who are due to undergo these procedures at the 
time of screening. 
12 Severe congestive heart failure (New York Heart Association Class IV). 
13 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. 


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14 History of substance dependence or a positive screen for drugs of abuse, likely to impact 
subject safety or compliance with study procedures, at the discretion of the Investigator. 
15 History of psychosis or bipolar disorder. History of major depressive disorder within the 
past year with the subject being clinically unstable, or any history of suicide attempt or 
history of suicidal ideation within the past year. 
16 Recent (within 3 months of baseline biopsy) use of therapies associated with development 
of NAFLD (e.g., systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long- 
term use of tetracyclines). 
17 Recent (within 3 months of baseline biopsy) use of obeticholic acid or other therapy 
under investigation for NASH. 
18 High dose vitamin E (> 400 IU) unless on a stable dose for at least 1 year prior to the 
baseline biopsy, and not initiated after the biopsy was taken. 
19 Recent (within 3 months of baseline biopsy) use of GLP-1 receptor agonist or GLP-1 
receptor agonist containing therapies. 
20 Any subject who has received another investigational product as part of a clinical study 
within the last 30 days or 5 half-lives of the therapy (whichever is longer) at the time of 
screening. Any prior exposure to MEDI0382 is not permitted. 
21 Concurrent participation in another interventional study of any kind or repeat 
randomization in this study. 
22 Severe allergy/hypersensitivity to any of the proposed study treatments or excipients. 
23 Contra-indication to MRI: such as subjects with pacemakers, metallic cardiac valves, 
magnetic material such as surgical clips, implanted electronic infusion pumps or other 
conditions that would preclude proximity to a strong magnetic field; subjects with history 
of extreme claustrophobia or subject cannot fit inside the MR scanner cavity. 
24 History of acute pancreatitis or current chronic pancreatitis. Subjects with serum 
triglyceride concentrations above 1000 mg/dL (11 mmol/L) at screening, as this can 
precipitate acute pancreatitis. 
25 Abnormal laboratory values including any of the following: 
(a) AST or ALT > 5 × upper limit of normal (ULN). 
(b) Impaired renal function defined as estimated glomerular filtration rate (eGFR) 
≤ 30 mL/minute/1.73 m2 at screening (estimated according to chronic kidney disease 
epidemiology collaboration [CKD-EPI]). 
(c) Albumin < 35 g/L. 
(d) International normalized ratio (INR) > 1.3. 
(e) Total Bilirubin (TBL) > 25 μmol/L in the absence of known Gilbert’s disease. 
(f) Platelets < 140-150,000/mm3. 
(g) Any other clinically significant abnormalities in clinical chemistry, hematology, or 
urinalysis results as judged by the investigator. 
26 Severely uncontrolled hypertension defined as systolic blood pressure ≥ 180 mmHg 
and/or diastolic blood pressure ≥ 110 mmHg on the average of 2 seated measurements 
after being at rest for at least 10 minutes at screening or randomization. 


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27 Basal calcitonin level > 50 ng/L at screening, or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2). 
28 Hemoglobinopathy, hemolytic anemia, or chronic anemia (hemoglobin concentration 
< 11.5 g/dL [115 g/L] for male subjects or < 10.5 g/dL [105 g/L] for female subjects) at 
screening, or any other condition known to interfere with interpretation of HbA1c 
measurements 
29 Any positive results for human immunodeficiency virus (HIV) infection. 
30 Any AstraZeneca, MedImmune, or study site employee, or close relatives of any of the 
aforementioned employees. 
31 Females who are pregnant or lactating. 
 
Subjects may be re-screened once if the reason for screen failure was transient (including but 
not limited to study-supplied equipment failure or unforeseen personal events that mandate 
missed screening visits). 
 
4.1.4 
Subject Enrollment and Randomization 
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (E-code) number will be 
assigned by a central system (e.g., an interactive web response system, IWRS), and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
E-code 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 
are not randomized), including the reason(s) for screening failure. 
 
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not be 
randomized or receive investigational product. 
 
4.1.5 
Screen Failures 
Screen failures are defined as subjects who signed the informed consent form (ICF) to 
participate in the clinical study but are not subsequently randomized into the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
subjects to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened one time if they fulfil the inclusion/exclusion criteria then. The subject should sign 
a new informed consent if rescreened. The same E-code will be assigned for the rescreened 
subject. 


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These subjects should have the reason for screen failure recorded in the eCRF. 
 
4.1.6 
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 adverse events (AEs). 
Subjects who are permanently discontinued from receiving investigational product will be 
recommended to continue the study and follow the original visit schedule without taking 
investigational product. If a subject discontinues from the investigational product, he or she 
should be asked, at the discretion of the treating physician, to return to the study site for the 
Early Discontinuation Visit (see Table 8). Where possible, the Early Discontinuation Visit 
should be within 7 days from last investigational product dose, unless consent is withdrawn 
from further study participation, or the subject is lost to follow-up (see Section 4.1.7). 
Subjects attending an Early Discontinuation Visit should also be asked to return 28 days (±3 
days) from the last investigational product dose for follow-up assessments (see Table 8) unless 
they are unable or unwilling to return. If the subject continues in the study, after the Early 
Discontinuation Visit, the next visits should be planned in accordance to the original visit 
schedule. However, only 3 MRIs should be completed during the treatment period, for 
subjects discontinuing after Week 12 but before Week 19, the last MRI will be performed at 
the Early Discontinuation Visit. Any subject who has been randomized into the study will 
only have 3 MRIs performed during the treatment period. In all instances, adverse events will 
be followed up and all study medications should be returned by the subject. 
If a subject withdraws from further participation in the study, then no further study visits or 
data collection should take place. 
 
If a subject withdraws from the study, then his/her enrollment/randomization code cannot be 
reused. Withdrawn subjects will not be replaced. 
 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
the treatment must be documented. 
 
4.1.7 
Discontinuation of Investigational Product 
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
 
1 
Withdrawal of consent from further treatment with investigational product. 
2 
Lost to follow-up. 
3 
An AE that, in the opinion of the investigator or the sponsor, warrants discontinuation of 
further dosing. 


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4 
Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation prior to start of study treatment but was 
entered into the study regardless. 
5 
Subject non-compliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (e.g., refusal to adhere to scheduled visits). 
6 
Pregnancy in a female subject. 
7 
Liver function tests meeting any of the following criteria: 
(a) ALT and/or AST are > 3 × ULN and TBL > 2 × ULN 
(b) ALT and/or AST are > 5 × ULN for ≥ 4 consecutive days, at any time after the initial 
confirmatory result in subjects with normal baseline values. 
(c) ALT and/or AST > 8 × ULN 
(d) New onset jaundice that is not explained by Gilbert’s irrespective of other liver 
biochemistries 
(e) Albumin < 28 g/L 
(f) INR > 2 
8 
Acute viral hepatitis. 
9 
Symptoms or signs of cirrhosis and/or hepatic decompensation (e.g., ascites, variceal 
bleeding, hepatic encephalopathy). 
10 Acute pancreatitis. 
 
Subjects who are permanently discontinued from receiving investigational product will be 
recommended to continue the study and follow the original visit schedule without taking 
investigational product. If a subject discontinues from the investigational product, he or she 
should be asked, at the discretion of the treating physician, to return to the study site for the 
Early Discontinuation Visit (see Table 8). Where possible, the Early Discontinuation Visit 
should be within 7 days from last investigational product dose, unless consent is withdrawn 
from further study participation, or the subject is lost to follow-up. Subjects attending an Early 
Discontinuation Visit should also be asked to return 28 days (±3 days) from the last 
investigational product dose for follow-up assessments (see Table 8) unless they are unable or 
unwilling to return. If the subject continues in the study, after the Early Discontinuation Visit, 
the next visits should be planned in accordance to the original visit schedule. However, only 3 
MRIs should be completed during the treatment period, for subjects discontinuing after Week 
12 but before Week 19, the last MRI will be performed at the Early Discontinuation 
Visit. Any subject who has been randomized into the study will only have 3 MRIs performed 
during the treatment period. 
4.1.8 
Study Stopping Criteria 
The study may be stopped if, in the judgement of MedImmune, study subjects are placed at 
undue risk because of clinically significant safety findings. The following criteria should be 
fulfilled: 


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 
Meet individual stopping criteria or are otherwise considered significant 
 
Are assessed as causally related to investigational product 
 
Are not considered to be consistent with continuation of the study. 
 
For the individual subject, all data available for the subject at the time of discontinuation or 
follow up must be recorded in the eCRF regardless of the reason for termination. All reasons 
for discontinuation of treatment must be documented. 
 
In terminating the study, the sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
 
4.1.9 
Replacement of Subjects 
Subjects will not be replaced. 
 
4.1.10 
Withdrawal of Informed Consent for Data and Biological Samples 
MedImmune ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent. 
 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
MedImmune is not obliged to destroy the results of this research. 
 
As collection of the biological samples is an integral part of the study, then the subject is 
withdrawn from further study participation. 
 
The Principal Investigator: 
 
 
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to MedImmune. 
 
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented. 
 
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented, 
and the signed document returned to the study site. 
 
Ensures that the subject and MedImmune are informed about the sample disposal. 
 
MedImmune ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 


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4.2 
Schedule of Study Procedures 
Whenever vital signs, 12-lead digital electrocardiogram (dECG), and blood draws are 
scheduled for the same nominal time, the blood draws should occur last. The timing of the 
first 2 assessments should be such that it allows the blood draw (e.g., pharmacokinetics blood 
sample) to occur at the proper nominal time. 
 
4.2.1 
Enrollment/Screening Period 
Table 5 shows all procedures to be conducted at the screening visit. 


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Study Period 
Screening 
Visit Number 
V1 
V2f 
Procedure/Study Day 
Day -28 to -11 
Day -10 ± 3 days 
Written informed consent/assignment of E-code number 
x 
 
Informed consent for future genetic research samples 
(optional) 
x 
 
Informed consent for future non-genetic research samples 
(optional) 
x 
 
Verify eligibility criteria 
x 
x 
CLDQ-NASH and SF-36 
x 
 
Dispensation/completion of diary (food intake) 
x 
x 
Medical history, including smoking and alcohol history 
x 
 
Demographics 
x 
 
Physical examination (full)a 
x 
 
Weightb, height and BMI calculation 
x 
 
dECGc 
x 
 
Vital signsd (BP, pulse, body temperature, RR) 
x 
 
ABPMe 
 
x 
MRI (including MRI-PDFF)f 
 
x 
Fibroscanf 
 
x 
AUDIT questionnaire 
x 
 
Assessment of SAEs 
x 
x 
Concomitant medications 
x 
x 
SC injection training/demonstration/verify subject’s ability 
to self-injectg 
x 
 
Collect blood for: 
Serum chemistry 
x 
 
Hematology 
x 
 
Coagulation parameters 
x 
 
Circulating markers (ALT, AST, GGT) 
x 
 
Calcitonin 
x 
 
HbA1c 
x 
 
Lipase and amylase 
x 
 
TSH 
x 
 
Serum triglycerides 
x 
 


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Study Period 
Screening 
Visit Number 
V1 
V2f 
Procedure/Study Day 
Day -28 to -11 
Day -10 ± 3 days 
Virology: hepatitis B surface antigen, hepatitis C virus 
antibody; HIV-1 and HIV-2 
x 
 
FSH (postmenopausal females only)h 
x 
 
ADA blood sample 
x 
 
Collect urine for: 
Urinalysis 
x 
 
Pregnancy test 
x 
 
Drug and alcohol screeni 
x 
 
ABPM = ambulatory blood pressure monitoring; ADA = anti-drug antibody; AE = adverse event; 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; AUDIT = Alcohol Use Disorder 
Identification Test; BMI = body mass index; BP = blood pressure; CLDQ-NASH = Chronic Liver Disease 
Questionnaire for non-alcoholic steatohepatitis; dECG = digital electrocardiogram; eCRF = electronic case 
report form; FSH = follicle-stimulating hormone; GGT = gamma glutamyl transferase; HbA1c = hemoglobin 
A1c; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging; MRI-PDFF = magnetic 
resonance imaging-proton density fat fraction; RR = respiratory rate; SAE = serious adverse event; 
SC = subcutaneous; SF-36 = Short-Form-36; E-code = subject identification number; TSH = thyroid 
stimulating hormone; V = visit. 
a 
Only the screening physical examination will be a full examination. For all time points thereafter, only 
an abbreviated physical examination is required. 
b 
Body weight should be measured in the morning, after the subject has toileted and removed bulky 
clothing, including shoes. Calibrated scales should be used. 
c 
A single dECG recording should be performed after the subject has rested in the supine position for at 
least 10 minutes. 
d 
Vital sign measurements should be measured after the subject has rested in the seated position for at 
least 10 minutes (rest period for dECG will suffice). Two consecutive BP readings should be taken at 
intervals of at least 1 minute, and the average recorded in the eCRF. 
e 
Subjects will be fitted with the ABPM device while at the clinical unit, which may involve practice 
inflations. The subject will then wear the monitor/cuff for approximately 24 hours (including overnight 
at home) and will remove the device at home at the end of the 24-hour period. 
f 
Subjects are required to fast for at least 8 hours overnight prior to Visit 2; subjects are permitted to drink 
water during this period of fasting. MRI-PDFF and fibroscan should be performed with the subject in a 
fasted state. Subjects with MRI (including MRI-PDFF) and fibroscan assessments performed within 60 
days prior to screening do not need to undergo these assessments. If the screening MRI is determined to 
be of inadequate image quality by the MRI analysis vendor the subject may return for repeat MRI 
within the screening visit period. 
g 
Subject’s ability to administer a SC injection should be verified by undergoing a single SC injection 
using normal saline provided by the site. Willingness to perform this for the duration of the study 
should be discussed with the subject. 
h 
FSH should only be checked in female subjects who are post-menopausal and have no previous 
confirmatory laboratory FSH result available. 
i 
An alcohol breath test is an acceptable alternative to an alcohol urine test. If multiple tests are 
performed and conflicting results occur any positive result should be documented. 


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4.2.2 
Randomized Treatment Period 
Table 6 and Table 7 show all procedures to be conducted during the treatment period for 
MEDI0382/matched placebo 300 μg and MEDI0382/matched placebo 600 μg, respectively. 
 
During the Coronavirus Disease 19 (COVID-19) Pandemic: 
 
 
If a subject is unable to attend clinic visits, and/or receive study intervention due to 
COVID-19, the site staff should keep in close contact with the subject, preferably through 
telephone calls at the time of the scheduled visit, to maintain awareness of their 
status. Assessments that can be performed over the phone should be completed such as 
adverse events, study drug administration and/or concomitant medications and any 
additional safety information and recorded in the eCRF and any assessments not 
performed should be recorded as ‘not done’. 
  If a subject is not able to attend their scheduled D78 MRI due to COVID-19 the MRI 
should be performed at the earliest opportunity and within 7 days of the original D78 
scheduled date. All other subsequent visits should follow the original schedule. 
 
If a subject cannot attend their scheduled D133 visit due to COVID-19, every effort 
should be made to perform the visit within 2 days of the original D133 scheduled date, 
with the exception of the MRI which can be performed within 7 days of the original D133 
scheduled date. If it is not possible to perform the visit within a 2-day window, then all 
assessments, excluding pharmacokinetic blood, should be performed at the earliest 
opportunity and within 7 days of the original D133 scheduled date where local 
regulations/public health guidance permit. 


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Study Period 
Treatment Period 
5-week Up-titration 
14-week Maintenance 
Dose 
50 μg 
100 μg 
200 μg 
300 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
(± 2 
days) 
D64 
(± 2 
days) 
D78 
(± 2 
days) 
D92 
(± 2 
days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
Outpatient visita 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Daily visits for dosingb 
 
x 
 
 
 
 
 
 
 
 
 
 
Dispense glucose meterc 
x 
 
 
 
 
 
 
 
 
 
 
 
Verify eligibility criteriad 
x 
 
 
 
 
 
 
 
 
 
 
 
Verify subject’s ability to self-inject 
x 
 
x 
 
 
 
 
 
 
 
 
 
Verify subject fasted for 8 hours 
prior to visit 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Randomization 
x 
 
 
 
 
 
 
 
 
 
 
 
Dose initiation or up-titration 
x 
 
x 
x 
x 
 
 
 
 
 
 
 
Physical examination (abbreviated) 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weighte and BMI calculation 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
Waist and hip circumference 
x 
 
 
 
 
 
 
x 
 
 
 
x 
dECGf 
x 
 
x 
x 
x 
 
 
 
x 
x 
x 
x 
Vital signsg (BP, pulse, body 
temperature, RR) 
x 
 
x 
x 
x 
 
 
 
x 
x 
x 
x 
MRI (including MRI-PDFF)h 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Fibroscanh 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Assessments of AEs/SAEs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Completion of diary (food intake / 
dosing) 
 
 


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Study Period 
Treatment Period 
5-week Up-titration 
14-week Maintenance 
Dose 
50 μg 
100 μg 
200 μg 
300 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
(± 2 
days) 
D64 
(± 2 
days) 
D78 
(± 2 
days) 
D92 
(± 2 
days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
IP dispensation for at home 
self-injection 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
IP accountability 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Collect bloodi for: 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
Hematology 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
Coagulation parameters 
x 
 
 
 
 
 
 
 
 
 
 
x 
MEDI0382 pharmacokineticsj 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
ADAk 
x 
 
x 
 
x 
 
 
x 
 
x 
 
x 
Circulating markers (ALT, 
AST, GGT) 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
TSH 
x 
 
 
 
 
 
 
 
 
 
 
x 
Lipase and amylase 
x 
 
 
 
 
 
 
 
 
 
 
x 
HbA1c 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Calcitonin 
x 
 
 
 
 
 
 
 
 
 
 
x 
Fasting lipid profilel 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Free fatty acids, β-HB, 
aceto-acetate 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Plasma glucose, insulin, 
glucagon, C-peptide and GLP-1 
x 
 
 
 
 
 
 
x 
 
 
 
x 


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Study Period 
Treatment Period 
5-week Up-titration 
14-week Maintenance 
Dose 
50 μg 
100 μg 
200 μg 
300 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
(± 2 
days) 
D64 
(± 2 
days) 
D78 
(± 2 
days) 
D92 
(± 2 
days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
Serum markers of liver 
fibrosism 
x 
 
 
 
 
 
 
x 
 
 
 
x 
NIS4 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Amino acids panel 
xn 
 
 
 
 
 
 
x 
 
 
 
x 
Adiponectin 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Lipidomics 
x 
 
 
 
 
 
 
x 
 
 
 
x 
CK18 and ELF™ 
x 
 
 
 
 
 
 
x 
 
 
 
x 
HOMA-IR calculation 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Sample for future genetic 
testing (optional) 
x 
 
 
 
 
 
 
 
 
 
 
 
Sample for future non-genetic 
testing (optional) 
x 
 
 
 
 
 
 
x 
 
 
 
x 
Collect urine for: 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
Pregnancy test (females of 
childbearing potential only) 
x 
 
 
 
x 
 
 
x 
 
x 
 
x 


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Study Period 
Treatment Period 
5-week Up-titration 
14-week Maintenance 
Dose 
50 μg 
100 μg 
200 μg 
300 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
(± 2 
days) 
D64 
(± 2 
days) 
D78 
(± 2 
days) 
D92 
(± 2 
days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-HB = β-hydroxybutyrate; BMI = body 
mass index; BP = blood pressure; C3M = neoepitope of metallopeptidase 9-mediated degraded type III collagen; C6M = neoepitope of matrix metallopeptidase 
2-mediated degraded type VI collage; CK18 = cytokeratin 18; D = day; dECG = digital electrocardiogram; eCRF =electronic case report form; 
ELF™ = enhanced liver fibrosis score; GGT = gamma glutamyl transferase; GLP-1 = glucagon-like peptide-1; HbA1c = hemoglobin A1c; HDLc = high 
density lipoprotein cholesterol; HOMA-IR = Homeostatic model assessment of insulin resistance; IP = investigational product; LDLc = low density lipoprotein 
cholesterol; MRI-PDFF = magnetic resonance imaging-proton density fat fraction; NIS4 = non-invasive diagnostic score 4; P4NP7S = internal epitope in the 
7S domain of type IV collagen; Pro-C3 = released N-terminal propeptide of type III collagen; Pro-C5 = released C-terminal propeptide of type V collagen; 
Pro-C6 = neoepitope in C-terminal of type VI collagen; RR = respiratory rate; T2DM = type 2 diabetes mellitus; TSH = thyroid stimulating hormone; 
SAE = serious adverse event 
Unless stated otherwise, blood samples are to be taken in a fasted state. 
Whenever vital signs, dECGs, and blood draws are scheduled for the same nominal time, the blood draws should occur last. 
a 
Subjects are required to be dosed at the clinic for the 50 μg dose and on all study day visits when predose procedures are required. Subjects are required to 
fast for at least 8 hours overnight prior to Visits 3 (Day 1), 10 (Day 78) and 14 (Day 133); subjects are permitted to drink water during this period of 
fasting. On days where subjects attend the clinic in a fasted state, blood and urine samples should be obtained prior to administration of IP. 
b 
Subjects are required to receive their doses at the clinic on Days 1-7, as preparation of the MEDI0382/matched placebo 50 μg dose necessitates dilution 
that must be performed by site staff. Subjects may travel to the site for daily visits during this time or alternatively should be given the option to stay 
overnight locally if this is more convenient. 
c 
A glucose meter and test strips should be provided to subjects with T2DM. The subjects should be trained in their use and advised to test their capillary 
blood glucose level as per their usual schedule and if they have symptoms of hypoglycemia (hunger, dizziness, shaking, sweating, etc) or feel unwell. 
d 
Check screening laboratory results and inclusion/exclusion criteria. 
e  Body weight should be measured predose in the morning while the subject is fasted (where applicable) and prior to breakfast, after the subject has toileted 
and removed bulky clothing, including shoes. Calibrated scales should be used. 
f  Triplicate dECG recording should be collected predose (within 20 minutes) on Visits 3 (Day 1), 5 (Day 8), 6 (Day 22), 7 (Day 36), and 14 (Day 133). At 
other time points, a single dECG recording will be collected predose (within 20 minutes). dECGs may be repeated per site’s local procedure. The dECG 
triplicate recording should be taken prior to the pharmacokinetic samples for MEDI0382. 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
Table 6 
MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of Procedures 
CONFIDENTIAL AND PROPRIETARY 
45 of 117 
Template 18.0 
 
 
 
 
Study Period 
Treatment Period 
5-week Up-titration 
14-week Maintenance 
Dose 
50 μg 
100 μg 
200 μg 
300 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
(± 2 
days) 
D64 
(± 2 
days) 
D78 
(± 2 
days) 
D92 
(± 2 
days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
g 
Vital signs schedule: 
 
Visits 3 (Day 1), 5 (Day 8), 6 (Day 22), 7 (Day 36), and 14 (Day 133): predose (within 20 minutes) then 15, 30 and 60 minutes (± 5 minutes) and 
2 hours (± 10 minutes). 
 
All other visits: predose (within 20 minutes). 
For the predose BP measurements, two consecutive BP readings should be taken at intervals of at least 1 minute, and the average recorded in the eCRF. 
h 
MRI (including MRI-PDFF) and fibroscan should be performed predose, in the morning with the subjects in a fasted state. The timing of the MRI and 
fibroscan should be kept as consistent as possible at each study visit where these assessments are required. 
i 
Blood collection to be drawn predose if assessment occurs on a dosing day. Subjects should be in a fasted stated for blood collection drawn on Visits 3 
(Day 1), 10 (Day 78) and 14 (Day 133). For other visits, subject should also be in fasted state for blood collection, whenever possible. 
j 
MEDI0382 pharmacokinetic sampling schedule: 
 
For Visit 3 (Day 1), Visit 5 (Day 8), Visit 6 (Day 22), Visit 7 (Day 36): predose and 6 hours (± 30 minutes) postdose 
 
For Visit 8 (Day 50), Visit 9 (Day 64), Visit 10 (Day 78) and Visit 12 (Day 106): predose 
 
For Visit 14 (Day 133): predose and at 2, 4, 6, 8, 10, 24, 48, 96 hours (± 30 minutes) postdose. Subjects will be given the option to stay at the 
clinical study site or stay overnight locally, if this is more convenient. 
k 
ADA samples will be collected prior to administration of MEDI0382. 
l 
Lipid profile includes total cholesterol, LDLc, HDLc, and triglycerides. 
m 
Markers of liver fibrosis (for collagen turnover) include Pro-C3, Pro-C5, Pro-C6, C3M, C6M and P4NP7S. 
n 
Predose on Day 1. 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
Table 7 
MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures 
CONFIDENTIAL AND PROPRIETARY 
46 of 117 
Template 18.0 
 
 
 
Study Period 
Treatment Period 
11-week Up-titration 
8-week Maintenance 
Dose 
50 μg 
100 
μg 
200 
μg 
300 
μg 
400 μg 
500 μg 
600 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78 
D79 
D80 
D92 (± 
2 days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
Outpatient visita 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Daily visits for dosingb  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucose 
meterc 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify eligibility 
criteriad 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify subject’s ability 
to self-inject 
x 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify subject fasted 
for 8 hours prior to 
visit 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Randomization 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose initiation or up- 
titration 
x 
 
X 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
Physical examination 
(abbreviated) 
x 
 
X 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Weighte and BMI 
calculation 
x 
 
X 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Waist and hip 
circumference 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
Table 7 
MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures 
CONFIDENTIAL AND PROPRIETARY 
47 of 117 
Template 18.0 
 
 
 
Study Period 
Treatment Period 
11-week Up-titration 
8-week Maintenance 
Dose 
50 μg 
100 
μg 
200 
μg 
300 
μg 
400 μg 
500 μg 
600 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78 
D79 
D80 
D92 (± 
2 days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
dECGf 
x 
 
X 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Vital signsg (BP, pulse, 
body temperature, RR) 
x 
 
X 
x 
x 
x 
xh 
xh 
x 
xh 
xh 
x 
xh 
xh 
x 
x 
x 
x 
ABPMi 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
x 
MRI-PDFFj 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Fibroscanj 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Assessments of 
AEs/SAEs 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Completion of diary 
(food intake / dosing) 
 
 
IP dispensation for at 
home self-injection 
 
 
X 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
 
IP accountability 
 
 
 
x 
x 
x 
 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
Collect bloodk for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
x 
Hematology 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Coagulation 
parameters 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
Table 7 
MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures 
CONFIDENTIAL AND PROPRIETARY 
48 of 117 
Template 18.0 
 
 
 
Study Period 
Treatment Period 
11-week Up-titration 
8-week Maintenance 
Dose 
50 μg 
100 
μg 
200 
μg 
300 
μg 
400 μg 
500 μg 
600 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78 
D79 
D80 
D92 (± 
2 days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
MEDI0382 
pharmacokineticsl 
x 
 
X 
x 
x 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
x 
ADAm 
x 
 
X 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
x 
Circulating 
markers (ALT, 
AST, GGT) 
 
x 
 
 
 
 
x 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
TSH 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Lipase and 
amylase 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
HbA1c 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Calcitonin 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Fasting lipid 
profilen 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Free fatty acids, β- 
HB, aceto-acetate 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Plasma glucose, 
insulin, glucagon, 
c-peptide, and 
GLP-1 
 
x 
 
 
 
 
 
x  
x  
x  
x  
x  
x  
x  
x  
x 
 
 
 
 
x 
Serum markers of 
liver fibrosiso 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
Table 7 
MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures 
CONFIDENTIAL AND PROPRIETARY 
49 of 117 
Template 18.0 
 
 
 
Study Period 
Treatment Period 
11-week Up-titration 
8-week Maintenance 
Dose 
50 μg 
100 
μg 
200 
μg 
300 
μg 
400 μg 
500 μg 
600 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78 
D79 
D80 
D92 (± 
2 days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
NIS4 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Amino acids panel 
xp 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Adiponectin 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Lipidomics 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
CK18 and ELF™ 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
HOMA-IR 
calculation 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Sample for future 
genetic testing 
(optional) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample for future 
non-genetic testing 
(optional) 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
Collect urine for: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Pregnancy test 
(females of 
childbearing 
potential only) 
 
x 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
 
x 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
Table 7 
MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures 
CONFIDENTIAL AND PROPRIETARY 
50 of 117 
Template 18.0 
 
 
 
Study Period 
Treatment Period 
11-week Up-titration 
8-week Maintenance 
Dose 
50 μg 
100 
μg 
200 
μg 
300 
μg 
400 μg 
500 μg 
600 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78 
D79 
D80 
D92 (± 
2 days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
ABPM = ambulatory blood pressure monitoring; ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
β-HB = β-hydroxybutyrate; BMI = body mass index; BP = blood pressure; C3M = neoepitope of metallopeptidase 9-mediated degraded type III collagen; C6M = 
neoepitope of matrix metallopeptidase 2-mediated degraded type VI collage; CK18 = cytokeratin 18; D = day; dECG = digital electrocardiogram; eCRF = electronic case 
report form; GGT = gamma glutamyl transferase; GLP-1 = glucagon-like peptide-1; ELF™ = enhanced liver fibrosis score; HbA1c = hemoglobin A1c; HDLc = high 
density lipoprotein cholesterol; HOMA-IR = Homeostatic model assessment of insulin resistance; IP = investigational product; LDLc = low density lipoprotein 
cholesterol; MRI-PDFF = magnetic resonance imaging-proton density fat fraction; NIS4 = non-invasive diagnostic score 4; P4NP7S = internal epitope in the 7S domain 
of type IV collagen; Pro-C3 = released N-terminal propeptide of type III collagen; Pro-C5 = released C-terminal propeptide of type V collagen; Pro-C6 = neoepitope in C-
terminal of type VI collagen; RR = respiratory rate; T2DM = type 2 diabetes mellitus; TSH = thyroid stimulating hormone; SAE = serious adverse event 
Unless stated otherwise, blood samples are to be taken in a fasted state. 
Whenever vital signs, dECGs, and blood draws are scheduled for the same nominal time, the blood draws should occur last. 
a 
Subjects are required to be dosed at the clinic for the 50 μg dose and on study day visits when predose procedures are required. Subjects are required to fast for at 
least 8 hours overnight prior to Visits 3 (Day 1), 14 (Day 78) and 20 (Day 133); subjects are permitted to drink water during this period of fasting. On days where 
subjects attend the clinic in a fasted state, blood and urine samples should be obtained prior to administration of IP. Subjects are required to visit the clinic on two 
subsequent days following up-titration to the 400, 500 and 600 μg dose for safety monitoring; subjects may travel to the site for daily visits during this time or 
alternatively should be given the option to stay overnight locally if this is more convenient. 
b 
Subjects are required to receive their doses at the clinic on Days 1-7, as preparation of the MEDI0382/matched placebo 50-μg dose necessitates dilution that must be 
performed by site staff. Subjects may travel to the site for daily visits during this time or alternatively should be given the option to stay overnight locally if this is 
more convenient. 
c 
A glucose meter and test strips should be provided to subjects with T2DM. The subjects should be trained in its use and advised to test their capillary blood glucose 
level as per their usual schedule and if they have symptoms of hypoglycemia (hunger, dizziness, shaking, sweating, etc) or feel unwell. 
d 
Check screening labs and inclusion/exclusion criteria. 
e 
Body weight should be measured predose in the morning while the subject is fasted (where applicable) and prior to breakfast, after the subject has toileted and 
removed bulky clothing, including shoes. Calibrated scales should be used. 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
Table 7 
MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures 
CONFIDENTIAL AND PROPRIETARY 
51 of 117 
Template 18.0 
 
 
 
Study Period 
Treatment Period 
11-week Up-titration 
8-week Maintenance 
Dose 
50 μg 
100 
μg 
200 
μg 
300 
μg 
400 μg 
500 μg 
600 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78 
D79 
D80 
D92 (± 
2 days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
f 
Triplicate dECG recording should be collected predose (within 20 minutes) on Visits 3 (Day 1), 5 (Day 8), 6 (Day 22), 7 (Day 36), 8 (Day 50), 11 (Day 64), 14 (Day 
78), and 20 (Day 133). At other time points, a single dECG recording will be collected predose (within 20 minutes). dECGs may be repeated per site’s local 
procedure. The dECG triplicate recording should be taken prior to the pharmacokinetic samples of MEDI0382. 
g 
Vital signs schedule: 
 
Visits 3 (Day 1), 5 (Day 8), 6 (Day 22), 7 (Day 36), 8 (Day 50), 11 (Day 64), 14 (Day 78), and 20 (Day 133): predose (within 20 minutes) then 15, 30 and 
60 minutes (± 5 minutes) and 2 
hours (± 10 minutes). 
 
All other visits: predose (within 20 minutes). 
For the predose BP measurement, two consecutive BP readings should be taken at intervals of at least 1 minute, and the average recorded in the eCRF. On days 
when ABPM is due to be checked, a set of vital signs should be performed prior to application of the ABPM cuff. 
h 
Orthostatic BP is to be taken predose at the timepoints specified above. Measurement of orthostatic BP changes will be performed as follows: 
 
After the subject has been supine for a minimum of 5 minutes, BP and pulse rate will be measured in duplicate (at least 1 minute apart). 
 
Immediately after supine measurements, a standing BP and pulse rate will be measured in duplicate as follows: 
 
First measurement: BP and pulse rate measured after at least 1 minute of standing. 
 
Second measurement: BP and pulse rate measured after at least 3 minutes of standing. 
Orthostatic hypotension is defined as a drop of 20 mmHg in systolic BP or a drop of 10 mmHg in diastolic BP within 2 to 5 minutes of standing up, or if standing 
causes signs and symptoms. 
i 
Subjects will be fitted with the ABPM device while at the clinical unit, which may involve practice inflations. The subject will wear the monitor/cuff for 
approximately 24 hours (including overnight at home) and will remove the device at home at the end of the 24-hour period and return the monitor at their next visit. 
j 
MRI (including MRI-PDFF) and fibroscan should be performed predose in the morning with the subjects in a fasted state. The timing of the MRI (including MRI- 
PDFF) and fibroscan should be kept as consistent as possible at each study visit where these assessments are required. 
k 
Blood collection to be drawn predose if assessment occurs on a dosing day. Subjects should be in a fasted state for blood collection drawn on Visits 3 (Day 1), 14 
(Day 78) and 20 (Day 133). For other visits, subject should also be in fasted state for blood collection, whenever possible. 
l 
MEDI0382 pharmacokinetic sampling schedule: 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
Table 7 
MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures 
CONFIDENTIAL AND PROPRIETARY 
52 of 117 
Template 18.0 
 
 
 
Study Period 
Treatment Period 
11-week Up-titration 
8-week Maintenance 
Dose 
50 μg 
100 
μg 
200 
μg 
300 
μg 
400 μg 
500 μg 
600 μg 
Visit Number 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Study Week 
1 
1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
19 
Procedure/Study Day 
D1 
D2, 3, 
4, 5, 6, 
7 
D8 
D22 
D36 
D50 
D51 
D52 
D64 
D65 
D66 
D78 
D79 
D80 
D92 (± 
2 days) 
D106 
(± 2 
days) 
D120 
(± 2 
days) 
D133 
 
For Visit 3 (Day 1), Visit 5 (Day 8), Visit 6 (Day 22), Visit 7 (Day 36), Visit 8 (Day 50), Visit 11 (Day 64), and Visit 14 (Day 78): predose and 6 hours 
(± 30 minutes) postdose 
 
For Visit 18 (Day 106) predose 
 
For Visit 20 (Day 133): predose and at 2, 4, 6, 8, 10, 24, 48, 96 hours (± 30 minutes) postdose. Subjects will be given the option to stay at the clinical study 
site or stay overnight locally, if this is more convenient. 
m 
ADA samples will be collected prior to administration of MEDI0382. 
n 
Lipid profile includes total cholesterol, LDLc, HDLc, and triglycerides. 
o 
Markers of liver fibrosis (for collagen turnover) include Pro-C3, Pro-C5, Pro-C6, C3M, C6M, and P4NP7S. 
p 
Predose on Day 1. 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
CONFIDENTIAL AND PROPRIETARY 
53 of 117 
Template 18.0 
 
 
 
4.2.3 
Follow-up Period 
Table 8 shows all procedures to be conducted during the follow-up period. 
 
Table 8 
Schedule of Follow-up Procedures 
 
Study Period 
Follow-up Period/Early Discontinuatione 
Visit Number 
Visit 15/21 (EoS) 
Study Week 
23 
Procedure/Study Day 
D161 (± 3 days) 
Physical examination (abbreviated) 
x 
Weight and BMI calculation 
x 
dECG 
x 
Vital signsa (BP, pulse, body temperature, RR) 
x 
Assessment of AEs/SAEs 
x 
Concomitant medications 
x 
Completion (food intake) / collection of diary 
x 
Collect blood for: 
Serum chemistry 
x 
Hematology 
x 
Coagulation parameters 
x 
HbA1c 
x 
ADAb 
x 
Circulating markers (ALT, AST, GGT) 
x 
Calcitoninc 
x 
Lipid profiled, free fatty acids, β-HB, 
aceto-acetate 
x 
Collect urine for: 
Urinalysis 
x 
Pregnancy test (females of childbearing 
potential only) 
x 
For Early discontinuation visit, the following should be performed in addition to the abovee: 
IP accountability 
x 
MRI-PDFFf 
x 
Fibroscan 
x 
MEDI0382 pharmacokineticsg 
x 


MedImmune 
Protocol D5671C00002 Amendment 6 
MEDI0382 
27Nov2020; Final 
CONFIDENTIAL AND PROPRIETARY 
54 of 117 
Template 18.0 
 
 
 
Table 8 
Schedule of Follow-up Procedures 
 
Study Period 
Follow-up Period/Early Discontinuatione 
Visit Number 
Visit 15/21 (EoS) 
Study Week 
23 
Procedure/Study Day 
D161 (± 3 days) 
ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; β-HB = β-hydroxybutyrate; BMI = body mass index; BP = blood pressure; D = day; 
dECG = digital electrocardiogram; EoS = end of study; GGT = gamma glutamyl transferase; 
HbA1c = hemoglobin A1c; HDLc = high-density lipoprotein cholesterol; LDLc = low-density lipoprotein 
cholesterol; MRI-PDFF = magnetic resonance imaging-proton density fat fraction; RR = respiratory rate; 
SAE = serious adverse event; ULN = upper limit of normal. 
a 
For BP measurements, two consecutive readings should be taken at intervals of at least 1 minute, and the 
average recorded in the eCRF. 
b 
If this sample is ADA positive, the subject will be asked to return to provide another sample at 
approximately 3 months after the end of study visit. If that sample is ADA positive, additional visit(s) 
approximately every 3 months should continue until a sample tests negative for ADA or return to 
baseline level. 
c 
Calcitonin need only be re-measured in subjects who had a level > ULN on Day 133. 
d 
Lipid profile include total cholesterol, LDLc, HDLc, and triglycerides. 
e 
Subjects are required to fast for at least 8 hours prior to the Early Discontinuation Visit; subjects are 
permitted to drink water during this period of fasting. Subjects should be asked to return within 7 days 
from last investigational product dose, where possible. Subjects should also be asked to return 28 days 
(±3 days) from the last investigational product dose for follow-up assessments unless they are unable or 
unwilling to return.Subjects who discontinue investigational product but wish to continue with study 
assessments should first perform the Early Discontinuation Visit and then continue the assessments as 
described in Table 6 or Table 7 as appropriate. Subjects who discontinue from investigational product 
but continue on the study should not have more than 3 MRIs performed within the study treatment 
period (following randomization). 
f  MRI (including MRI-PDFF) and fibroscan should be performed predose in the morning with the subjects 
in a fasted state. Subjects who discontinue from investigational product but continue on the study should 
not have more than 3 MRIs performed within the study treatment period (following randomization). 
g  One pharmacokinetic sample should be taken at any time during the visit, but should be as close to the 
ADA sample as possible. 
 
4.3 
Description of Study Procedures 
4.3.1 
Efficacy 
Changes in HFF will be assessed by MRI-PDFF (Section 4.3.5.1). 
 
4.3.2 
Safety 
4.3.2.1 
Medical History 
Complete medical history will include history and current medical conditions, past or present 
cardiovascular disorders, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, 
lymphatic, hematologic, immunologic, dermatological, psychiatric, genitourinary, drug and 
surgical history, or any other diseases or disorders. 


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Smoking and alcohol history will also be recorded. 
 
In addition, the subjects will be asked the following questions: 
 
 
In the last 2 years, have you ever been treated with high dose Vitamin E to manage 
NASH (or any other condition)? 
 
Did your prescriber consider your response adequate or inadequate? 
 
In the last 2 years, have you ever been treated with pioglitazone to manage NASH (or any 
other condition)? 
 
Did your prescriber consider your response adequate or inadequate? 
 
When was the last time you tried weight loss and exercise? 
 
Did you lose weight that time and have you been successful keeping the new weight? 
 
The AUDIT questionnaire (Appendix F and Appendix G) to assess alcohol use habits will be 
completed at screening only (Table 5). The results will be used for determining subject 
eligibility (Section 4.1.3). 
 
4.3.2.2 
Physical Examination 
The full physical examination includes an assessment of the following: general appearance 
including skin inspection, lymph nodes, thyroid, musculoskeletal/extremities, cardiovascular 
system, lungs, abdomen, and reflexes. 
 
The abbreviated physical examination includes the following: skin, extremities, cardiovascular 
system, lungs, and abdomen. 
 
Physical examinations will be performed at the time points specified in the schedule of 
procedures (Table 5, Table 6, Table 7, and Table 8). Investigators should pay special attention 
to clinical signs related to previous serious illnesses; new or worsening abnormalities may 
qualify as AEs (additional details are provided in Section 5). In addition, the injection site will 
be assessed. 
 
At study termination clinically significant abnormalities in physical examination findings at 
study termination must be followed up by the investigator and evaluated with additional tests 
if necessary, until the underlying cause is diagnosed, or resolution occurs. 
 
4.3.2.3 
Digital Electrocardiogram 
Digital ECGs will be recorded at the sites according to Table 5, Table 6, Table 7, and Table 8. 
Subjects should rest in the supine position at least 10 minutes before dECG recordings are 
conducted. Digital ECGs may be repeated per site’s local procedure. The dECGs will be 
interpreted by a qualified physician (the investigator or qualified designee) at the clinical 
study site. The investigator should date and sign the dECG tracing and record the clinical 


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significance of any abnormal result on the tracing. Digital ECG evaluation will be recorded in 
the eCRF. 
 
Paper copies of the dECGs will be stored at the study site and digital copies transmitted to a 
central archive. Digital copies may be interpreted where required by other qualified physicians 
outside the study site. 
 
The following variables will be reported: PR, QRS, QT, HR, QTcB and QTcF intervals. The 
investigator may add extra 12-lead dECG safety assessments if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason. 
 
4.3.2.4 
Vital Signs 
Vital sign measurements will be obtained at the visits specified in Table 5, Table 6, Table 7, 
and Table 8. Body temperature and respiratory rate will be measured after the subject has 
rested in the seated position for at least 10 minutes in a quiet setting without distractions. 
Postural BP changes should be measured as described below. Vital sign measurements should 
be taken prior to investigational product administration (where applicable) and before blood 
drawing. BP, and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
 
Route of body temperature measurement will be according to local procedures but should be 
consistent throughout the study for an individual subject. 
Orthostatic hypotension is defined as a drop of 20 mmHg in systolic BP or a drop of 
10 mmHg in diastolic BP within 2 to 5 minutes of standing up, or if standing causes signs and 
symptoms. 
 
Measurement of postural BP changes will be performed as follows: 
 
 
After the subject has been in the supine position for a minimum of 5 minutes, BP and 
pulse rate will be measured in duplicate (at least 1 minute apart). 
 
Standing BP and pulse rate will be measured in duplicate as follows: 
 
First measurement: BP and pulse rate measured after at least 1 minute of standing. 
 
Second measurement: BP and pulse rate measured after at least 3 minutes of 
standing. 
 
On days where ambulatory blood pressure monitoring (ABPM) is due to be checked, a 
predose set of vital signs should be performed prior to application of the ABPM cuff. BP 
should be measured once with the arm at heart level with the subject supine for at least 
10 minutes prior to the measurement and measurements performed using an adequate arm cuff 
size. For time points where dECG recording precedes vital sign measurement, the 10-minute 


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rest in the supine position prior to the dECG suffices for the rest prior to vital sign 
measurement. The pulse rate should be measured for 30 seconds to determine the rate. 
 
Training for Application and Wearing of ABPM Device 
 
Subjects will be given training at their local study site about how to set up and apply the 
ABPM device. In brief, an appropriate size BP cuff will be selected, and the device will be 
fitted to the nondominant arm of the subject, with the bladder placed over the artery and an 
initial test reading performed. The subjects will be advised that for the first reading, the device 
will inflate to a pressure of 180 mmHg, and thereafter the device will adapt to inflate to a 
pressure just above the last recorded BP. The subject will be advised to undergo normal daily 
activities while wearing the cuff, and he/she will be advised to avoid any strenuous form of 
activity, bathing or showering while wearing the cuff. The subject will be advised to remain 
still during a measurement with the arm relaxed at heart level. The subject will also be given 
advice on how to wear the device during the day and at night while sleeping, and what to 
expect in terms of frequency of readings during the day and overnight. During ABPM, 
systolic BP, diastolic BP, heart rate pressure, heart rate, and mean arterial pressure readings 
will be recorded over a period of 24 hours. 
4.3.2.5 
Weight, Height, BMI, Waist and Hip Circumference 
Height and body weight will be measured at the time points specified in Table 5, Table 6, 
Table 7, and Table 8. Body mass index will be calculated directly in RAVE 
[BMI = weight/(height)2], where weight is measured in kg, and height in meters). The height 
measurement recorded at screening will be used to calculate BMI for the eligibility 
assessment. The height measurement recorded at Visit 3 (Day 1) will be used for each 
subsequent BMI calculation. 
 
Waist and hip circumference will be measured at the time points specified in the schedules of 
procedures (Table 5, Table 6, Table 7, and Table 8). The correct position for measuring waist 
circumference is midway between the uppermost border of the iliac crest and the lower border 
of the costal margin. A measuring tape of adequate length should be placed around the 
abdomen at the level of this midway point and a reading taken when the tape is snug but does 
not compress the skin, and at the end of a normal respiratory expiration. Hip circumference 
should be measured around the widest portion of the buttocks, with the tape parallel to the 
floor. Waist-hip ratio is calculated as waist measurement divided by hip measurement (ie, 
waist ÷ hip). For both measurements, the subject should stand with feet close together, arms at 
the side and body weight evenly distributed. Each measurement should be repeated twice; if 
the measurements are within 1 cm of one another, the average should be calculated. If the 
difference between the 2 measurements exceeds 1 cm, the 2 measurements should be repeated. 


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4.3.5 
Pharmacodynamic Evaluation and Methods 
4.3.5.1 
Magnetic Resonance Imaging (Including MRI-PDFF) 
MRI (including MRI-PDFF) will be performed, at the time points specified in Table 5, 
Table 6, Table 7 and Table 8 according to the Imaging Manual to assess HFF, CCI 
 
 
. Subjects with an MRI-PDFF assessment 
performed within 60 days prior to screening do not need to repeat this assessment at Visit 2 
(Day -10). If the screening MRI is determined to be of inadequate image quality by the MRI 
analysis vendor the subject may return for repeat MRI within the screening visit period 
 
4.3.5.2 
Fibroscan 
Fibroscan will be performed, at the time points specified in Table 5, Table 6, Table 7 and 
Table 8 to assess liver stiffness and attenuation parameters. Subjects with a fibroscan 
assessment performed within 60 days prior to screening do not need to repeat this assessment 
at Visit 2 (Day -10). 
 
4.3.6 
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 central 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). 
 
All clinical laboratory tests will be performed according to the timing and frequency presented 
in Table 5, Table 6, Table 7, and Table 8. All protocol-required laboratory assessments must 
be conducted in accordance with the Laboratory Manual. 
 
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
center as source data for laboratory variables. The investigator should follow all clinically 
significant laboratory abnormalities occurring during the study that were not present at 
baseline. These abnormalities should be evaluated with additional tests, if necessary, until the 
underlying cause is diagnosed, or resolution occurs. The diagnosis and resolution date must be 
reported to the sponsor. 
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Information about how AEs based on laboratory tests should be recorded and reported are 
provided in Section 5. 
 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF. 
 
The clinical chemistry, hematology, and urinalysis will be performed at a central laboratory. 
 
Serum chemistry 
• 
blood urea nitrogen 
• 
calcium 
• 
creatinine 
• 
glucose (fasting where required) 
• 
total protein 
• 
sodium 
• 
albumin 
• 
potassium 
• 
TBL 
• 
chloride 
• 
alkaline phosphatase (ALP) 
• 
bicarbonate 
• 
ALT 
• 
phosphorus 
• 
AST 
• 
gamma glutamyl transferase 
Notes for serum chemistry 
Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed concurrently. 
The additional collection time points for circulating markers (ALT, AST, GGT) should be noted (Table 5, 
Table 6, Table 7, and Table 8). 
 
Hematology 
• 
red blood cell count 
• 
platelet count 
• 
hemoglobin 
• 
mean cell volume 
• 
hematocrit 
• 
mean corpuscular hemoglobin concentration 
• 
absolute white blood cell count 
• 
mean corpuscular hemoglobin 
• 
white blood cell count with percent differential 
 
Coagulation parameters 
• 
prothrombin time 
• 
thrombin time 
• 
activated partial thromboplastin time 
• 
international normalized ratio 
 
Urinalysis 
• 
pH 
• 
ketones 
• 
specific gravity 
• 
protein 
• 
glucose 
• 
microscopic analysis (if positive for blood, 
nitrites, or protein) 
• 
blood (urine hemoglobin/erythrocytes/blood) 
• 
bilirubin 


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and GLP-1 
 
• 
color 
• 
leukocytes 
• 
appearance 
• 
urobilinogen 
• 
nitrites 
 
Females only 
• 
pregnancy test: urine human chorionic 
gonadotropin (hCG) (females of childbearing 
potential) 
 
 
• 
follicle stimulating hormone (FSH) (post- 
menopausal women only) 
 
Screening only 
• 
human immunodeficiency virus (HIV)-1 and 
HIV-2 antibodies 
• 
drug and alcohol screen 
 
 
• 
hepatitis B surface antigen (HBsAg) and 
hepatitis C antibody (anti-HCV) 
 
Additional laboratory assessments 
• 
calcitonin 
• 
triglycerides 
• 
HbA1c 
• 
amylase and lipase 
• 
thyroid stimulation hormone (TSH) 
• 
plasma glucose, insulin, glucagon, c-peptide, 
• 
total cholesterol 
• 
free fatty acids 
• 
low-density lipoprotein cholesterol (LDLc) 
• 
beta-hydroxybutyrate 
• 
high-density lipoprotein cholesterol (HDLc), 
• 
aceto-acetate 
• 
amino acid panel 
• 
non-invasive diagnostic score 4 (NIS4) 
• 
collagen turnover (markers of liver fibrosis) 
• 
adiponectin: total and high molecular weight 
• 
lipidomics 
• 
CK18 
• 
enhanced liver fibrosis (ELF™) 
 
4.3.7 
Pharmacokinetic Evaluation and Methods 
Blood will be collected at predose and at specific postdose times to evaluate pharmacokinetics 
of MEDI0382 in plasma at the time points specified in Table 5, Table 6, Table 7, and Table 8. 
The pharmacokinetics of MEDI0382 in plasma will be measured utilizing a validated liquid 
chromatography-tandem mass spectrometry method (LC-MS/MS). 
 
4.3.8 
Immunogenicity Evaluation and Methods 
Immunogenicity blood samples will be collected to evaluate ADA responses to MEDI0382. 
Anti-drug antibody sampling will occur by groups(s) at the time points specified in Table 5, 
Table 6, Table 7, and Table 8. A validated screening assay will be used to determine ADA 
positive samples. Any positive samples will be tested in a confirmatory assay whereby the 
specificity of the ADA response will be confirmed as either positive or negative with respect 
to MEDI0382. Titer evaluation and cross-reactivity to GLP-1 and glucagon may be performed 


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on samples that are confirmed positive for ADA. Serum samples collected for ADA should be 
stored as described in the Laboratory Manual. 
 
Additional immunogenicity data will be reported in the clinical study report (CSR) or in an 
addendum, if applicable. Additional analyses may be conducted on anonymized, individual or 
pooled immunogenicity samples to further evaluate and validate the analytical method. Any 
results from such analyses may be reported separately from the CSR. Immunogenicity 
samples will be retained until point of license for this program and may be utilized for further 
characterization of the antibody response. 
 
4.3.9 
Genetic Evaluations and Method 
The subject’s consent to participate in the genetic research components of the study is 
optional. See Appendix E or further information. 
 
4.3.10 
Biomarker Evaluation 
 
4.3.11 
Storage, Re-use and Destruction of Biological Samples 
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed. 
 
4.3.12 
Estimate of Volume of Blood to be Collected 
The estimated volume of blood to be collected from each subject over the entire course of 
their participation in the study is approximately 461 mL, plus an optional 60 mL for the 
MEDI0382 300 μg/matched placebo group and 557 mL, plus an optional 60 mL for the 
MEDI0382 600 μg/matched placebo group. 
 
4.4 
Study or Study Component Suspension or Termination 
MedImmune reserves the right to temporarily suspend or permanently terminate this study or 
component of the study at any time. The reasons for temporarily suspending or permanently 
terminating the study may include but are not limited to the following: 
 
1 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects 


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2 
Subject enrollment is unsatisfactory 
3 
Non-compliance that might significantly jeopardize the validity or integrity of the study 
4 
Sponsor decision to terminate development of the investigational product for this 
indication 
5 
Sponsor decision to terminate the study based on a planned futility analysis 
 
If MedImmune determines that temporary suspension or permanent termination of the study 
or component of the study is required, MedImmune will discuss the reasons for taking such 
action with all participating investigators (or head of the medical institution, where 
applicable). When feasible, MedImmune will provide advance notice to all participating 
investigators (or head of the medical institution, where applicable) of the impending action. 
 
If the study or component of the study is suspended or terminated for safety reasons, 
MedImmune will promptly inform all investigators, heads of the medical institutions (where 
applicable), and/or institutions conducting the study. MedImmune will also promptly inform 
the relevant regulatory authorities of the suspension/termination along with the reasons for 
such action. Where required by applicable regulations, the investigator or head of the medical 
institution must inform the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) promptly and provide the reason(s) for the suspension/termination. If the study or 
component of the study is suspended for safety reasons and it is deemed appropriate by 
MedImmune to resume the study or component of the study, approval from the relevant 
regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to resuming the 
study. 
4.5 
Investigational Products 
4.5.1 
Identity of Investigational Product(s) 
MedImmune will provide the investigator(s) with investigational product (Table 9) and diluent 
using designated distribution centers. 
 
Table 9 
Identification of Investigational Products 
 
Investigational Product 
Manufacturer 
Concentration and Formulation as 
Supplied 
MEDI0382 
MedImmune 
2 mg/mL sterile liquid formulation, 1 mL 
nominal volume. Single dose vial. 
Matched placebo 
MedImmune 
Sterile liquid formulation buffer, 1 mL 
nominal volume. Single dose vial 
Note: Diluent solution (manufactured by sponsor) will be provided to sites. 
Note that the diluent solution is the same as the placebo. 


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MEDI0382 is provided as a sterile liquid drug product (nominal concentration of 2 mg/mL) in 
50 mM sodium phosphate buffer containing 1.85% weight per volume (w/v) propylene glycol, 
pH 7.8 intended for SC administration. 
 
Matched placebo is provided as a sterile solution of 50 mM sodium phosphate buffer 
containing 1.85% (w/v) propylene glycol, pH 7.8 intended for SC administration. 
 
Investigational product will be supplied to the site in blinded kits each containing 1 vial. Each 
kit has a unique number that is printed on all labels within the kit (ie, the outer carton label 
and the label on the vial within the carton). When investigational product is dispensed for 
at-home dosing, the site should transfer the required number of 1 vial kits into the supplied 
empty, double-blind labelled carton, which can hold up to 8 single vial kits. 
 
4.5.1.1 
Investigational Product Handling 
In-clinic Investigational Product Handling 
Investigational product should be stored at 2°C to 8°C in the original container and should be 
protected from heat and light. 
 
Investigational products are supplied in single-use vials and do not contain preservatives, so 
after dose preparation any unused portion must be discarded. Preparation of syringes for dose 
administration is to be performed using aseptic techniques. Total in-use storage time from 
needle puncture of the investigational product vial to start of administration should not exceed 
4 hours at room temperature. If storage time exceeds these limits, a new dose must be 
prepared from a new vial. 
 
At-home Investigational Product Handling 
The entire carton of investigational product should be stored in the refrigerator. Subjects 
should be asked to ensure they have a normal domestic refrigerator at home, which should be 
between 2°C and 8°C. Investigational product should be protected from heat and light. 
 
Subjects should be instructed not to store the investigational product directly adjacent to the 
refrigerator cooling element. Investigational product should not be used if it has been frozen. 
 
The subject should be instructed to remove from the refrigerator only the 1-vial kit required 
for their daily dose. All other kits are to be kept in the original carton in the refrigerator until 
required. 
 
4.5.1.2 
Investigational Product Inspection 
Each vial selected for dose preparation should be inspected prior to use. The MEDI0382 or 
placebo solution in vials should not be cloudy, discolored, or contain any visible particles. If 
there are any defects noted with the investigational product, the investigator and site monitor 


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should be notified immediately. Refer to the Product Complaint section (Section 4.5.1.6) for 
further instructions. 
 
4.5.1.3 
Dose Preparation Steps 
No incompatibilities between MEDI0382 and plastics passing compatibility tests (ie, 
polyolefin or polyvinylchloride bags) have been observed. 
 
In-clinic Dose Preparation 
Investigational product is supplied in 3 mL glass vials at a nominal concentration of 2 mg/mL. 
The final delivery volume and concentration for each dose period and the syringe sizes to be 
used for preparation are described in Table 10. No incompatibilities have been observed 
between 2 mg/mL MEDI0382 stock solution and plastics passing compatibility tests (ie, 
polypropylene syringes). The diluted stock must be prepared and administered using 1 mL 
polypropylene syringes; the diluted stock is incompatible with 0.3 mL insulin syringes. 
 
For the MEDI0382/matched placebo 50 μg dose, a 10-fold dilution of the supplied stock is 
required. Dilutions must be prepared by site staff at the clinical unit prior to administration in 
the clinic. Only the supplied diluent may be used for this dilution step. 
 
If dilution is required, investigational product should be removed from the refrigerator and 
kept at room temperature for at least 30 minutes and a maximum of 4 hours for temperature 
equilibration. If no dilution is required, 15 minutes is recommended for temperature 
equilibration. 
 
To make a 10-fold dilution of MEDI0382 or placebo, it is recommended to withdraw 0.1 mL 
of the supplied investigational product using a 1 mL syringe and 27 G needle and add it into a 
sterile empty vial. Using a new 1 mL syringe and 27 G needle, add 0.9 mL of diluent into the 
same vial. The vial should be mixed by swirling gently to make a homogenous final 
admixture. Do not shake. The diluted dose should be administered using a 1.0 mL syringe 
(Table 10). Dilution and preparation of doses for administration is to be performed using 
aseptic techniques. 
Doses of 100 μg or greater do not require a dilution step and should be administered directly 
using a 0.3 mL insulin syringe. 


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Table 10 
MEDI0382 and Placebo Dose Preparation 
 
 
 
Dose Period 
MEDI0382 
Concentration 
(mg/mL) 
Volume of 
Injection (mL) 
Syringe Size to be Used 
for Dose Administration 
(mL) 
Number of 
Unitsa 
50 μg or placebob 
0.2 
0.25 
1.0 
NA 
100 μg or placebo 
2.0 
0.05 
0.3 
5 
200 μg or placebo 
2.0 
0.10 
0.3 
10 
300 μg or placebo 
2.0 
0.15 
0.3 
15 
400 μg or placebo 
2.0 
0.20 
0.3 
20 
500 μg or placebo 
2.0 
0.25 
0.3 
25 
600 μg or placebo 
2.0 
0.30 
0.3 
30 
NA = not applicable 
a 
The 0.3 mL insulin syringe is marked in ‘units’ where each unit = 0.01 mL, and 0.3 mL = 30 units. 
b 
For MEDI0382/matched placebo doses of 50 μg, a 10-fold diluted stock concentration of 0.2 mg/mL will be 
prepared by site staff at the clinical unit, prior to administration. 
 
At-home Dose Preparation 
Only doses of 100 μg or above can be administered at home. No dilution steps are required for 
these doses, and subjects should withdraw the required volume directly from the supplied vial 
using a 0.3 mL insulin syringe prior to administration. 
 
Prior to administration at home, the single vial of investigational product to be used for 
injection should be removed from the refrigerator and kept at room temperature for 
approximately 15 minutes for temperature equilibration. The subject is not to administer 
investigational product if the time outside of the refrigerator exceeds 4 hours; if storage time 
exceeds this limit, a new dose must be prepared from a new vial. 
 
4.5.1.4 
Treatment Administration 
In-clinic Treatment Administration 
The first day of dosing is considered Day 1. On the day of each dose, investigational product 
will be administered according to the schedule of procedures, as soon as practical upon 
waking each morning prior to breakfast, ideally at the same time each day. Investigational 
product will be administered by the subject under supervision as an SC injection in the lower 
abdomen using either a 1 mL syringe for 50 μg doses, or a 0.3 mL insulin syringe for the 
100 to 600 μg doses. 
 
At-home Treatment Administration 
A dose is to be self-administered by SC injection once daily using a 0.3 mL insulin syringe for 
100 to 600 μg dose, as soon as practical upon waking each morning prior to breakfast, ideally 


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at the same time each day. Subjects should be instructed to rotate the injection site around the 
abdomen. Vials are single-use only, and the subject should be instructed not to re-use the vial 
after administration of a single dose. 
 
After administration, the used vial, needle and syringe should all be directly discarded in the 
provided sharps bin. Further details are provided in the home dosing instructions. 
 
Subjects must return any unused investigational product, and the sharps bin, at their next visit 
to the clinical site. All items can be returned at room temperature. 
 
4.5.1.5 
Monitoring of Dose Administration 
Monitoring of In-clinic Dose Administration 
Injection sites should be routinely examined at each study site visit. If any injection-site 
reaction meets the criteria for an AE (see Section 5), the event is to be reported on the AE 
eCRF, with the reaction described as specifically as possible. 
 
As with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. 
 
Recording of Daily Dosing and Missed Doses During At-home Dose Administration 
Subjects will be instructed to record the date and approximate time of each dose administered 
at home. If a dose of investigational product is missed, subjects should contact the site, who 
will contact the medical monitor, for further instructions. 
 
4.5.1.6 
Reporting Product Complaints 
Any defects with the investigational product must be reported immediately to the MedImmune 
Product Complaint Department by the site with further notification to the site monitor. All 
defects will be communicated to MedImmune and investigated further with the Product 
Complaint Department. During the investigation of the product complaint, all investigational 
product must be stored at labeled conditions unless otherwise instructed. 
 
MedImmune contact information for reporting product complaints: 
Email: productcomplaints@medimmune.com 
Phone: +1-301-398-2105 


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Mail: MedImmune 
Attn: Product Complaint Department 
One MedImmune Way, 
Gaithersburg, MD USA 20878 
 
4.5.2 
Additional Study Medications 
No other study medications are specified for use in this clinical protocol. 
 
4.5.3 
Labeling 
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines. Label text will be translated 
into local languages, as required. 
 
4.5.4 
Storage 
Investigational product must be stored at 2; to 8; in their original container, including 
during transit to, and storage at, the subject’s home. Investigational products do not contain 
preservatives and are supplied for single-dose use only. Investigational product should be 
protected from heat and light. The investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit for all study treatment received 
and any discrepancies are reported and resolved before use of the study treatment. 
Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. The 
label on the investigational product kit specifies the appropriate storage. 
 
4.5.5 
Treatment Compliance 
Investigational product will be administered at the study site by study site personnel for the 
50 μg dose. Subjects are also required to dose at the study site on study day visits when 
predose assessments are required. Study site personnel will monitor compliance during these 
visits. 
 
Compliance during the at-home dosing period will be monitored by study site personnel 
through home-diary review and drug accountability (returned unused vials) at each study visit. 
 
4.5.6 
Accountability 
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to MedImmune. All unused 


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investigational product will be returned to a MedImmune-authorized depot or disposed of 
upon authorization by MedImmune. 
 
For at home dosing periods subjects will be instructed to return any unused vials, and the 
sharps bin, to the site when they return for their next clinic visits. 
 
4.6 
Treatment Assignment and Blinding 
4.6.1 
Methods for Assigning Treatment Groups 
An IWRS will be used for randomization to a treatment group and assignment of blinded 
investigational product kit numbers. A subject is considered randomized into the study when 
the investigator notifies the IWRS that the subject meets eligibility criteria and the IWRS 
provides the assignment of blinded investigational product kit numbers to the subject. 
Subjects will be randomized using a 2:1:2:1 ratio to receive either MEDI0382 300 μg or 
matched placebo, or MEDI0382 600 μg or matched placebo. 
 
Investigational product (MEDI0382 or placebo) must be administered within 24 hours after 
the investigational product is assigned. If there is a delay in the administration of 
investigational product such that it will not be administered within the specified timeframe, 
the study monitor must be notified immediately. 
 
4.6.2 
Methods to Ensure Blinding 
This is a double-blind study in which MEDI0382 and placebo are identically labeled and 
indistinguishable in appearance. As such, 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). 
 
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, MedImmune must be notified 
immediately. 
 
4.6.3 
Methods for Unblinding 
4.6.3.1 
Unblinding in the Event of a Medical Emergency 
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IWRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
subject having received investigational product. In the majority of cases, the management of a 
medical emergency would be the same whether or not investigational product was received by 
the subject. If this was the case, the investigational product allocation should not be unblinded. 


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In the event there is unblinding, the investigator should promptly document and explain to 
MedImmune the reason for any premature unblinding. 
 
MedImmune retains the right to unblind the treatment allocation for serious adverse events 
(SAEs) that are unexpected and are suspected to be causally related to an investigational 
product and that potentially require expedited reporting to regulatory authorities. 
 
If a subject’s investigational product allocation is unblinded to the blinded staff or blinded 
MedImmune study team, the subject should be discontinued from investigational product. 
 
4.6.3.2 
Unblinding for Interim Analysis Purposes 
All personnel involved with the conduct of the study will remain blinded until database lock. 
The interim analysis will be conducted by an unblinded analysis group comprising 
statisticians, SAS programmers, and a physician. The results will be reviewed by the 
Unblinded Review Committee (URC). A limited number of sponsor personnel who are not 
involved in the conduct of the study will form the URC. Any study team members who have 
access to the unblinded analyses will not be involved in further conduct of the study. 
Additional details about the interim analysis and the URC will be provided in the interim 
analysis charter. 
In the event that emergent safety data require it, the sponsor’s core cross-functional safety 
team will have the capacity to introduce an ad-hoc review of unblinded safety data by the 
URC. The conduct and composition of the URC will be the same as those for the interim 
analysis. The sponsor’s core cross-functional safety team in collaboration with the study 
statistician and the study physician will decide about the timing and the scope of the ad-hoc 
review. Analyses will be performed by MedImmune or its representatives. More details will 
be provided in the statistical analysis plan. 
4.7 
Restrictions During the Study and Concomitant Treatment(s) 
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the final study visit. Any concomitant medication(s), including herbal 
preparations, taken during the study will be recorded in the eCRF. 
 
4.7.1 
Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.7.2. Specifically, subjects with T2DM should continue to take their 
antidiabetic medication (see inclusion criterion 4) at the regular dose prescribed and any other 
medication prescribed for the treatment of co-morbidities associated with T2DM. 


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Subjects should receive full supportive care during the study, including transfusions of blood 
and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their institutional 
guidelines. 
 
If nausea or vomiting occurs, subjects should be encouraged to reduce oral intake of food until 
symptoms pass. In the event that symptoms do not improve, subjects should be offered 
antiemetic therapy in accordance with institutional and local practice guidelines. A centrally 
acting antiemetic such as a 5HT-3 antagonist is the preferred treatment in the first instance, 
rather than a prokinetic agent such as domperidone or metoclopramide (Section 3.1.3.1). 
Subjects on a stable dose (for at least 1 year) of high dose of vitamin E (> 400 IU) at the time 
of the baseline biopsy will be permitted to remain on this medication during the course of the 
study providing no changes are made to the dose (Table 11). 
 
4.7.2 
Prohibited Concomitant Medications 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
 
Use of the following medications will be restricted (Table 11) or prohibited (Table 12) as 
specified: 
 
Table 11 
Restricted medications 
 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
Herbal preparations or dietary supplements 
marketed for control of body weight or appetite 
Concurrent or prior use within 1 week prior to the start of 
screening and during the study 
Systemic corticosteroids by oral, intravenous, intra- 
articular, or intramuscular route 
Within 3 months prior to start of screening and during the 
study unless prescribed for a very brief period of less than 
7 days 
Vitamin E (high doses > 400 IU) 
Concurrent use, unless on a stable dose for at least 1 year 
prior to baseline biopsy and no changes made during study. 
Vitamin E must not have been initiated after the baseline 
liver biopsy was performed. 
Pioglitazone or other PPAR-γ agonists 
Concurrent use, unless on a stable dose for at least 1 year 
prior to baseline biopsy, and no changes made during study 
Domperidone and metoclopramide 
Only to be used during the study for the treatment of 
nausea and vomiting in the instance of intolerance to a 
centrally-acting anti-emetic 
Insulin 
Only to be used for treatment of severe hyperglycemia as 
rescue medication and according to local guidelines 
IU = International units, PPAR-γ = Peroxisome proliferator-activated receptor gamma 


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Table 12 
Prohibited medications 
 
Prohibited medication/class of drug: 
Usage 
Therapies associated with development of NAFLD 
such as methotrexate, tamoxifen, amiodarone, or 
long-term use of tetracyclines 
Within 3 months of baseline biopsy until the end of the 
study. In the case of tetracyclines, these drugs are restricted 
during the study unless prescribed for a very brief period of 
less than 7 days 
Therapies in classes under investigation for the 
treatment of NASH (except for SGLT-2 inhibitors 
and PPAR-γ agonists), such as obeticholic acid 
Within 3 months of baseline biopsy until the end of the 
study 
GLP-1 receptor agonists and GLP-1 receptor 
agonist containing therapies 
Within 3 months of baseline biopsy until the end of the 
study 
Drugs approved for weight loss (eg, orlistat, 
bupropion/naltrexone, phentermine-topiramate, 
phentermine, lorcaserin), as well as those drugs 
used off-label 
Concurrent or previous use within the last 3 months prior 
to the start of screening and during the study 
GLP-1 = glucagon-like peptide-1; NAFLD = Non-alcoholic fatty liver disease; NASH = Non-alcoholic 
steatohepatitis; PPAR-γ = Peroxisome proliferator-activated receptor gamma; SGLT-2 = Sodium-glucose 
co-transporter 2 
 
4.8 
Statistical Evaluation 
4.8.1 
General Considerations 
In general, data will be provided in listings and tabular summaries. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous variables 
will be summarized by descriptive statistics, including mean, standard deviation (SD), median, 
minimum, and maximum. Baseline values will be defined as the last assessment prior to the 
first administration of investigational product. Additional details will be described in the 
statistical analysis plan. 
 
4.8.2 
Sample Size 
The primary objective of the study is safety, but sample size and power are calculated on 
pharmacodynamic endpoint HFF. Assuming 20% treatment difference on percent change in 
HFF with SD = 20%, and assuming a 25% dropout rate, 24 subjects per group will provide 
about 83% power to detect a treatment difference between a MEDI0382 group and the 
placebo (alpha = 0.05, 2-sided). No multiplicity adjustment for alpha is planned. 
 
4.8.3 
Efficacy 
4.8.3.1 
Efficacy Analysis 
The efficacy analyses will be based on the Intent-to-treat population. 


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The pharmacodynamic endpoint, percent change from baseline in HFF at Week 19, is an 
efficacy endpoint for the study. The percent change from baseline to Week 19 in HFF will be 
analyzed using analysis of covariance (ANCOVA) adjusting for treatment and baseline value. 
For the other pharmacodynamic and biomarker endpoints that are continuous variables, 
similar ANCOVA analyses as the above analysis will be carried out. For ANCOVA analyses, 
last observation carried forward (LOCF) method will be applied for efficacy endpoints to 
handle missing data, that is, a missing endpoint will be replaced with the last available 
post-baseline measurement prior to the missing endpoint. 
 
4.8.3.2 
Additional Analyses of the Efficacy Endpoint 
The sensitivity analysis 1 will be conducted on the percent change from baseline to Week 19 
in HFF using a mixed model for repeated measures approach under unstructured covariance 
structure including fixed effects of treatment, visit, and treatment-by-visit interaction as well 
as covariate of baseline. 
 
The sensitivity analysis 2 will consist of conducting Wilcoxon sum-rank test on percent 
change from baseline in HFF at Week 12 and Week 19 for all treatment groups. 
 
The sensitivity analysis 3 will consist of repeating the descriptive analysis and the ANCOVA 
model on the same population used for the main analysis but including only data in the on- 
treatment phase. It is performed at interim analysis and at final analysis. 
 
The sensitivity analysis 4 consists on repeating the descriptive analysis and the ANCOVA 
model on the Per-protocol population. It is performed at interim analysis and at final analysis. 
 
4.8.4 
Safety 
4.8.4.1 
Analysis of Adverse Events 
Safety analyses will be based on As-treated population. Treatment-emergent AEs 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 study investigational product 
will be summarized by MedDRA System Organ Class and Preferred Term and by treatment. 
Specific AEs will be counted once for each subject for calculating percentages. In addition, if 
the same AE occurs multiple times within a subject, the highest severity and level of 
relationship observed will be reported. 
Other safety data, such as vital signs, clinical laboratory data, and dECG will be descriptively 
summarized at each time point by treatment. 


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4.8.4.2 
Analysis of Clinical Laboratory Parameters 
Laboratory parameters will be assessed at baseline as well as throughout the study. Laboratory 
parameters will be assessed by presenting tables containing information related to laboratory 
shifts from baseline relative to the normal range, as well as descriptively over time. 
 
Hepatic safety analyses: 
 
 
Proportion of subjects with marked changes (5 × ULN, 8 × ULN) from baseline in ALT 
and AST 
 
Mean changes from baseline to end of treatment in ALT and AST levels 
 
4.8.5 
Analysis of Immunogenicity/Pharmacokinetics 
Subjects who have at least one measurable concentration time point of investigational product 
will be used for this analysis. 
 
Pharmacokinetic parameters such as, but not limited to, Cmax, time to maximum observed 
plasma drug concentration (tmax), and AUC, per group on the last day of dosing, may be 
estimated from plasma concentration-time data for MEDI0382 if data permit. Descriptive 
statistics will be generated for pharmacokinetic parameters for MEDI0382 in group. 
Additional summary statistics on predose concentrations and specific postdose concentrations 
may be listed, if data permits, by group, treatment and day and will be summarized as 
maximum, minimum, arithmetic mean, and geometric mean. 
The number and percentage of subjects with confirmed positive serum antibodies to 
MEDI0382 will be reported by dose level and titer data will be summarized descriptively. The 
potential impact of ADA on MEDI0382 pharmacokinetics, efficacy and safety will be 
evaluated. 
ADA incidence rate and titer will be tabulated by treatment. Samples confirmed positive for 
ADA will be analyzed for titer and reported. 
 
4.8.6 
Interim Analysis 
An interim analysis is planned after approximately 39 subjects have completed approximately 
19 weeks of treatment. 
 
The purpose of this interim analysis is to help inform further clinical development; no changes 
will be made to this study unless a safety signal is observed. The interim analysis will be 
described in the interim analysis charter. The interim analysis results will not be provided to 
the investigator. 


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5 
ASSESSMENT OF SAFETY 
5.1 
Definition of Adverse Events 
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or non-serious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
 
5.2 
Definition of Serious Adverse Events 
An SAE is any AE that: 
 
 
Results in death 
 
Is immediately life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
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 


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SAE and therefore requires immediate notification to MedImmune (see Section 5.4). See 
Section 5.2 for the definition of SAEs and Appendix B for guidelines for assessment of 
severity and relationship. 
 
If an AE evolves into a condition that meets the regulatory definition of “serious,” it will be 
reported on the SAE Report Form. 
 
5.3.1 
Time Period for Collection of Adverse Events 
SAEs will be collected from time of signature of informed consent, throughout the treatment 
period and including the follow-up period. 
 
AEs will be recorded from time of first dose of investigational product, throughout the 
treatment period and including the follow-up period. 
 
5.3.2 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically indicated, 
but without further recording in the eCRF. MedImmune retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary. 
 
5.3.3 
Deaths 
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as an SAE. 
 
5.3.4 
Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’ or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
 
5.3.5 
Adverse Events Based on Examination and Tests 
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the CSR. An abnormal laboratory finding (including dECG 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, 


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hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cell 
increased) 
 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
 
5.3.6 
Potential Hy’s Law and Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN will need to be 
reported as SAEs. Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law. 
 
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 eCRF. 
 
If any SAE occurs in the course of the study, then investigators or other site personnel must 
inform the appropriate sponsor representative(s) within 1 day, ie, immediately but no later 
than 24 hours after becoming aware of the event. 
 
The designated study representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor’s Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs. 
 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform sponsor 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event. 
 
Once the investigators or other site personnel indicate an AE is serious in the eCRF, an 
automated email alert is sent to inform the designated sponsor representative(s). 


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If the eCRF is not available, then the investigator or other study site personnel reports an SAE 
to the appropriate sponsor representative by telephone. The sponsor representative will advise 
the investigator/study site personnel how to proceed. 
 
The reference document for definition of expectedness/listedness is the IB for the 
MedImmune drug. 
 
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 eCRF and on the Overdose eCRF module. 
 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on a MedImmune investigational product occurs during the course of the study, 
then the investigator or other site personnel should inform appropriate sponsor representatives 
immediately, but no later than 24 hours after becoming aware of the event. 
 
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site. 
 
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.4. 
For other overdoses (ie, those not associated with an AE or SAE), reporting must occur within 
30 days. 
 
5.5.2 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor except for: 
 
 
If the pregnancy is discovered before the study subject has received any investigational 
product. 
 
Pregnancies in the partner of male subjects. 
 
5.5.2.1 
Maternal Exposure 
If a subject becomes pregnant during the course of the study investigational product should be 
discontinued immediately. 
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 


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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, ie, immediately 
but no later than 24 hours after becoming aware of the event. 
 
The designated study representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 5.4) 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. 
 
5.5.3 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for a MedImmune investigational product that either causes harm to the 
subject or has the potential to cause harm to the subject. 
 
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or subject. 
 
Medication error includes situations where an error: 
 
 
Occurred 
 
Was identified and intercepted before the subject received the drug 
 
Did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
 
Drug name confusion (ie, instead of receiving the investigational product, the subject 
received a drug that has a similar-sounding name) 
 
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject 
 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 


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 
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 
 
Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature 
 
Wrong subject received the medication (excluding IWRS errors) 
 
Wrong drug administered to subject (excluding IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
 
 
Errors related to or resulting from IWRS - including those which lead to one of the above 
listed events that would otherwise have been a medication error 
 
Subject accidentally missed drug dose(s), eg, forgot to take medication 
 
Accidental overdose (will be captured as an overdose) 
 
Subject failed to return unused medication or empty packaging 
 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ or MedImmune product 
 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error. 
 
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate MedImmune representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it. 
 
The designated MedImmune representative works with the investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 5.4) and within 30 days for all other medication errors. 
Medication errors should be reported using a Medication Error Report Form. 
 
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. 


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The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff). 
 
6.2 
Monitoring of the Study 
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to: 
 
 
Provide information and support to the investigator(s). 
 
Confirm that facilities remain acceptable. 
 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that investigational product 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 site needs information and advice about the study conduct. 
 
6.2.1 
Source Data 
Refer to the Clinical Study Agreement (CSA) for location of source data. 
 
6.2.2 
Study Agreements 
The Principal Investigator at each/the site should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study. In the event of any inconsistency 
between this protocol and the CSA, 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 CSA 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 CSA. 


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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 or assessed for the primary end 
point of the study, regardless of the number of doses of investigational product that was 
received. 
 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.6 and Section 4.1.7). 
 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. 
 
6.4 
Data Management 
Data management will be performed by MedImmune Data Management staff or other party 
according to the Data Management Plan. 
 
An eCRF 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 CSA. 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 telephone 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 E-code to ensure that personally identifiable information is 
kept separate from the study data. Subject data that are relevant to the study, eg, demographic 


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information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc. will only be collected with the subject’s informed consent. The ICF will 
incorporate (or, in some cases, be accompanied by a separate document incorporating) 
wording that describes how subject data will be collected, used, and distributed in compliance 
with relevant data protection and privacy legislation. Data (clinical and biological sample) 
from this study may be used and may be combined with results from other studies for 
additional scientific-related research, based on agreement from the subject as defined in the 
informed consent. 
 
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. MedImmune will not provide individual genotype results 
to subjects, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law. 
 
7.2 
Ethics and Regulatory Review 
The IRB/IEC responsible for each site must review and approve the final study protocol, 
including the final version of the ICF and any other written information and/or materials to be 
provided to the subjects. The IRB/IEC must also approve all advertising used to recruit 
subjects for the study. The investigator is responsible for submitting these documents to the 
applicable IRB/IEC and distributing them to the study site staff. 
The opinion of the IRB/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 ICF that are needed to meet 
local requirements. 
 
If required by local regulations, the protocol must be re-approved by the IRB/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, IRB/IEC, and 
principal investigators. 
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 
IRB/IEC. MedImmune will provide this information to the Principal Investigator so that 
he/she can meet these reporting requirements. 


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7.3 
Informed Consent 
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. MedImmune will develop a core 
ICF for use by all investigators in the clinical study. MedImmune must approve any 
modifications to the ICF that are needed to meet local requirements. 
 
The Principal Investigator(s) at each site will: 
 
 
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
 
Ensure each subject is notified that they are free to discontinue from the study at any time 
 
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 
 
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study 
 
Ensure the original, signed ICF is 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 ICF that is approved by an IRB/IEC 
 
7.4 
Changes to the Protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune. Any changes must be documented in a study protocol 
amendment. 
 
For a substantial change to the protocol, MedImmune will distribute amended versions of the 
protocol to the Principal Investigator(s). Before implementation, amended protocols must be 
approved by relevant IRB/IEC (see Section 7.2) and reviewed as per local regulatory authority 
requirements. The IRB/IEC must also approve revisions to the ICF, advertising, and any other 
written information and/or materials resulting from the change to the protocol. 
Any non-substantial changes will be communicated to or approved by each IRB/IEC. 
 
7.5 
Audits and Inspections 
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the site, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities 
and documents, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP, guidelines of the 


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International Conference on Harmonisation (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 
Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L et al. MEDI0382, 
a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 
diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 
(London, England). 2018;391(10140):2607-18. 
 
Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Alimentary pharmacology & 
therapeutics. 2007;25(8):883-9. 
 
Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P et 
al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes 
of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2015;149(2):389- 
97.e10. 
 
Armstrong MJ, Hull D, Guo K, Barton D, Yu J, Tomlinson J et al. Effect of liraglutide on 
adipose insulin resistance and hepatic de-novo lipogenesis in non-alcoholic steatohepatitis: 
substudy of a phase 2, randomised placebo-controlled trial. The Lancet. 2014;383S21. 
 
Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R et al. Liraglutide safety and 
efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, 
randomised, placebo-controlled phase 2 study. Lancet (London, England). 
2016;387(10019):679-90. 
 
Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME et al. Safety, tolerability and 
sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. 
International journal of obesity (2005). 2012;36(6):843-54. 
 
Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver 
disease. Digestive diseases (Basel, Switzerland). 2010;28(1):155-61. 
 
Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver international : 
official journal of the International Association for the Study of the Liver. 2017;37 Suppl 181- 
4. 
 
Cegla J, Troke RC, Jones B, Tharakan G, Kenkre J, McCullough KA et al. Coinfusion of low- 
dose GLP-1 and glucagon in man results in a reduction in food intake. Diabetes. 
2014;63(11):3711-20. 
 
Center for Drug Evaluation and Research. Byetta Pharmacology Review. 2005. 
Cholankeril G, Patel R, Khurana S, Satapathy SK. Hepatocellular carcinoma in non-alcoholic 
steatohepatitis: Current knowledge and implications for management. World journal of 
hepatology. 2017;9(11):533-43. 


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Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z et al. Increased risk of mortality by 
fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. 
Hepatology (Baltimore, Md). 2017;65(5):1557-65. 
 
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of 
nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. 
Hepatology (Baltimore, Md). 2018;67(1):123-33. 
 
Habegger KM, Stemmer K, Cheng C, Muller TD, Heppner KM, Ottaway N et al. Fibroblast 
growth factor 21 mediates specific glucagon actions. Diabetes. 2013;62(5):1453-63. 
 
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. 
 
Marra F, Lotersztajn S. Pathophysiology of NASH: perspectives for a targeted treatment. 
Current pharmaceutical design. 2013;19(29):5250-69. 
 
Meisamy S, Hines CD, Hamilton G, Sirlin CB, McKenzie CA, Yu H et al. Quantification of 
hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of 
fat: blinded comparison with MR spectroscopy. Radiology. 2011;258(3):767-75. 
 
Mishra A, Younossi ZM. Epidemiology and Natural History of Non-alcoholic Fatty Liver 
Disease. Journal of clinical and experimental hepatology. 2012;2(2):135-44. 
 
Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC medicine. 2017;15(1):45. 
Pais R, Barritt ASt, Calmus Y, Scatton O, Runge T, Lebray P et al. NAFLD and liver 
transplantation: Current burden and expected challenges. Journal of hepatology. 
2016;65(6):1245-57. 
 
Patel J, Bettencourt R, Cui J, Salotti J, Hooker J, Bhatt A et al. Association of noninvasive 
quantitative decline in liver fat content on MRI with histologic response in nonalcoholic 
steatohepatitis. Therapeutic advances in gastroenterology. 2016;9(5):692-701. 
 
Petit JM, Cercueil JP, Loffroy R, Denimal D, Bouillet B, Fourmont C et al. Effect of 
Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 
Diabetes: The Lira-NAFLD Study. The Journal of clinical endocrinology and metabolism. 
2017;102(2):407-15. 
 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine 
Society. The Journal of clinical endocrinology and metabolism. 2013;98(5):1845-59. 


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Valdecantos MP, Pardo V, Ruiz L, Castro-Sanchez L, Lanzon B, Fernandez-Millan E et al. A 
novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and 
liver regeneration in mice. Hepatology (Baltimore, Md). 2017;65(3):950-68. 
 
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, 
Gonzalez-Fabian L et al. Weight Loss Through Lifestyle Modification Significantly Reduces 
Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367-78.e5; quiz e14- 
5. 
 
Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. 
Hepatology (Baltimore, Md). 2014;59(6):2188-95. 
 
Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS et al. Oxyntomodulin 
increases energy expenditure in addition to decreasing energy intake in overweight and obese 
humans: a randomised controlled trial. International Journal Of Obesity. 2006;301729. 
 
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology 
of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and 
outcomes. Hepatology (Baltimore, Md). 2016;64(1):73-84. 
 
 
9 
CHANGES TO THE PROTOCOL 
9.1 
Protocol Amendment 6 
The following change has been incorporated into the current version, considered Protocol 
Amendment 6, of the protocol. 
 
The change is considered non-substantial. 
Title page: The medical monitor was changed from PPD 
 to PPD 
. 
9.2 
Protocol Amendment 5 
All changes described below have been incorporated into the current version of the protocol. 
 
Text revisions resulting from this amendment are incorporated in the body of 
Protocol Amendment 5. All changes made to the body of the protocol have been reflected in 
the Protocol Synopsis. Editorial mistakes have been corrected and are not noted below. 
 
The following change is considered substantial: 
 
1. Section 3.1.1 (Overview) and Section 4.8.6 (Interim Analysis): to improve the 
distribution of subjects with a sufficient range of disease to be included in the interim 


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analysis, the timeframe was changed from 13 weeks to 19 weeks of completed 
treatment for approximately 39 subjects (a change from 30 subjects). 
 
The following changes are considered non substantial: 
 
2. Table 5 (Screening Schedule of Procedures) Footnote ‘f’ and Section 4.3.5.1 
(Magnetic Resonance Imaging [Including MRI-PDFF]): to allow for repeat screening 
MRI the following text was added ‘If the screening MRI is determined to be of 
inadequate image quality by the MRI analysis vendor the subject may return for repeat 
MRI within the screening visit period’. 
 
3. Section 4.2.2 (Randomized Treatment Period): to maintain subject safety, and to allow 
for continued data collection during the COVID-19 pandemic, text was added to allow 
for telephone contact where study visits are not possible, to allow D78 MRI to be 
collected at the earliest opportunity and within 7 days of the original D78 scheduled 
date, and to allow D133 assessments to be collected within a 2 days window (7 days 
for MRI), and if 2 days are not possible, to be collected at the earliest opportunity and 
within 7 days, excluding pharmacokinetic blood, of the original D133 scheduled date. 
It is noted that all other visits should follow the original schedule. 
9.3 
Protocol Amendment 4 
All changes described below have been incorporated into the current version of the protocol. 
 
Text revisions resulting from this amendment are incorporated in the body of 
Protocol Amendment 4. All changes made to the body of the protocol have been reflected in 
the Protocol Synopsis. Editorial mistakes have been corrected and are not noted below. 
The following changes are considered substantial: 
 
Body weight, although collected, was not described as a specific objective in the original 
protocol. Body weight changes are an important parameter for the assessment of MEDI0382 
in NASH and therefore body weight and BMI have been called out as a distinct objective and 
included as a dose response endpoint. 
 
1 
Table 2 (Secondary Objectives and Associated Endpoints): change in body weight and 
BMI added as a new secondary objective. 
2 
Table 2 (Secondary Objectives and Associated Endpoints): body weight added to the dose 
response endpoints. 
 
Due to the nature of the study population, some subjects will be receiving prescribed 
medication which could result in a positive screen for drugs of abuse. However, where 
medication is prescribed and does not indicate an addiction or safety concern the Investigator 


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is permitted to include the subject at their discretion. Exclusion Criterion 14 was amended as 
follows: 
 
3 
Section 4.1.3 (Exclusion Criteria): reworded from History of substance dependence likely 
to impact subject safety or compliance with study procedures, or positive screen for drugs 
of abuse at screening to History of substance dependence or a positive screen for drugs of 
abuse, likely to impact subject safety or compliance with study procedures, at the 
discretion of the Investigator. 
 
The following changes are considered non-substantial: 
 
4 
Table 2 (Secondary Objectives and Associated Endpoints): liver sagittal diameter and 
liver transversal diameter changed to abdominal sagittal diameter and abdominal 
transversal diameter. 
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analysis plan changed to interim analysis charter. 
9 
Section 3.1.3.3 (Persistent Hyperglycemia): DPP-4i should be avoided and alternative 
options considered. 
10 Section 3.2.3 (Rationale for Endpoints): rationale for the addition of body weight and 
BMI to secondary endpoints. 
11 Section 4.1.5 (Screen Failures): text added to clarify that the same E-code will be used for 
subjects who are rescreened. 
12 Section 4.1.8 (Study Stopping Criteria): clarification to text due to site feedback. 
13 Table 5 (Screening Schedule of Procedures): 
 
Clarification that virology at a minimum includes hepatitis B surface antigen, 
hepatitis C virus antibody; HIV-1 and HIV-2 
 
Footnote ‘c’: clarification that screening dECG measurements should be performed 
after the subject has rested in the supine position for at least 10 minutes. 
 
 
 
 
 
 
 
 
 
 
 
Section 4.8.6 (Interim Analysis): interim unblinding 


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 
Footnote ‘f’: MRI (including MRI-PDFF) changed to MRI-PDFF. Change 
implemented to avoid confusion regarding which screening MRI protocol should be 
used. 
 
Footnote ‘i’: text added to confirm that if multiple alcohol screening tests are 
performed and conflicting results occur any positive result should be documented. 
14 Table 6 (MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of Procedures) 
and Table 7 (MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of 
Procedures) footnotes ‘f’ and ‘g’: to allow for flexibility, dECG and vital sign predose 
collection times changed to allow assessments within 20 minutes, respectively. 
15 Table 8 (Schedule of Follow-up Procedures) footnote ‘b’: the requirement for a HbA1c 
sample for subjects requiring an ADA follow-up sample was removed. This assessment is 
not required to interpret the immunogenicity profile during safety follow-up. 
16 Section 4.3.2.4 (Vital Signs): to allow flexibility, it was clarified that blood pressure 
should be performed after the subject has rested in the supine position for at least 10 
minutes. 
17 
 
 
18 Section 4.3.5.2 (Fibroscan): according to the Imaging Manual removed because this is 
inaccurate. 
19 Section 4.3.6 (Clinical Laboratory Tests): nitrites added, as they were previously omitted 
from the urinalysis tests. Low molecular weight adiponectin removed to reflect laboratory 
standard practice. 
20 
 
21 Section 4.5.1.6 (Reporting Product Complaints): telephone and fax numbers removed to 
reflect organisational changes. 
22 Section 4.6.3.2 (Unblinding for Interim Analysis Purposes): text updated to reflect the 
unblinding plans. Specifically, the following text was added: The conduct and 
composition of the URC will be the same as those for the interim analysis. The sponsor’s 
core cross-functional safety team in collaboration with the study statistician and the study 
physician will decide about the timing and the scope of the ad-hoc review. 
23 Section 4.8.3.2 (Additional Analyses of the Efficacy Endpoint): additional sensitivity 
analyses of the efficacy endpoint were added. 
24 Section 6.5 (Medical Monitor Coverage): clarification to the text that the telephone 
number will not be toll-free. 
25 Appendix E (Genetic Research): changes made to informed consent description to clarify 
that a single informed consent document will be used during the study. This single 
document enables a subject to decide whether to be included in the optional genetic and 
non-genetic samples. 
9.4 
Protocol Amendment 3 
All changes described below have been incorporated into the current version of the protocol. 
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Text revisions resulting from this amendment are incorporated in the body of 
Protocol Amendment 3. 
 
All changes are considered non-substantial and that there are no substantial changes. 
 
1 
Section 3.1.1 (Overview): the study flow diagram was corrected to accurately reflect the 
numbers of subjects per group. 
2 
Section 4.1.3 (Exclusion Criteria): criterion 32 incorrectly included, text is for 
information only, criterion numbering has been removed. 
3 
Section 4.1.6 (Withdrawal from the Study) and Section 4.1.7 (Discontinuation of 
Investigational Product): clarification to text to specify that subjects who discontinue 
early, but are not continuing with study assessments, should in addition to the Early 
Discontinuation Visit return for a follow-up visit. Text regarding 3 MRIs was also 
clarified. 
4 
Section 4.3.5.1 (Magnetic Resonance Imaging [Including MRI-PDFF]) and Section 
4.3.5.2 (Fibroscan): Table 8 added as a cross reference. 
5 
Table 6 (MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of Procedures), 
Table 7 (MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures), 
Section 4.5.1.3 (Dose Preparation Steps), Table 10 (MEDI0382 and Placebo Dose 
Preparation) and Section 4.6.2 (Methods to Ensure Blinding): to mitigate the need for 
unblinded study personnel the 50 μg matched placebo dose will now require dilution. 
Text stating that placebo does not require dilution and text describing unblinded study 
personnel has been removed. 
6 
Table 8 (Schedule of Follow-up Procedures): 
(a) Footnote ‘e’ updated to specify that subjects who discontinue early, but are not 
continuing with study assessments, should also return for a follow-up visit. 
(b) Clarification added to footnote ‘f’ to clarify that only 3 MRIs should be completed 
per subject. 
(c) Footnote ‘g’ added to clarify the timing of the pharmacokinetic sample. 
7 
Appendix D (Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law): to the lab kit table the requirement for IgM anti-HCV testing 
was removed and a footnote added to confirm when HCV RNA testing is required. 
 
9.5 
Protocol Amendment 2 
All changes described below have been incorporated into the current version of the protocol. 
 
Text revisions resulting from this amendment are incorporated in the body of 
Protocol Amendment 2. All changes made to the body of the protocol have been reflected in 
the protocol synopsis. For consistency EDC was changed to eCRF and SID to E-code 
throughout the protocol and any reference to a CRO was removed. 
 
Changes to the protocol considered substantial are: 


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1 
Section 2.2 (Secondary Objective and Associated Endpoints): ‘percent change’ added to 
the pharmacodynamics endpoints for clarification. 
2 
 
3 
Section 4.1.6 (Withdrawal from the Study) and 4.1.7 (Discontinuation of Investigational 
Product): text added to clarify the process in the event of a subject withdrawal. If only the 
investigational product is withdrawn but the subjects continues they should complete an 
Early Discontinuation visit and if possible all scheduled assessments, however, if the 
subject wishes to withdraw completely the investigator should ask them to return for an 
Early Discontinuation Visit. The number of MRI should not exceed 3 for any subject 
randomized into the study 
4 
Table 6 (MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of Procedures): 
(a) HbA1c and fasting lipid profile assessments added to D78. 
(b) Adiponectin assessments added to D1, D78, and D133. 
5 
Table 7 (MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures): 
(a) HbA1c and fasting lipid profile assessments added to D78. 
(b) Adiponectin assessments added to D1, D78, and D133. 
6 
Table 8 (Schedule of Follow-up Procedures): 
(a) Calcitonin assessment added with corresponding footnote. 
(b) Assessments, and corresponding footnote, for IP accountability, fasting MRI-PDFF 
(including specification to not exceed 3 MRI following randomization), fibroscan, 
and pharmacokinetics added for those subjects completing the Early Discontinuation 
Visit. 
(c) Footnoted the requirement for HbA1c to be taken to evaluate the subjects glycemic 
control. 
7 
 
 
8 
Section 4.3.12 (Estimate of Volume of Blood to be Collected): total blood volumes were 
updated to reflect additional sampling, approximately 461 mL, plus an optional 60 mL for 
the MEDI0382 300 μg/matched placebo group and 557 mL, plus an optional 60 mL for 
the MEDI0382 600 μg/matched placebo group. 
9 
Section 5.3.1 (Time Period for Collection of Adverse Events) and Table 5: in the previous 
amendment AEs and SAEs were to be collected from signed informed consent and first 
dose of investigational product. This has been changed to only SAEs to be collected from 
signed informed consent and first dose of investigational product. 
 
 
Changes considered minor are provided below: 
 
10 Section 3.1.1 (Overview): the study flow diagram was updated to include the run-in 
period with accompanying footnote and total treatment duration. 
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11 Section 3.1.1 (Overview) and (Interim Analysis): interim analysis text updated to say ’30 
subjects have completed approximately 13 weeks of treatment’ 
12 Section 4.1.2 (Exclusion Criteria): exclusion criterion 30 changed from Any AstraZeneca, 
MedImmune, contract research organization (CRO), or study site employee, or close 
relatives of any of the aforementioned employees to Any AstraZeneca, MedImmune, or 
study site employee, or close relatives of any of the aforementioned employees. The 
update was made to reflect organizational changes. 
13 Section 4.1.4 (Subject Enrollment and Randomization), Table 5: SID number changed to 
E-code for consistency. 
14 New Section 4.1.5 (Screen Failures): section added to clarify how screening failures will 
be handled during the study. 
15 Section 4.3.2.2 (Physical Examination): text changed to clarify that clinically significant 
physical examination findings should be recorded as AEs. 
16 Section 4.3.2.3 (Digital Electrocardiogram): ‘data’ removed for clarification. The 
investigators are not expected to input data into the dECG, the data will be transferred 
directly. For the variables to be reported, RR was removed and HR and QTcB were added 
in order to align the text with the data to be collected at the site. 
17 Section 4.3.6 (Clinical Laboratory Tests): the following tests were added to the additional 
laboratory assessments: adiponectin, lipidomics, ELF™, and CK18. Only adiponectin is 
an additional test, all other tests were included in the previous version of the protocol and 
have been added here for clarity. Adiponectin is an important lipid parameter for NASH. 
18 Table 5 (Screening Schedule of Procedures): an additional check of eligibility criteria was 
added at V2. 
19 Table 6 (MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of Procedures): 
(a) Requirement for height measurement at D133 removed. 
(b) IP accountability assessment added. 
(c) The term ‘future samples for testing’ removed from lipidomics, CK18, and Elf™ 
assessments. 
(d) Serum lipid profile changed to lipid profile. 
20 Table 7 (MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures): 
(a) Requirement for height measurement at D133 removed. 
(b) IP accountability assessment added. 
(c) The term ‘future samples for testing’ removed from lipidomics, CK18, and Elf™ 
assessments. 
(d) Changes made to footnote ‘h’ to make BP collection consistent with main body. 
(e) Serum lipid profile changed to lipid profile. 
21 Table 8 (Schedule of Follow-up Procedures): 
(a) Requirement for height measurement removed. 
(b) Serum lipid profile changed to lipid profile. 
(c) IP accountability assessment added. 


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22 Section 4.8.3.2 (Additional Analyses of the Efficacy Endpoint): the ANCOVA analysis 
was removed as this analysis is already discussed in Section 4.3.8.1. 
23 Appendix B (Adverse Event Definitions and Additional Safety Information): updated to 
reflect operational changes affecting AE reporting. 
 
9.6 
Protocol Amendment 1 
All changes described below have been incorporated into the current version of the protocol. 
 
Text revisions resulting from this amendment are incorporated in the body of 
Protocol Amendment 1. All changes made to the body of the protocol have been reflected in 
the Protocol Synopsis. 
 
The principal reason for this amendment was to incorporate feedback from the US FDA to 
improve safety monitoring. 
 
Changes, made in response to US FDA guidance, are considered substantial and are as 
follows: 
1 
Section 4.1.3 (Exclusion Criteria): new exclusion criterion 9 added: ‘Physician-diagnosed 
diabetic subjects with clinically significant gastroparesis (as judged by the investigator) or 
those treated for gastroparesis within 6 months prior to screening’. 
2 
Section 4.1.3 (Exclusion Criteria): exclusion criterion 25 (f) changed from 
‘Platelets < 100 × 109/L’ to ‘Platelets < 140-150,000/mm3’. 
3 
Table 5 (Screening Schedule of Procedures): an extra visit was added to screening to 
accommodate ABPM (and corresponding footnote) at -10 days ± 3 days. 
4 
Table 7 (MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures): 
(a) Six additional visits at Days 51, 52, 65, 66, 79, and 80 added at 24 and 48 hours after 
uptitration to 400, 500 and 600 μg, respectively. 
(b) Postural BP specified at Visits 9 (Day 51), 10 (Day 52), 12 (Day 65), 13 (Day 66), 15 
(Day 79) and 16 (Day 80) with accompanying explanatory footnote. 
(c) ABPM added to Visits 8 (Day 50), 11 (Day 64), 14 (Day 78), and 20 (Day 133). 
(d) Extra sampling was added for plasma glucose, insulin, glucagon, c-peptide, and 
GLP-1 at Visits 8 (Day 50), 9 (Day 51), 10 (Day 52), 11 (Day 64), 12 (Day 65), 13 
(Day 66), 15 (Day 79), and 16 (Day 80). 
5 
Section 4.3.2.4 (Vital Signs): clarification and new text added to allow for postural BP 
and ABPM measures at time points specified in Table 7. Section also added to provide 
details regarding training for the application and wearing of the ABPM device. 
6 
Section 4.6.3.2 (Unblinding for Interim Analysis Purposes): clarification added that the 
sponsor’s core cross-functional safety team have the capacity to introduce an earlier, 
ad-hoc review of unblinded safety data by the URC in the event that emergent safety data 
require it. 


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Further changes, to improve safety monitoring and endpoint reporting, and to correct minor 
errors were also implemented. It should be noted that visit numbers have been updated 
throughout the protocol to reflect additional visits, however, the overall time period of the 
study was not changed. 
 
Additional changes to the protocol considered to be substantial are summarized below: 
 
7 
Section 1.6 (Benefit-risk and Ethical Assessment): section updated to align with most 
recent edition of the IB. 
8 
Section 2.1 (Primary Objectives and Associated Endpoints): clarifications made to 
primary endpoint wording. Changes made to allow to allow standard reporting on 
clinicaltrials.gov. All other safety endpoints will be reviewed and detailed in the statistical 
analysis plan. 
9 
Section 2.1.1 (Secondary Objectives and Associated Endpoints): clarifications made to 
the other related imaging parameters secondary objective and endpoint wording. PDFF 
deleted from MRI, CCI 
 
10 Section 3.1.1 (Overview) and Section 4.8.6 (Interim Analysis): ‘interim analysis of safety 
data’/’interim safety analysis’/‘safety interim analysis’ was considered too restrictive, 
therefore, ‘safety data’/‘safety’ was removed. The interim analysis will be described in 
the interim analysis unblinding plan. 
11 Section 3.1.3.1 (Tolerability): addition of instructions for investigators to monitor subjects 
with vomiting for signs of hypovolemia and instructions regarding hydration for subjects 
with impaired renal function. 
12 Section 3.1.3.2 (Hypoglycemia): text clarified to confirm glucose reading and 
hypoglycemic events will be reviewed and managed by the investigator as per local 
standards of care and that glucose meters will be provided to subjects with T2DM. 
13 Table 5 (Screening Schedule of Procedures): 
(a) MRI (including MRI-PDFF) and fibroscan moved to new Visit 2 at -10 days to 
maintain the timeframe between these procedures and randomization. 
(b) Footnote added to confirm historical MRI (including MRI-PDFF)/fibroscan 
assessments can be used for screening procedures. 
14 Table 6 (MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of Procedures): 
(a) dECG and vital sign measures on Days 50, 64, and 78 were deleted, to reduce subject 
burden. 
(b) Footnote to clarify dosing added: Subjects are required to be dosed at the clinic for 
the 50 μg dose and on all study day visits when predose procedures are required. 
Subjects are required to fast for at least 8 hours overnight prior to Visits 3 (Day 1), 10 
(Day 78) and 14 (Day 133); subjects are permitted to drink water during this period 
of fasting. On days where subjects attend the clinic in a fasted state, blood and urine 
samples should be obtained prior to administration of investigational product. 
(c) On Visit 20 (Day 133), the 12-hour pharmacokinetic sampling time point was 
changed to 10 hours to make sampling easier for the subject. 


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15 Table 7 (MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures): 
(a) Footnote to clarify dosing added: Subjects are required to be dosed at the clinic for 
the 50 μg dose and on all study day visits when predose procedures are required. 
Subjects are required to fast for at least 8 hours overnight prior to Visits 3 (Day 1), 14 
(Day 78) and 20 (Day 133); subjects are permitted to drink water during this period 
of fasting. On days where subjects attend the clinic in a fasted state, blood and urine 
samples should be obtained prior to administration of investigational product. 
Subjects are required to visit the clinic on two subsequent days following up-titration 
to the 400, 500 and 600 μg dose for safety monitoring; subjects may travel to the site 
for daily visits during this time or alternatively should be given the option to stay 
overnight locally if this is more convenient. 
(b) To monitor subject safety, extra sampling was added for serum chemistry at Visits 8 
(Day 50), 9 (Day 51), 10 (Day 52), 11 (Day 64), 12 (Day 65), 13 (Day 66), 15 
(Day 79), and 16 (Day 80). 
(c) On Visit 20 (Day 133), the 12-hour pharmacokinetic sampling time point was 
changed to 10 hours to make sampling easier for the subject. 
16 
 
 
 
17 
 
18 Section 4.3.12 (Estimate of Volume of Blood to be Collected): total blood volumes were 
updated to reflect additional sampling, approximately 389.4 mL, plus an optional 81.4 mL 
for the MEDI0382 300 μg/matched placebo group and 480.4 mL, plus an optional 
81.4 mL for the MEDI0382 600 μg/matched placebo group. 
CCI 
CCI 


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Changes to the protocol considered to be non-substantial are summarized below: 
 
19 To reflect organizational changes Covance was removed from the title page. 
20 Section 4.1.2 (Inclusion Criteria 6): Added clarification that the MRI assessment should 
be PDFF, and that an historical MRI-PDFF can be used for the screening hepatic steatosis 
or liver fat assessment. 
21 Table 5 (Screening Schedule of Procedures), Table 7 (MEDI0382/Matched Placebo 
600 μg Treatment Period Schedule of Procedures): AE and concomitant medication 
monitoring included in the extra visits during this amendment. 
22 Table 6 (MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of Procedures): 
NIS4 sample removed from Week 2, as this was incorrectly included in the original 
protocol. 
23 Table 6 (MEDI0382/Matched Placebo 300 μg Treatment Period Schedule of Procedures) 
and Table 7 (MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of 
Procedures): for clarity ‘dispense glucose meter’ added with accompanying footnote. 
24 Table 7 (MEDI0382/Matched Placebo 600 μg Treatment Period Schedule of Procedures): 
footnote ‘g’, regarding vital signs, which was missing from the original protocol was 
added. 
25 Table 8 (Schedule of Follow-up Procedures): 
(a) footnote ‘a’ deleted from ADA, this was incorrectly included in the original protocol. 
(b) Clarification added to new footnote ‘a’ to confirm consecutive measurements are for 
BP only. 
26 Section 4.3.2.5 (Weight, Height, BMI, Waist and Hip Circumference): clarification to 
confirm height recorded at screening will be used for eligibility assessment, and height 
recorded at Visit 3 (Day 1) will be used for subsequent BMI calculations. 
27 Section 4.3.5.1 (Magnetic Resonance Imaging (including MRI-PDFF): CCI 
 
Added clarification that subjects with 
an MRI performed within 60 days of screening do not need to repeat this assessment at 
Visit 2 (Day -10). 
28 Section 4.3.5.2 (Fibroscan): added clarification that subjects with a fibroscan performed 
within 60 days of screening do not need to have a fibroscan performed at 
Visit 2 (Day -10). 
29 Section 4.5.1.3 (Dose Preparation Steps): clarification added Table 10 (MEDI0382 and 
Placebo Dose Preparation). 
30 Section 4.5.4 (Storage): clarification added to confirm storage conditions for transit to and 
storage at the subject’s home. 
31 Section 4.7.1 (Permitted Concomitant Medications): screening biopsy deleted as no 
screening biopsy will be taken in this study; historical biopsy changed to baseline biopsy 
for consistency. 
32 Appendix E (Genetic Research): clarification that sample will only be taken on Visit 3 
(Day 1), not at any timepoint as incorrectly included in the original protocol. 


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Appendix A Contraception Guidance 
For females of childbearing potential: 
 
 
Females of childbearing potential are defined as those who are not surgically sterile (ie, 
surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) or those who are not premenarchal or postmenopausal defined as 
12 months with no menses without an alternative medical cause and have an elevated 
follicle-stimulating hormone [FSH] central laboratory level > 40 mIU/mL). FSH testing 
will be conducted at the screening visit to confirm postmenopausal status). 
 
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 A1. 
 
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 A1 
Highly Effective Methods of Contraception 
 
Barrier Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing intrauterine system or 
implant; eg, Mirena®) a 
• 
Implants 
• 
Hormone shot or injection 
• 
Combined pill 
• 
Minipill 
• 
Patch 
a 
This is also considered a hormonal method. 


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Appendix B 
Adverse Event Definitions and Additional Safety Information 
B 1 
Definition of Adverse Events 
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered. 
 
B 2 
Definitions of Serious Adverse Event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
 
 
Results in death 
 
Is immediately life-threatening 
 
Requires in-subject hospitalisation or prolongation of existing hospitalisation 
 
Results in persistent or significant disability or incapacity. 
 
Is a congenital abnormality or birth defect 
 
Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above. 
B 3 
Life Threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure). 
 
B 4 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
 
B 5 
Important Medical Event or Medical Treatment 


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Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
 
 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation 
 
Development of drug dependency or drug abuse 
B 6 
Intensity Rating Scale: 
1 
mild (awareness of sign or symptom, but easily tolerated) 
2 
moderate (discomfort sufficient to cause interference with normal activities) 
3 
severe (incapacitating, with inability to perform normal activities) 
B 7 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
 
 
Time Course. Exposure to suspect drug. Has the subject actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
 
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors. 
 
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re- 
challenge. 


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 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
 
 
Is this a recognized feature of overdose of the drug? 
 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
 
B 8 
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
 
Medication error includes situations where an error. 
 
 
occurred 
 
was identified and intercepted before the participant received the drug 
 
did not occur, but circumstances were recognize that could have led to an error 
 
 
Examples of events to be reported in clinical studies as medication errors: 
 
 
Drug name confusion 
 
Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to 
the participant 


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 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
 
Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet 
 
Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature 
 
Wrong participant received the medication (excluding IVRS/IWRS errors) 
 
Wrong drug administered to participant (excluding IVRS/IWRS errors) 
 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
 
 
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 
 
Participant accidentally missed drug dose(s) e.g. forgot to take medication 
 
Accidental overdose (will be captured as an overdose) 
 
Participant failed to return unused medication or empty packaging 
 
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 


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Appendix C 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, dyspnea, 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, dyspnea, 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 mmHg or greater than 30% decrease from that 
person’s baseline 


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Appendix D Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
D 1 
Introduction 
This appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
 
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study. 
 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
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. 
 
D 2 
Definitions 
D 2.1 
Potential Hy’s Law 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of investigational product irrespective of an increase in alkaline 
phosphatase (ALP). 


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D 2.2 
Hy’s Law 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the investigational product, can be found to explain the combination of increases; eg, elevated 
ALP indicating cholestasis, viral hepatitis, or another drug. 
 
For potential Hy’s Law and Hy’s Law, the elevation in transaminases must precede or be 
coincident with (ie, on the same day) the elevation in TBL, but there is no specified timeframe 
within which the elevations in transaminases and TBL must occur. 
 
D 3 
Identification of Potential Hy’s Law Cases 
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any subject who meets any of the following identification criteria 
in isolation or in combination: 
 
 
ALT ≥ 3 × ULN 
 
AST ≥ 3 × ULN 
 
TBL ≥ 2 × ULN 
 
When a subject meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the investigator (also sent to sponsor study 
representative). 
 
The investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the investigator will: 
 
 
Notify the sponsor study representative 
 
Request a repeat of the test (new blood draw) by the central laboratory without delay 
 
Complete the appropriate unscheduled laboratory case report form (CRF) module(s) with 
the original local laboratory test result 
 
When the identification criteria are met from central or local laboratory results the investigator 
will without delay: 
 
  Determine whether the subject meets potential Hy’s Law criteria (see Section D 2) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results) 


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D 4 
Follow-up 
D 4.1 
Potential Hy’s Law Criteria Not Met 
If the subject does not meet potential Hy’s Law criteria the investigator will: 
 
 
Inform the study representative that the subject has not met potential Hy’s Law criteria. 
 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the study protocol. 
 
D 4.2 
Potential Hy’s Law Criteria Met 
If the subject does meet potential Hy’s Law criteria the investigator will: 
 
 
Notify the sponsor study representative who will then inform the study team 
 
Within 1 day of potential Hy’s Law criteria being met (Appendix D 6), 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 
 
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. This includes deciding which the tests available 
in the Hy’s Law lab kit should be used. 
 
Complete the relevant CRF Modules as information becomes available 


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D 5 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this section should be followed for all cases where potential Hy’s Law 
criteria are met. 
 
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 an SAE: 
 
 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
 
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. 
 
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 are related to the 


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investigational product and seriousness criteria is 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 
 
D 6 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a subject meets potential Hy’s Law criteria on study treatment 
and has already met potential Hy’s Law criteria at a previous on study treatment visit. 
 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
potential Hy’s Law is based on the nature of the alternative cause identified for the previous 
occurrence. 
 
The investigator should determine the cause for the previous occurrence of potential Hy’s Law 
criteria being met and answer the following question: 
 
 
Was the alternative cause for the previous occurrence of potential Hy’s Law criteria being 
met found to be the disease under study eg, chronic or progressing malignant disease, 
severe infection, or liver disease. 
 
If No: follow the process described in Section D 4.2, for reporting potential Hy’s Law as an 
SAE. 
 
If Yes: Determine if there has been a significant change in the subject’s condition compared 
with when potential Hy’s Law criteria were previously met: 
 
 
If there is no significant change no action is required 
 
If there is a significant change follow the process described in Section D 4.2, for reporting 
potential Hy’s Law as an SAE 
 
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the medical monitor if there is any uncertainty. 


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D 7 
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 
IgG anti-HCV 
HCV RNA* 
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin (CD-transferrin) 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation 
*HCV RNA is only tested when IgG anti-HCV is positive or inconclusive 
 
REFERENCES 
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815. 


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FDA Guidance for Industry (issued July 2009) 'Drug-induced liver injury: Premarketing 
clinical evaluation' 


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Appendix E 
Genetic Research 
Rationale and Objectives 
MedImmune intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical studies 
and, possibly, to genetically guided treatment strategies. 
 
Genetic Research Plan and Procedures 
Selection of genetic research population 
Study selection record 
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject decline 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: 
 
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 4.1.7 of the protocol. 


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Collection of samples for genetic research 
The blood sample for genetic research will be obtained from the subjects at Visit 3 (Day 1). 
Only one sample should be collected per subject for genetics during the study. Samples will 
be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
 
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last subject last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached. 
 
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable by the second, unique number only. This number is used to identify the sample 
and corresponding data at the MedImmune genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(MedImmune employee or designated organizations working with the DNA). 
 
The link between the subject enrolment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at MedImmune or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit 
and to trace samples for destruction in the case of withdrawal of consent. 
 
Ethical and Regulatory Requirements 
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 7 of the protocol. 
 
Informed consent 
The genetic component of this study is optional, and the subject may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the subject must sign and date the consent form for the 
main study and on the same consent form indicate their agreement to be included in the 
genetic component of the study. A copy of the signed and dated consent form must be given to 
the subject and the original filed at the study center. The Principal Investigator(s) is 
responsible for ensuring that consent is given freely and that the subject understands that they 
may freely discontinue from the genetic aspect of the study at any time. 


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


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Appendix F 
Alcohol use disorder identification test (AUDIT) 
 
Alcohol Use Disorders Identification Test - Self Report Version - (AUDIT) 
PATIENT: Because alcohol use can affect your health and can interfere with certain medications and 
treatments, it is important that we ask some questions about your use of alcohol. Your answers will 
remain confidential so please be honest. 
Place an X in 1 box that best describes your answer to each question. 
Questions 
0 
1 
2 
3 
4 
1 
 
How often do you have a drink 
containing alcohol? 
 
 
 
 
 
 
 
 
 
 
Never 
Monthly or 
less 
2-4 times 
a month 
2-3 times 
a week 
4 or more 
times 
a week 
 
2 
 
How many drinks containing 
alcohol do you have on a typical day 
when you are drinking? 
 
 
 
 
 
 
 
 
 
 
1 or 2 
3 or 4 
5 or 6 
7 to 9 
10 or more 
 
3 
 
How often do you have six or 
more drinks on one occasion? 
 
 
 
 
 
 
 
 
 
 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost daily 
 
4 
 
How often during the last year 
have you found that you were not able 
to stop drinking once you had started? 
 
 
 
 
 
 
 
 
 
 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost daily 
 
5 
 
How often during the last year 
have you failed to do what was 
normally expected of you because of 
drinking? 
 
 
 
 
 
 
 
 
 
 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost daily 
 
6 
 
How often during the last year 
have you needed a first drink in the 
morning to get yourself going after a 
heavy drinking session? 
 
 
 
 
 
 
 
 
 
 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost daily 
 
7 
 
How often during the last year 
have you had a feeling of guilt or 
remorse after drinking? 
 
 
 
 
 
 
 
 
 
 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost daily 
 
8 
 
How often during the last year 
have you been unable to remember 
what happened the night before 
because of your drinking? 
 
 
 
 
 
 
 
 
 
 
Never 
Less than 
monthly 
Monthly 
Weekly 
Daily or 
almost daily 


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Alcohol Use Disorders Identification Test - Self Report Version - (AUDIT) 
PATIENT: Because alcohol use can affect your health and can interfere with certain medications and 
treatments, it is important that we ask some questions about your use of alcohol. Your answers will 
remain confidential so please be honest. 
Place an X in 1 box that best describes your answer to each question. 
Questions 
0 
1 
2 
3 
4 
 
9 
Have you or someone else been 
injured because of your drinking? 
 
 
 
 
 
 
 
 
No 
 
Yes, but not 
in the last 
year 
 
Yes, during 
the last year 
 
10 
 
Has a relative, friend, doctor, or 
other health care worker been 
concerned about your drinking or 
suggested you cut down? 
 
 
 
 
 
 
 
 
No 
 
Yes, but not 
in the last 
year 
 
Yes, during 
the last year 
 
Total 
 
 


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Appendix G Alcohol use disorder identification test (AUDIT) - Scoring 
instructions 
Scoring the AUDIT questionnaire 
Scores for each question range from 0 to 4, with the first response for each question (eg, 
never) scoring 0, the second (eg, less than monthly) scoring 1, the third (eg, monthly) scoring 
2, the fourth (eg, weekly) scoring 3, and the last response (eg, daily or almost daily) scoring 4. 
For questions 9 and 10, which only have 3 responses, the scoring is 0, 2, and 4 (from left to 
right). A score of 8 or more is associated with harmful or hazardous drinking, a score of 13 or 
more in women, and 15 or more in men, is likely to indicate alcohol dependence. 
 
Definition of a standard drink 
In the AUDIT, questions 2 and 3 it is assumed that a standard drink equivalent is 10 grams of 
alcohol. The alcohol content of a drink depends on the strength of the beverage and the 
volume of the container. 
 
The investigator should adjust the number of drinks in the response categories for these 
questions in order to fit the most common drink sizes and alcohol strength in their country. 


 
 
 
 
SIGNATURE PAGE 
This is a representation of an electronic record that was signed 
electronically and this page is the manifestation of the electronic signature 
 
Document Name: d5671c00002-csp-amendment-6 
Document Title: 
D5671C00002 Clinical Study Protocol Amendment 6 
Document ID: 
Doc ID-004250975 
Version Label: 
2.0 CURRENT LATEST APPROVED 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’Z) 
Signed by 
Meaning of Signature 
02-Dec-2020 16:03 UTC 
PPD 
 
Management Approval 
02-Dec-2020 16:17 UTC 
PPD 
 
Content Approval 
03-Dec-2020 13:04 UTC 
PPD 
 
Content Approval 
03-Dec-2020 04:56 UTC 
PPD 
PPD 
Content Approval 
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PPD 
 
Qualified Person Approval 
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.