Clinical trial NCT03351738
Conditions: Stable Coronary Heart Disease
Keywords: Coronary heart disease Pharmacokinetic Pharmacodynamics
Sponsor: MedImmune LLC
Start date: 2017-12-13; Completion date: 2018-11-09
Enrollment: 133 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamic Effects of MEDI5884 in Adults With Stable Coronary Heart Disease.

Detailed description:
A Randomized, Double-blind, Placebo-controlled, Parallel-designed Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamic Effects of MEDI5884 in Participants with Stable Coronary Heart Disease.

Arms: arm 1: Participants will receive subcutaneous (SC) dose of placebo (volume matched to MEDI5884) on Days 1, 31, and 61. arm 2: Participants will receive SC dose of MEDI5884 50 mg on Days 1, 31, and 61. arm 3: Participants will receive SC dose of MEDI5884 100 mg on Days 1, 31, and 61. arm 4: Participants will receive SC dose of MEDI5884 200 mg on Days 1, 31, and 61. arm 5: Participants will receive SC dose of MEDI5884 350 mg on Days 1, 31, and 61. arm 6: Participants will receive SC dose of MEDI5884 500 mg on Days 1, 31, and 61.
Interventions: intervention 1: MEDI5884 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive SC dose of MEDI5884 50 mg or 100 mg or 200 mg or 350 mg or 500 mg on Days 1, 31, and 61. intervention 2: Participants will receive SC dose of placebo (volume matched to MEDI5884) on Days 1, 31, and 61.

Protocol documents:
Prot_002.pdf: 
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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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A Phase 2a Randomized, Double-blind, Placebo-controlled, 
Parallel-designed Study to Evaluate the Safety, 
Pharmacokinetics, and Pharmacodynamic Effects of 
MEDI5884 in Subjects with Stable Coronary Heart Disease
Sponsor Protocol Number: D7870C00002
Application Number:
IND Number: 130981
Investigational Product:
MEDI5884
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of AstraZeneca 
PLC, One MedImmune Way, Gaithersburg, Maryland, 20878, 
USA
Medical Monitor:
Contract Research Organization: Medpace
Protocol History, Date
Protocol Amendment 4, 29May2018
Protocol Amendment 3, 27Feb2018
Protocol Amendment 2, 28Nov2017
Protocol Amendment 1, 05Oct2017
Original Protocol, 03Oct2017


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PROTOCOL SYNOPSIS
TITLE
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Parallel-designed Study to Evaluate the Safety, 
Pharmacokinetics, and Pharmacodynamic Effects of MEDI5884 in Subjects with Stable Coronary Heart 
Disease
HYPOTHESES
Primary Hypothesis: Repeated 
 dosing of MEDI5884 exhibits an acceptable safety and tolerability 
profile in subjects with stable coronary heart disease (CHD)
Secondary Hypotheses:
1. MEDI5884 demonstrates a pharmacokinetic (PK) profile that supports once 
 dosing 
2. MEDI5884 increases high-density lipoprotein cholesterol (HDL-C) without raising apolipoprotein B 
(apoB)
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Evaluate the safety and tolerability of repeated 
 dosing with MEDI5884 in subjects with 
stable CHD
•
Occurrence of treatment-emergent adverse events 
(TEAEs) and treatment-emergent serious adverse 
events (TESAEs) and clinically important changes 
in electrocardiograms (ECGs), vital signs, clinical 
laboratory evaluations and physical examination up 
to end of study (
).
Secondary
Establish the PK profile of MEDI5884 following 
repeat dosing
•
Maximum serum concentration (Cmax) of 
MEDI5884, area under the curve (AUC), terminal 
half-life (t1/2).
Evaluate the effect of MEDI5884 on HDL-C and 
apoB
•
Change in apoB (mg/dL) from baseline to 
.
•
Percent change in HDL-C from baseline to 
.
Assess immunogenicity
•
Antidrug antibody incidence and titer at 
 
Exploratory
 
 
•
 
 
 
 
 
 
 
 
•


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STUDY DESIGN
This is a Phase 2a randomized, double-blind, placebo-controlled, parallel-design study to evaluate the safety, 
PK, pharmacodynamics (PD), and immunogenicity of multiple subcutaneous (SC) doses of MEDI5884 in 
subjects with stable CHD who are currently receiving high-intensity statin therapy. At least 120 subjects are 
planned to be randomized across approximately 25 study sites in the United States of America to evaluate up 
to 5 dose levels of MEDI5884 via SC injection 
compared to placebo. 
Subjects will 
 will be randomized 
 to receive 
MEDI5884 
 or placebo (volume matched for 
MEDI5884).
Subjects will undergo a screening period of up to 
. Subjects will arrive at the study center the 
morning of each visit. Subjects will be followed for 
 after last dose (up to 
). Additional 
follow-up visits will be required if a subject’s ADA value is > the Baseline value at the last visit, if a 
subject’s directly measured LDL-C value at the last visit is ≥the Baseline value + 30 mg/dL, or if a subject’s 
triglyceride value is > 1000 mg/dL at the last visit.
TARGET SUBJECT POPULATION  
Adult males or females, aged 45 through 80 years inclusive, with stable CHD who are currently receiving 
high-intensity statin therapy. Females of childbearing potential and lactating females will be excluded.
TREATMENT GROUPS AND REGIMENS
Cohort
Dose Level
Number of Doses & Dosing Frequency
Number of 
Subjects
1
20
2
20
3
20
4
20
5
20
6
20
STATISTICAL METHODS
Sample size:
 
 
 
 
 
Statistical analyses: Safety analysis will be based on the As-treated Population. TEAEs and TESAEs will be 
coded by the most updated version of the Medical Dictionary for Regulatory Activities (MedDRA), and the 
type, incidence, severity and relationship to investigational product will be summarized by MedDRA System 
Organ Class and Preferred Term. Other safety data, such as vital signs and clinical laboratory data will be 
descriptively summarized by treatment group at each time point. Change from Baseline to each postbaseline 
time point in these data will also be summarized, where appropriate. ECG parameters will also be assessed 
and summarized descriptively. Injection site reactions, regardless of being recorded as AEs or not, will also 
be summarized.
Descriptive statistics of serum MEDI5884 concentration data will be provided. Individual and mean serum 
concentration-time profiles of MEDI5884 per treatment group and/or visit will be generated. 
Non-compartmental PK data analysis will be performed and PK parameters such as Cmax, AUC, t1/2, will be 
generated. Additional PK and PK/PD analyses may be conducted as appropriate. 


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Immunogenicity incidence rate and titers will be summarized for each treatment group.
PD analysis will be based on the As-treated Population. The primary PD endpoints, including change from 
Baseline to 
 in apoB and percent change from Baseline to 
 in HDL-C, will be summarized by 
treatment group and analyzed by comparing each MEDI5884 treatment group and placebo using an analysis 
of covariance by adjusting baseline value and treatment group. A one-sided upper 95% confidence interval 
comparing each MEDI5884 treatment group versus placebo for change from Baseline to 
 in apoB will 
be provided. 
 
 
 
 
 
Interim analysis: An interim analysis is planned after all subjects have completed their 
 visit.


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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ......................................................................................................2
LIST OF ABBREVIATIONS..............................................................................................11
1
INTRODUCTION ....................................................................................................13
1.1
Disease Background........................................................................................13
1.2
MEDI5884 Background..................................................................................13
1.3
Summary of Nonclinical Experience ...............................................................14
1.4
Summary of Clinical Experience.....................................................................14
1.5
Rationale for Conducting the Study.................................................................15
1.6
Benefit-Risk and Ethical Assessment ..............................................................15
1.7
Research Hypotheses ......................................................................................15
1.7.1Primary Hypothesis.................................................................................15
1.7.2Secondary Hypotheses.............................................................................16
2
OBJECTIVES AND ENDPOINTS ...........................................................................16
2.1
Primary Objective and Associated Endpoint....................................................16
2.2
Secondary Objectives and Associated Endpoints.............................................16
2.3
Exploratory Objectives and Associated Endpoints...........................................17
3
STUDY DESIGN......................................................................................................17
3.1
Description of the Study..................................................................................17
3.1.1Overview…….........................................................................................17
3.1.2Treatment Regimen.................................................................................18
3.2
Rationale for Dose, Population, and Endpoints................................................19
3.2.1Dose Rationale ........................................................................................19
3.2.2Rationale for Study Population................................................................25
3.2.3Rationale for Endpoints...........................................................................25
3.2.3.1
Primary Endpoints..................................................................25
3.2.3.2
Secondary Endpoints..............................................................25
3.2.3.3
Exploratory Endpoints............................................................26
4
MATERIALS AND METHODS...............................................................................27
4.1
Subjects ..........................................................................................................27
4.1.1Number of Subjects.................................................................................27
4.1.2Inclusion Criteria.....................................................................................27
4.1.3Exclusion Criteria....................................................................................28
4.1.4Subject Enrollment and Randomization...................................................29
4.1.5Withdrawal from the Study......................................................................30
4.1.6Discontinuation of Investigational Product ..............................................31
4.1.7Replacement of Subject...........................................................................31
4.1.8Withdrawal of Informed Consent for Data and Biological Samples .........32


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4.1.8.1
Biological Samples Obtained for the Main Study ...................32
4.1.8.2
Samples Obtained for Genetic Research or Future Research...32
4.2
Schedule of Study Procedures.........................................................................33
4.2.1Enrollment/Screening Period...................................................................33
4.2.2Randomized Treatment Period and Follow-up.........................................34
4.2.2.1
Early Discontinuation Visit or Unscheduled Study Visit.........39
4.2.3Additional Follow-up ..............................................................................39
4.3
Description of Study Procedures .....................................................................39
4.3.1Efficacy………. ......................................................................................39
4.3.2Medical History, Physical Examination, Height, Weight, Vital Signs, 
Electrocardiogram, and Injection Site Reaction Assessment...39
4.3.2.1
Medical History .....................................................................39
4.3.2.2
Physical Examination, Height, and Weight.............................40
4.3.2.3
Vital Signs .............................................................................40
4.3.2.4
Electrocardiogram..................................................................40
4.3.2.5
Injection Site Reaction Assessment ........................................41
4.3.3Clinical Laboratory Tests ........................................................................42
4.3.3.1
Serum Chemistry ...................................................................43
4.3.3.2
Hematology ...........................................................................43
4.3.3.3
Urinalysis...............................................................................43
4.3.3.4
Pregnancy Test (Females Only)..............................................43
4.3.3.5
Lipids for Eligibility at Screening (Fasting for a Minimum 
of 8 Hours)...............................................................43
4.3.3.6
Other Safety Tests (Screening Only) ......................................43
4.3.3.7
Other Tests:............................................................................44
4.3.4Pharmacokinetic Evaluation and Methods ...............................................44
4.3.5Immunogenicity Evaluation and Methods................................................44
4.3.6Pharmacodynamic Evaluation and Methods.............................................44
4.3.7Estimate of Volume of Blood to Be Collected .........................................45
4.4
Study Suspension or Termination....................................................................46
4.5
Investigational Products..................................................................................46
4.5.1Identity of Investigational Product(s).......................................................46
4.5.1.1
Investigational Product Handling ...........................................47
4.5.1.2
Investigational Product Inspection..........................................47
4.5.1.3
Dose Preparation Steps...........................................................48
4.5.1.4
MEDI5884 Reconstitution Procedure.....................................48
4.5.1.5
Dose Calculations ..................................................................48
4.5.1.6
Subcutaneous Dose Preparation: ............................................49
4.5.1.7
Treatment Administration ......................................................49


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4.5.1.8
Monitoring of Dose Administration........................................50
4.5.1.9
Reporting Product Complaints ...............................................50
4.5.2Additional Study Medications .................................................................50
4.5.3Labeling……….......................................................................................51
4.5.4Storage………. .......................................................................................51
4.5.5Treatment Compliance ............................................................................51
4.5.6Accountability.........................................................................................51
4.6
Treatment Assignment and Blinding ...............................................................51
4.6.1Methods for Assigning Treatment Groups ...............................................51
4.6.2Methods to Ensure Blinding ....................................................................52
4.6.2.1
Unblinding in the Event of a Medical Emergency...................52
4.6.2.2
Unblinding for the Interim Analysis .......................................53
4.6.2.3
Unblinding for Pharmacokinetic and Immunogenicity 
Analysis...................................................................53
4.7
Restrictions During the Study and Concomitant Treatment(s) .........................53
4.7.1Permitted Concomitant Medications........................................................53
4.7.2Prohibited Concomitant Medications.......................................................53
4.8
Statistical Evaluation.......................................................................................54
4.8.1General Considerations ...........................................................................54
4.8.2Sample Size.............................................................................................54
4.8.3Safety………. .........................................................................................55
4.8.3.1
Analysis of Adverse Events....................................................55
4.8.3.2
Analysis of Clinical Laboratory Parameters, Vital Signs, 
and Electrocardiograms............................................55
4.8.4Efficacy………. ......................................................................................55
4.8.5Analysis of Immunogenicity and Pharmacokinetics.................................55
4.8.5.1
Immunogenicity Analysis.......................................................55
4.8.5.2
Pharmacokinetic Analysis ......................................................56
4.8.6Pharmacodynamic Analysis.....................................................................56
4.8.7Interim Analysis......................................................................................56
5
ASSESSMENT OF SAFETY....................................................................................57
5.1
Definition of Adverse Events ..........................................................................57
5.2
Definition of Serious Adverse Events..............................................................57
5.3
Definition of Adverse Events of Special Interest .............................................58
5.4
Recording of Adverse Events..........................................................................58
5.4.1Time Period for Collection of Adverse Events.........................................58
5.4.2Follow-up of Unresolved Adverse Events................................................59
5.5
Reporting of Serious Adverse Events ..............................................................59
5.6
Other Events Requiring Immediate Reporting .................................................60


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5.6.1Overdose 60
5.6.2Hepatic Function Abnormality ................................................................60
5.6.3Pregnancy 60
5.6.3.1
Maternal Exposure .................................................................60
5.6.3.2
Paternal Exposure ..................................................................61
6
STUDY AND DATA MANAGEMENT...................................................................61
6.1
Training of Study Site Personnel.....................................................................61
6.2
Monitoring of the Study..................................................................................61
6.2.1Source Data.............................................................................................62
6.2.2Study Agreements ...................................................................................62
6.2.3Archiving of Study Documents................................................................62
6.3
Study Timetable and End of Study..................................................................62
6.4
Data Management ...........................................................................................63
6.5
Medical Monitor Coverage..............................................................................63
7
ETHICAL AND REGULATORY REQUIREMENTS..............................................63
7.1
Subject Data Protection...................................................................................63
7.2
Ethics and Regulatory Review.........................................................................64
7.3
Informed Consent............................................................................................64
7.4
Changes to the Protocol and Informed Consent Form......................................65
7.5
Audits and Inspections ....................................................................................65
8
REFERENCES .........................................................................................................67
9
CHANGES TO THE PROTOCOL............................................................................69
9.1
Protocol Amendment 4, 29May2018...............................................................69
9.2
Protocol Amendment 3, 27Feb2018 ................................................................69
9.3
Protocol Amendment 2, 28Nov2017 ...............................................................72
9.4
Protocol Amendment 1, 05Oct2017 ................................................................74
10
APPENDICES ..........................................................................................................75
10.1
Appendix 1 - Signatures..................................................................................76
10.2
Appendix 2 – Contraception Guidance............................................................78
10.3
Appendix 3 - Additional Safety Guidance .......................................................78
10.3.1Further Guidance on the Definition of a Serious Adverse Event (SAE)..78
10.3.1.1
Life threatening........................................................78
10.3.1.2
Hospitalization.........................................................78
10.3.1.3
Important Medical Event or Medical Intervention ....79
10.3.1.4
Assessment of Severity ............................................79
10.3.1.5
Assessment of Relationship......................................80
10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases and Food 
Allergy and Anaphylaxis Network Guidance for Anaphylaxis 
Diagnosis.............................................................................................82


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10.5
Appendix 5 - Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law.................................................................83
10.5.1Introduction...........................................................................................83
10.5.2Definitions ............................................................................................83
10.5.2.1
Potential Hy’s Law ..................................................83
10.5.2.2
Hy’s Law .................................................................83
10.5.3Identification of Potential Hy’s Law Cases............................................84
10.5.4Follow-up..............................................................................................84
10.5.4.1
Potential Hy’s Law Criteria Not Met........................84
10.5.4.2
Potential Hy’s Law Criteria Met...............................85
10.5.5Review and Assessment of Potential Hy’s Law Cases ...........................85
10.6
References ......................................................................................................86


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LIST OF TABLES
Table 2.1-1
Primary Objective and Associated Endpoints....................................16
Table 2.2-1
Secondary Objectives and Associated Endpoints...............................16
Table 2.3-1
Exploratory Objectives and Associated Endpoints ............................17
Table 3.1.2-1
Treatment Regimen ..........................................................................19
Table 3.2.1-1
Estimated Human PK/PD Parameters from SAD Study D7870C00001 
(Cohorts 1 to 3).................................................................................21
Table 4.2.1-1
Schedule of Screening Procedures ....................................................33
Table 4.2.2-1
Schedule of Randomized Treatment Period and Follow-up 
Procedures........................................................................................35
Table 4.3.2.5-1
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product as Reported by Subjects in their Injection Site Reaction 
Assessments .....................................................................................41
Table 4.3.7-1
Estimate of Blood Volume to be Collected........................................45
Table 4.5.1-1
Identification of Investigational Products..........................................47
Table 4.5.1.6-1
Investigational Product Dose Preparation..........................................49
Table 9.1-1
Summary of Revisions to the Protocol (Amendment 4).....................69
Table 9.2-1
Summary of Revisions to the Protocol (Amendment 3).....................69
Table 9.3-1
Summary of Revisions to the Protocol (Amendment 2).....................72
Table 9.4-1
Summary of Revisions to the Protocol (Amendment 1).....................74
Table 10.2-1
Highly Effective Methods of Contraception......................................78
LIST OF FIGURES
Figure 3.1.1-1
Study Flow Diagram.........................................................................18
Figure 3.2.1-1
Model Scheme for MEDI5884 PK and PD........................................20
Figure 3.2.1-2
Observed MEDI5884 PK Profiles and Population PK/PD Model 
Prediction from SAD Study D7870C00001 (
) .....22
Figure 3.2.1-3
Observed MEDI5884 PD Profiles from SAD Study D7870C00001 
(
) and Population PK/PD Model Prediction........23
Figure 3.2.1-4
Predicted MEDI5884 PK Profiles .....................................................24
Figure 3.2.1-5
Predicted Baseline Adjusted HDL Profiles........................................24


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LIST OF ABBREVIATIONS
ADA
antidrug antibody
AE
adverse event
AESI
adverse event of special interest
ALT
alanine transaminase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
apoB
apolipoprotein B
AST
aspartate transaminase
AUC
area under the concentration-time curve
BP
blood pressure
CETP
cholesteryl ester transfer protein
CHD
coronary heart disease
CL
clearance
Cmax
maximum observed concentration
CV
cardiovascular risk
dECG
digital electrocardiogram
ECG
electrocardiogram
EDC
electronic data capture
eCRF
electronic case report form
EDV
early discontinuation visit
EL
endothelial lipase
FSH
follicle-stimulating hormone
GCP
good clinical practice
GMP
Good Manufacturing Practice
GLP
Good Laboratory Practice
HCV
hepatitis C virus
HDL
high-density lipoprotein
HDL-C
high-density lipoprotein cholesterol
HR
heart rate
IC50
half of the maximal inhibitory concentration
ICH
International Council for Harmonisation
IgG
immunoglobulin G
IRB
Institutional Review Board
IXRS
interactive voice or web response system
LDL
low-density lipoprotein 
LDL-C
low-density lipoprotein cholesterol
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
NOAEL
no-observed-adverse-effect-level
PD
pharmacodynamic(s)


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PK
pharmacokinetic(s)
PR(PQ)
ECG interval measured from the onset of the P wave to the onset of the QRS 
complex
QRS
ECG interval measured from the onset of the QRS complex to the J point
QT
ECG interval measured from the onset of the QRS complex to the end of the T 
wave
QTcF
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event
SAD
single ascending dose
SC
subcutaneous
SD
standard deviation
SID
subject identification
t1/2
terminal half-life
TBL
total bilirubin
TC
total cholesterol
TEAE
treatment-emergent adverse events
TESAE
treatment-emergent serious adverse events
TG
triglycerides
ULN
upper limit of normal
WHO
World Health Organization


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1
INTRODUCTION
1.1
Disease Background
Coronary heart disease (CHD) remains the leading cause of death worldwide (world health 
organization, [WHO, 2017]). Despite highly effective low-density lipoprotein cholesterol 
(LDL-C) lowering therapies, high-density lipoprotein (HDL) is a key mediator of reverse 
cholesterol transport, a system that removes cholesterol from the vessel wall. In 
epidemiologic studies, low plasma levels of high-density lipoprotein cholesterol (HDL-C) are 
associated with an increased risk of major adverse cardiovascular events while elevated 
levels are associated with lower cardiovascular (CV) risk (Prospective Studies Collaboration 
et al., 2007). However, existing pharmacological approaches to raising plasma HDL-C, for 
example by cholesteryl ester transfer protein (CETP) inhibition have not been convincingly 
shown to reduce CV risk (Aim-High Investigators et al., 2011; Barter et al., 2007; Hps Timi 
Reveal Collaborative Group et al., 2017; Schwartz et al., 2012). Lowering risk may require 
improving HDL-C function as well as quantity, and employing a mechanism which promotes 
reverse cholesterol transport.
Endothelial lipase (EL) is a circulating phospholipase A1 enzyme that hydrolyzes HDL-C 
phospholipids and increases the catabolism of HDL-C and its loss through the kidney 
resulting in low HDL-C levels. Partial and complete loss-of-function EL gene mutations 
result in elevated HDL-C, increased cholesterol efflux, and CV risk reduction in otherwise 
healthy individuals. MEDI5884 is a high affinity and selective human EL neutralizing 
antibody. Studies of MEDI5884 in nonhuman primates demonstrate increases in HDL 
particle numbers and ATP-binding cassette transporter 1 mediated cholesterol efflux. It is 
hypothesized that MEDI5884 will inhibit EL resulting in an increase in HDL-C levels and 
improved HDL function in humans.
1.2
MEDI5884 Background
MEDI5884 is briefly described below. Refer to the current Investigator’s Brochure for 
details. 
 
 
 
 
 
 


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1.3
Summary of Nonclinical Experience
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4
Summary of Clinical Experience
 
 
 
 
 


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1.5
Rationale for Conducting the Study
Safety, PK, and PD data following multiple dose administrations of MEDI5884 will confirm 
target engagement and support dose selection for subsequent studies. Stable CHD subjects 
are chosen in order to assess the effects of EL inhibition in subjects with known 
cardiovascular disease. 
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.
 
 
General risks based on the administration of biologics include injection site reactions, 
hypersensitivity, anaphylactic type reactions, and development of antidrug antibodies (ADA).
To mitigate against these risks, this study will be conducted at clinical sites that have 
experience in managing clinical studies with biologic investigational products. Appropriate 
drugs and medical equipment to treat acute anaphylactic and serious allergic reactions will be 
immediately available, and study personnel will be trained to recognize and treat 
anaphylaxis. Subjects will be closely monitored after the administration of investigational
product on 
 for immediate drug reactions or other adverse effects.
1.7
Research Hypotheses
1.7.1
Primary Hypothesis
1. Repeated 
 dosing of MEDI5884 exhibits an acceptable safety and tolerability 
profile in subjects with stable CHD


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1.7.2
Secondary Hypotheses
1. MEDI5884 demonstrates a PK profile that supports once 
 dosing 
2. MEDI5884 increases HDL-C without raising apolipoprotein B (apoB)
2
OBJECTIVES AND ENDPOINTS
2.1
Primary Objective and Associated Endpoint
Table 2.1-1
Primary Objective and Associated Endpoints
Type
Objective
Endpoint
Safety
Evaluate the safety and tolerability of 
repeated 
 dosing with 
MEDI5884 in subjects with stable 
CHD
•
Occurrence of TEAEs and TESAEs and 
clinically important changes in ECGs, 
vital signs, clinical laboratory 
evaluations and physical examination up 
to end of study (
)
CHD = coronary heart disease; ECG = electrocardiogram; TEAE = treatment-emergent adverse events; 
TESAE = treatment-emergent serious adverse events
2.2
Secondary Objectives and Associated Endpoints
Table 2.2-1
Secondary Objectives and Associated Endpoints
Type
Objective
Endpoint
PK
Establish the PK profile of 
MEDI5884 following repeat dosing
•
Maximum serum concentration (Cmax) of 
MEDI5884, area under the curve (AUC), 
terminal half-life (t1/2).
PD
Evaluate the effect of MEDI5884 on 
HDL-C and apoB
•
Change in apoB (mg/dL) from Baseline
to 
.
•
Percent change in HDL-C from Baseline
to 
.
Immunogenicity
Assess immunogenicity
•
Antidrug antibody incidence and titer at 
 
.
ApoB = apolipoprotein B; HDL-C = high-density lipid cholesterol; PD = pharmacodynamic; 
PK = pharmacokinetics


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2.3
Exploratory Objectives and Associated Endpoints
 
 
 
 
 
 
 
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview……..
This is a Phase 2a randomized, double-blind, placebo-controlled, parallel-design study to 
evaluate the safety, PK, PD, and immunogenicity of multiple SC doses of MEDI5884 in 
subjects with stable CHD who are currently receiving high-intensity statin therapy. At least 
120 subjects are planned to be randomized across approximately 25 study sites in the United 
States of America 
 
 
 
Subjects will undergo a screening period of up to 
. Subjects will arrive at the study 
center the morning of each visit. Subjects will be followed for 
 (up to 
 Figure 3.1.1-1). Additional follow-up visits will be required if a subject’s ADA 
level is > Baseline at the last visit, if a subject’s directly measured LDL-C at the last visit is 
≥Baseline + 30 mg/dL, or if a subject’s triglyceride value is > 1000 mg/dL at the last visit 
(Section 4.2.3).


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The endpoints to be measured in this study are described in Section 2.
3.1.2
Treatment Regimen
 


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Table 3.1.2-1
Treatment Regimen
Cohort
Dose Level
Number of Doses & Dosing Frequency
Number of 
Subjects
1
20
2
20
3
20
4
20
5
20
6
20
3.2
Rationale for Dose, Population, and Endpoints
3.2.1
Dose Rationale
Doses for this study have been selected based on the preliminary results of PK/PD (Cohorts 1 
to 3) data from the ongoing Phase 1 SAD study of MEDI5884 (D7870C00001).
A PK/PD model was developed to describe MEDI5884 PK and the corresponding HDL 
changes over time using an indirect response model. Model estimates were based on fitting 
PK/PD data simultaneously in healthy volunteers 
 


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MEDI5884 PK appeared nonlinear. A 2 –compartment population PK model with linear and 
nonlinear clearance described the data of all 3 cohorts well. The estimated PK parameters are 
presented in Table 3.2.1-1 and Figure 3.2.1-2. 
 
 
 


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In summary, the proposed doses of MEDI5884 in this study are expected to be well tolerated, 
and the collected PK/PD data will be appropriate to fulfill the objectives of this study. The 
follow-up duration is sufficient to evaluate the potential immunogenic profile of MEDI5884 
and monitor any potential impact on PD markers as a result of neutralizing ADA.
3.2.2
Rationale for Study Population
The study population consists of adults with CHD who are clinically stable and taking a 
high-intensity statin. 
 
 
 
Subjects will be required to be on a stable high-intensity statin regimen (≥40-mg atorvastatin 
or ≥20-mg rosuvastatin for non-Asian subjects; ≥10-mg rosuvastatin for Asian subjects) for 
≥28 days as is the standard of care for atherosclerotic disease, with LDL-C levels 
≤100 mg/dL at Screening. 
3.2.3
Rationale for Endpoints
3.2.3.1
Primary Endpoints
Safety and tolerability endpoints including TEAEs, TESAEs, ECGs, vital signs, clinical 
laboratory evaluations, and physical examinations are standard measures.
3.2.3.2
Secondary Endpoints
Pharmacokinetic Profile
Serum MEDI5884 concentrations will be used to establish the PK profile of MEDI5884, to 
characterize exposure, and relate to toxicological exposures. The PK may also be used to 
develop dose-exposure-PD response relationships to help inform dose selection for future 
clinical studies.
High-density Lipoprotein Cholesterol and Apolipoprotein B 
Percent change in HDL-C from Baseline to 
 and change in apoB (mg/dL) from 
Baseline to 
 are the primary PD endpoints in this study. Based on large prospective 
studies of CV risk factors, low HDL-C levels have been shown to be an independent and 
inverse predictor of atherosclerotic heart disease (Emerging Risk Factor Collaboration et al., 
2009). However, increasing evidence suggests that measures of HDL function in contrast to 
HDL-C levels are better predictors for atherosclerotic burden 


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(Bhatt and Rohatgi, 2016; Khera et al., 2011; Rohatgi et al., 2014). 
 
 
 
 
 
 
 
 
In the extensive lipid literature, apoB has more consistently predicted CV risk than LDL-C. 
For example, in the Treating to New Targets study which randomized 9251 patients with 
CHD to atorvastatin 10 mg or 80 mg, 729 CV events were identified after median 4.9 year 
follow up. In univariate analysis, many variables including LDL-C, HDL-C, apoA1, and 
apoB were associated with subsequent CV events. In multivariable analysis, apoB 
independently predicted CV events whereas LDL-C did not (Mora et al., 2012). This is an 
established concept; the American Association for Clinical Chemistry issued a position paper 
in 2009 stating “apoB is a better measure of circulating LDL particle concentration and is a 
more reliable indicator of risk than LDL-C” (Contois et al., 2009).
Immunogenicity
ADA incidence rate and titer will be tabulated for each subject to monitor immunogenicity. 
Tiered analyses will be performed to include screening, confirmatory and titer assay 
components; samples confirmed positive for ADA will be tested and analyzed for antibody 
titer and reported and may be utilized for further characterization of the ADA response.
 
 
 
 


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4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
At least 120 subjects are planned to be randomized across approximately 25 study sites in the 
United States of America as described in Sections 3.1.1 and 3.1.2.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Male or female adult aged 45 through 80 years, inclusive, at the time of Screening
2. Written informed consent and any locally required authorization (eg, data privacy) 
obtained from the subject prior to performing any protocol-related procedures, including 
screening evaluations
3. Written informed consent if participating in the optional future use research or genetic
research. Declining to participate in this part of the study will not result in penalty or loss 
of benefit to the subject 
4. Ability to meet all eligibility requirements for randomization within up to 
 after 
signing the informed consent form
5. Ability and willingness to adhere to visit/protocol schedule and complete the follow-up 
period 
6. Diagnosis of stable CHD documented prior to Screening defined as a history of at least 
one of the following: 
a.
prior myocardial infarction, 
b. coronary revascularization, 
c.
coronary atherosclerosis diagnosed >3 months prior to Screening, based on invasive 
or non-invasive imaging, 
d. abnormal stress testing diagnostic of CHD
7. Currently receiving any high-intensity statin (≥40-mg atorvastatin or ≥20-mg rosuvastatin 
for non-Asian subjects; ≥10-mg rosuvastatin for Asian subjects) at a stable dose for
≥30 days prior to Screening and intending to remain at a stable dose throughout the study 
duration. 
8. Females must not be of childbearing potential and must not be lactating (see Section 10.2
for definition of females of childbearing potential)
9. Nonsterilized male subjects who are sexually active with a female partner of childbearing 
potential must use a male condom with spermicide from 
 through the end of their 
participation in the study. It is strongly recommended for the female partner of a male 
subject to also use a highly effective method of contraception throughout this period, as 
described in Section 10.2.


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4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Unstable cardiovascular conditions, including acute coronary syndrome, stroke or 
transient ischemia attack, critical limb ischemia, arterial revascularization, life-
threatening arrhythmias, or heart failure hospitalization within 
of Screening
2. Any planned arterial revascularization (coronary, peripheral or carotid)
3. New York Heart Association Class III or IV congestive heart failure or treatment with 
advanced therapies (cardiac transplant, ventricular assist device, cardiac 
resynchronization therapy, and/or chronic intravenous ionotropic support)
4. Severe valvular heart disease
5. Fasting laboratory values at Screening for any of the following:
a.
Triglycerides >500 mg/dL
b. LDL-C >100 mg/dL (by direct measure)  
6. Clinically significant BP abnormalities at Screening after 10 minutes supine rest:
a.
Systolic BP <90 or >160 mmHg
b. Diastolic BP >100 mmHg 
Note: BP may be retested one time at the discretion of the investigator.
7. ECG results from the central lab report at Screening, demonstrating:
a.
Prolonged QTcF >460 milliseconds based on reported mean of any ECG, or 
b. QRS >160 milliseconds based on reported mean of any ECG
8. Family history of long QT, or any clinically significant ECG finding as judged by the
investigator (at 
) that may interfere with the interpretation of serial 
ECG and QT interval changes
9. Current or previous use of lipid-lowering medications within 
 prior to Screening, 
except for statins and/or <100-mg/day niacin, and/or 10-mg/day ezetimibe, and/or 
<2-g/day fish oil
10. History of any of the following:
a.
Documented genetic disorder of cholesterol metabolism
b. Chronic kidney disease stage 4-5, defined by estimated glomerular filtration rate 
<30 mL/min/1.73 m2 by the modification of diet in renal disease equation, or end 
stage renal disease treated with kidney transplant or renal replacement therapy
c.
History of clinically overt chronic liver disease or biochemical evidence of liver 
disease (eg, aspartate transaminase [AST] or alanine transaminase [ALT] >1.5 × 
upper limit of normal [ULN] and/or total bilirubin [TBL] >ULN [unless due to 
Gilbert’s syndrome])
d. Poorly controlled endocrine disorder including Type 1 or Type 2 diabetes mellitus 
with glycated hemoglobin >10% as assessed at Screening 
e.
Uncontrolled thyroid disorder defined as thyroid stimulating hormone >1.5 × ULN 
and abnormal free T4; subjects with thyroid deficiency should have received a stable 
dose of thyroid hormone for >6 weeks prior to Screening


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f.
Current or previous use of systemic corticosteroids within 
 prior to Screening. 
Topical, intra-articular, intranasal, inhaled, and ophthalmic steroid therapies are 
permitted
g. History of severe infection or ongoing febrile illness within 
 of Screening 
h. Positive hepatitis B surface antigen or positive hepatitis C virus (HCV) antibody 
serology 
i.
History of active malignancy within 5 years (subjects with non-melanotic skin cancer 
may be included)
j.
Any other disease or condition or laboratory value that, in the opinion of the 
investigator or medical monitor, would place the subject at an unacceptable risk or 
interfere with the evaluation of the investigational product. Note: abnormal laboratory 
values may be re-tested one time only if, in the investigator’s judgment, the values are 
not representative of the subject. The rationale for retest must be documented in 
source documents.  
11. History of alcohol or recreational substance abuse within the past 6 months, with abuse 
defined in accordance with the judgment of the investigator
12. Known allergy/hypersensitivity to any component of the investigational product 
formulation, other biologics, plastics, adhesive or silicone, or ongoing clinically 
important allergy/hypersensitivity as judged by the investigator
13. Pregnant females (a negative urine pregnancy test is required at Screening and 
 
and lactating females are excluded.
14. An employee, or close relative of an employee, of AstraZeneca, MedImmune, the 
contract research organization, or the study site, regardless of the employee’s role
15. Either:

Use of any biological agent within 6 months or 5 half-lives of its dosing prior to 
Screening, whichever is longer

Receipt of any investigational drug therapy within 5 half-lives of its dosing prior to 
Screening 

Concurrent enrollment in an interventional study
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice/web response system [IXRS], and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable. 
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria), 
including the reason(s) for screening failure.


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Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not 
be randomized (if applicable) or receive investigational product. Subjects who are 
randomized but do not receive MEDI5884 or placebo may be rescreened.
Subjects may be rescreened once to permit eligibility based on time-dependent factors 
including: 
•
Not being on a stable dose of high-intensity statin therapy for the required 
 
(inclusion criterion 7) 
•
Not being at least 
 since an unstable cardiovascular condition (exclusion 
criterion 11)
•
To permit a change in antihypertensive therapy so that clinically significant bp 
abnormalities have resolved (
) 
•
To be at least 
 out from lipid-lowering medication not permitted in 
 
 
•
To be on a stable dose of thyroid hormone for at least 
 prior to screening 
(
)
•
To have been off of systemic corticosteroids for at least 
 prior to screening 
(
) 
•
To avoid having had a severe infection or ongoing febrile illness within 
 of 
screening (
). 
Rescreening to meet laboratory- or ECG-based enrollment criteria is not permitted with the 
following exception: 
•
Subjects who were excluded based on fasting triglyceride or LDL-C levels may be 
rescreened once if their lipid-lowering therapy has been increased; rescreening must be 
 after change in therapy. 
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments) at any time, without prejudice to further treatment. Subjects who withdraw 
consent will be asked about the reason(s) and the presence of any adverse events (AEs). If 
the subject is willing, the subject will be seen and assessed by the investigator. 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.


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4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question:
1. Withdrawal of consent from further treatment with investigational product or lost to 
follow-up
2. An AE that, in the opinion of the investigator or the sponsor, warrants discontinuation of 
further dosing 
3. Subject is determined to have met one or more of the exclusion criteria or failed to meet 
all of the inclusion criteria for study participation at study entry and continuing 
investigational product might constitute a safety risk
4. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)
5. Pregnancy in any female subject
6. Any of the following liver function abnormalities: ALT or AST ≥3 × ULN and total 
bilirubin >2 × ULN
7. Subject’s most recent apoB value, obtained at least 
 after the subject’s previous 
dose, exceeds his or her baseline (
 predose) level by ≥30 mg/dL. ApoB testing may 
be repeated once within the protocol-specified dosing window for Doses 2 or 3, and if 
that value is <30 mg/dL higher than the baseline value, the subject may be dosed. If the 
subject’s apoB level is ≥30 mg/dL above the baseline level the subject cannot be dosed 
but will remain in the study to be followed for safety.
8. Subject’s pre-dose triglyceride value is ≥1000 mg/dL.
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments, including follow-up of any AEs, unless consent 
is withdrawn from further study participation (Section 4.1.5). 
4.1.7
Replacement of Subject
Subjects who do not complete dosing per randomization for any reason other than for safety
(which includes subjects who withdrew due to an AE or by having met withdrawal criteria 
for withdrawal of investigational product (Section 4.1.6) may be replaced if deemed 
necessary by the medical monitor to ensure that safety and PK data are collected from a 
sufficient number of subjects and to maintain the balance of the study.


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4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
4.1.8.1
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor the safety of the subject.
4.1.8.2
Samples Obtained for Genetic Research or Future Research
Samples obtained for genetic research or future research will be labeled with a sample 
identification number linked to the SID number but will not be labeled with personal 
identifiers such as the subject’s name. If the subject withdraws consent for participating in 
genetic research or future research, the sponsor will locate the subject’s sample and destroy 
it. The coding of samples and results is to ensure that these research results are kept 
confidential by keeping the subject’s identity and these results separate.
If the subject consents to have his/her samples used for genetic research or future research, 
this additional research may not start immediately and may start at any time during the 
storage period. The subject’s sample(s) including any specimens of extracted DNA will be 
stored by the sponsor with similar samples from other subjects at a secure central laboratory. 
The subject’s samples will not be kept for more than 25 years after the end of the study in 
which they were collected. If the subject chooses not to allow his/her study samples to be 
used for genetic research or future research, the samples will be destroyed by the sponsor 
once they are no longer required for the main study.
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the sponsor for genetic research or future research, the investigator will arrange to have it 
destroyed. If consent is withdrawn after the subject’s sample(s) have been sent to the sponsor 
for genetic research or future research, the sponsor and the investigator will ensure that these 
sample(s) are destroyed unless the sample identification number has been removed and the 
subject can no longer be linked to any sample(s). However, if the subject’s samples have 
already been used for research, the sponsor is not required to destroy results of this research. 
In this case only the remaining sample(s) will be destroyed.


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4.2
Schedule of Study Procedures
4.2.1
Enrollment/Screening Period
Table 4.2.1-1 shows all procedures to be conducted at Screening.
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, and then 
blood draws. 
Table 4.2.1-1
Schedule of Screening Procedures
Study Period
Screening
Visit Number
V1
Procedure/Study Day
Main study informed consent / assignment of SID 
number
X
Future use informed consent (optional)
X
Genetic research informed consent (optional)
X
Medical History
X
Body Weight
X
Height
X
Physical Examination (Detailed)
X
Vital Signs
X
dECGa
X
Serum Chemistry and Hematology
X
Thyroid Stimulating Hormone
X
HbA1c
X
Lipids for Eligibilityb
X
Urinalysis 
X
FSHc
X
Urine Pregnancy Testc
X
Hepatitis and HIV
X
Assessment of AEs and SAEs
X
Assessment of Concomitant Medications
X
Verify Eligibility Criteria
X
EL Mass and Exploratory Biomarkersb
X
c


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4.2.2
Randomized Treatment Period and Follow-up
Table 4.2.2-1 shows all procedures to be conducted at the treatment and follow-up periods.
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, and then 
blood draws. The timing of the first 2 assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the proper nominal time.


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Table 4.2.2-1
Schedule of Randomized Treatment Period and Follow-up Procedures
Study Period
Treatment Period
Follow
-up
LDL-C or 
Triglycerides
Follow-upc
Visit
V2
V3
V4
V5
V6
V7
V8a
V9b
V10
V11a
V12
V13
V14
V15
V16 
V17
V18
V19
V20
Medical 
history
X
Body weight
X
X
Physical 
examination 
(abbreviated)
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
dECGe
X
X
X
X
X
X
X
Serum 
chemistry and 
hematology
X
X
X
X
X
Urinalysis 
X
X
X
X
X
Urine 
pregnancy 
testf,g
X
Assessment of 
AEs and SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Verify 
eligibility 
criteria
X
 


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Table 4.2.2-1
Schedule of Randomized Treatment Period and Follow-up Procedures
Study Period
Treatment Period
Follow
-up
LDL-C or 
Triglycerides
Follow-upc
Visit
V2
V3
V4
V5
V6
V7
V8a
V9b
V10
V11a
V12
V13
V14
V15
V16 
V17
V18
V19
V20
Total 
cholesterol, 
nonHDL-C, 
LDL-C (direct 
and 
Friedewald), 
HDL-C, 
VLDL-C, 
triglycerides, 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ApoA1 and 
ApoB blood 
samplei,j
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Table 4.2.2-1
Schedule of Randomized Treatment Period and Follow-up Procedures
Study Period
Treatment Period
Follow
-up
LDL-C or 
Triglycerides
Follow-upc
Visit
V2
V3
V4
V5
V6
V7
V8a
V9b
V10
V11a
V12
V13
V14
V15
V16 
V17
V18
V19
V20
Future use 
blood sample
X
X
X
X
X
Genetic 
research 
sample
X
Randomization
X
Assessment of 
injection sitesm
X
X
X
X
X
X
Physical 
examination 
(detailed)
X
 
 
 
 
 
 
 


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Table 4.2.2-1
Schedule of Randomized Treatment Period and Follow-up Procedures
Study Period
Treatment Period
Follow
-up
LDL-C or 
Triglycerides
Follow-upc
Visit
V2
V3
V4
V5
V6
V7
V8a
V9b
V10
V11a
V12
V13
V14
V15
V16 
V17
V18
V19
V20
 
 
 
 
 


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4.2.2.1
Early Discontinuation Visit or Unscheduled Study Visit
Study procedures should be completed as per 
/early discontinuation visit for subjects 
who prematurely discontinue from the study and for subjects who require an unscheduled 
study visit. Subjects should be encouraged to remain in the study for follow-up. 
4.2.3
Additional Follow-up
 
 
 
Subjects whose direct LDL-C at the 
 visit is ≥30 mg/dL above their baseline (
 
predose) value will return 
 after their last visit for repeat LDL-C testing, 
and, for continued elevation of LDL-C ≥30 mg/dL above Baseline, again on 
and 
for LDL-C testing (see Table 4.2.2-1). 
Subjects whose triglyceride value at the 
 visit is > 1000 mg/dL will return for a 
repeat triglyceride testing on 
. If the triglyceride value remains > 1000 mg/dL on 
, an additional follow-up visit (
) will occur for repeat testing
(Table 4.2.2-1).
4.3
Description of Study Procedures
4.3.1
Efficacy……….
No efficacy assessments are being conducted in this study. PD assessments related to the 
effects of MEDI5884 are described in Section 4.3.6.
4.3.2
Medical History, Physical Examination, Height, Weight, Vital Signs, 
Electrocardiogram, and Injection Site Reaction Assessment 
4.3.2.1
Medical History
A complete history will include medical and disease history, current medical conditions, 
smoking and alcohol history, 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. A medical and disease history will be performed at Screening and 


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4.3.2.2
Physical Examination, Height, and Weight
A detailed physical examination will be performed at Screening and at last follow-up visit. 
The full physical examination will include examination of the following: general appearance, 
head, ears, eyes, nose, throat, neck, skin, heart, lung, abdomen, musculoskeletal system, 
endocrine system, and nervous system. An abbreviated physical exam will be performed as 
outlined in Table 4.2.2-1. The abbreviated physical exam will include examination of: 
general appearance, skin, heart, lung, and abdomen, at a minimum. Each clinically significant 
abnormal finding will be recorded for all physical examinations. Weight and height will be 
measured as outlined in Table 4.2.1-1 and Table 4.2.2-1.
4.3.2.3
Vital Signs
Vital signs (BP, HR, respiratory rate, and body temperature) will be obtained at Screening
and on study days as outlined in Table 4.2.2-1. With respect to dosing, vital signs (BP, HR, 
respiratory rate, and body temperature) on 
should be collected predose 
(within 60 minutes prior to start of dosing) and 1 hour (± 15 minutes) postdose. Predose vital 
signs should not be clinically significantly different from the subject’s screening value 
according to the judgment of the investigator. All vital sign measurements will be measured 
with the subject in a supine position having rested for at least 10 minutes before each 
reading, and should be taken before any blood draws scheduled in close proximity
4.3.2.4
Electrocardiogram
At the visits specified in Table 4.2.1-1 and Table 4.2.2-1, 12-lead ECGs will be obtained 
after 10 minutes supine rest. Predose triplicate digital ECG on
 should be collected at 
3 different time points (3 × 3 replicates) prior to dosing; each triplicate must be separated by 
at least 5 minutes. On all other days of ECGs, they will be captured in triplicate, up to 
5 minutes apart. In addition, a 10-second paper ECG print-out from the 12-lead ECGs will be 
taken predose, for overall evaluation (normal/abnormal) before administration and during 
study days. Subjects with predose ECGs showing clinically significant abnormalities, 
according to the judgment of the investigator, should not be dosed. 
The same recorder will be used for each subject at each time point, if possible. Date and time 
settings should be checked at the start of each study day and aligned with an official 
timekeeper for all machines used in the study.
Skin preparation should be thorough and electrode positions should be according to standard 
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The following variables will be reported: heart rate, RR, PR, QRS and QT intervals from the 
primary lead of the digital 12-lead ECG. Derived parameters (QTcF, QTcB, and others, as 
applicable) will also be calculated.
The investigator may add extra 12-lead ECG safety assessments if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason.
4.3.2.5
Injection Site Reaction Assessment
Assessment of the injection sites for injection site reactions should be conducted as specified 
in Table 4.2.2-1.
Subjects will be given a tape measure and an injection site worksheet. They will be instructed 
to record onto the worksheet whether or not an injection site reaction has occurred at any 
injection site during the 24 hours after each dose of investigational product. If an injection 
site reaction has occurred, the subject is to record the measured maximal redness and 
swelling and a graded assessment of pain (per Table 4.3.2.5-1) for the maximum observation 
at any injection site. Measurements <¼ inch at the largest diameter should be recorded as 0 
inches. Measurements ≥¼ inch but <1 inch would result in a subject recording “yes” to 
injection site reaction, but the reaction would not be graded (< Grade 1). The subject will 
report injection site reactions to the Investigational Site and this information will be recorded 
in the electronic data capture (EDC) system. The subject should return the worksheet to the 
site to be included in the subject’s investigational records. If the subject fails to return the 
worksheet, the site should query the subject, and, if the subject is able to report the 
information, it should be recorded, even if incomplete.
Table 4.3.2.5-1
Tables for Clinical Abnormalities: Local Reactions to 
Injectable Product as Reported by Subjects in their 
Injection Site Reaction Assessments
Local Reaction to 
Injectable Product
Reaction Grade
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of non-
narcotic pain reliever 
>24 hours or 
interferes with 
activity
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity
ER visit or 
hospitalization
Erythema/rednessa
1-2 inches
>2-4 inches
>4 inches
Necrosis or 
exfoliative 
dermatitis
Induration/swellingb
1-2 inches 
>2-4 inches  
>4 inches  
Necrosis


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Local Reaction to 
Injectable Product
Reaction Grade
Mild (Grade 1)
Moderate (Grade 2)
Severe (Grade 3)
Potentially Life 
Threatening 
(Grade 4)
ER = emergency room
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable
b
Induration/swelling should be evaluated and graded using the functional scale as well as the actual 
measurement
Injection site reactions that occur beyond the 24 hours of collection will be recorded as AEs 
according to the criteria described in Section 5.1. 
Investigators may choose to enter significant injection site reactions occurring during the first 
24 hours postdose as AEs, but reporting of injection site reactions as an AE is not required 
during the first 24 hours postdose and may not occur for low-grade reactions. Injection site 
reaction data are recorded separately by patient reported injection site reaction assessments 
and also by investigator reported injection site reactions. These data will be reported 
separately and may not be identical. 
4.3.3
Clinical Laboratory Tests
A laboratory manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study. 
Clinical laboratory safety tests, including urine pregnancy tests, will be performed in a 
licensed clinical laboratory. Urine pregnancy test will be conducted at Screening and on 
Urine pregnancy tests may be performed at the site using a licensed test (dipstick). 
Clinically significant (as determined by the investigator) abnormal laboratory results should 
be repeated as soon as possible (preferably within 24 to 48 hours).
The following clinical laboratory tests will be performed:


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4.3.3.1
Serum Chemistry
•
Calcium
•
ALP
•
Phosphorus
•
Total bilirubin
•
Chloride
•
Gamma glutamyl transferase
•
Potassium
•
Creatinine
•
Sodium
•
Blood urea nitrogen
•
Bicarbonate
•
Glucose 
•
AST
•
Albumin
•
ALT
•
Creatinine kinase
Note: Tests for AST, ALT, ALP, and total bilirubin must be conducted concurrently and assessed concurrently. 
Please refer to Section 10.5 if a subject shows an AST or ALT ≥3 × ULN or total bilirubin ≥2 × ULN.
4.3.3.2
Hematology
•
White blood cell count with differential (% 
and absolutes)
•
Platelet count
•
Red blood cell count
•
Mean corpuscular volume
•
Hematocrit
•
Mean corpuscular hemoglobin concentration
•
Hemoglobin
4.3.3.3
Urinalysis
•
Color
•
Blood
•
Appearance
•
Leukocyte esterase
•
Specific gravity
•
Bilirubin
•
pH
•
Urobilinogen
•
Protein
•
Nitrite
•
Glucose
•
Urine microscopy and urine casts (as required if 
dipstick at central laboratory is abnormal)
•
Ketones
4.3.3.4
Pregnancy Test (Females Only)
•
Urine human chorionic gonadotropin (hCG)
4.3.3.5
Lipids for Eligibility at Screening (Fasting for a Minimum of 8 Hours)
•
Triglycerides
•
HDL-C
•
LDL-C (by direct measure)
4.3.3.6
Other Safety Tests (Screening Only)
•
Thyroid stimulating hormone
•
Follicle stimulating hormone (FSH; females only)
•
Hepatitis B surface antigen, Hepatitis C antibody
•
HIV-1, -2 antibodies
•
Glycated hemoglobin


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4.3.3.7
Other Tests:
•
 
•
TC
•
HDL-C
•
NonHDL-C
•
LDL-C (direct and Friedewald equation)
•
Very-low-density lipoprotein cholesterol (VLDL-C)
•
Triglycerides
•
ApoA1
•
ApoB
 
 
4.3.4
Pharmacokinetic Evaluation and Methods
Blood samples will be collected to evaluate PK of MEDI5884 in serum (see Section 4.2.2 for
collection time points). The PK of MEDI5884 in serum will be measured utilizing a validated 
immunoassay method. Specific procedures for sample collection, processing, storage, and 
shipment can be found in a separate laboratory manual provided to the sites.
4.3.5
Immunogenicity Evaluation and Methods
Blood samples will be collected to evaluate ADA response to MEDI5884 (see Section 4.2.2
for collection time points). These evaluations will be performed utilizing a validated 
immunoassay method. Specific procedures for sample collection, processing, storage, and 
shipment can be found in a separate laboratory manual provided to the site.
If a subject’s final scheduled immunogenicity sample is > Baseline, the subject will return to 
the study site as described in Section 4.2.3. 
Serum samples collected for ADA should be stored for 2 years after marketing approval, and 
they may be utilized for further characterization of the antibody response.
4.3.6
Pharmacodynamic Evaluation and Methods
Blood samples will be collected to evaluate the PD response to MEDI5884 (see Section 4.2.2
for collection time points). PD endpoints may include HDL-C, TC, nonHDL-C, LDL-C 
(direct and Friedewald equation), VLDL-C, triglycerides,


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. HDL-C, TC, nonHDL-C, 
LDL-C, VLDL-C, triglycerides, 
 
will be measured by using a validated assay. 
, apoB, and apoA1 will be 
measured by using a qualified immunoassay method. 
 
Specific procedures for sample collection, processing, storage, and shipment can be found in 
a separate laboratory manual provided to the site.
4.3.7
Estimate of Volume of Blood to Be Collected
The estimated volume of blood to be collected per subject is presented in Table 4.3.7-1. 
Additional blood samples may be collected at the discretion of the investigator in the event of 
abnormal laboratory findings or an AE.
Table 4.3.7-1
Estimate of Blood Volume to be Collected
Visit Day
Estimated Blood Volume (mL)
15.0
102.0
8.5
10.5
8.5
8.5
8.5
32.5
3.0
32.5
8.5
8.5
8.5
40.5
10.5
32.5
3.0
3.0
6.0
Total
350.5
a
blood draws will occur only for subjects who require additional follow-up (See 
Section 4.2.3)


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4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or permanently terminate this study at 
any time. The reasons for temporarily suspending or permanently terminating the study may 
include but are not limited to the following: 
1. The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects
2. Anaphylaxis in any subject assessed as related to MEDI5884
3. Subject enrollment is unsatisfactory
4. Noncompliance that might significantly jeopardize the validity or integrity of the study 
5. Sponsor decision to terminate development of the investigational product for this 
indication
If MedImmune determines that temporary suspension or permanent termination of the study 
is required, MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Institutional Review Board (IRB) promptly and provide the reason(s) for the 
suspension/termination. If the study is suspended for safety reasons and it is deemed 
appropriate by the sponsor to resume the study, approval from the relevant regulatory 
authorities (and IRBs when applicable) will be obtained prior to resuming the study.
4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
 


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4.5.1.1
Investigational Product Handling
 
 
 
 
 
 
 
 
 
 
 
4.5.1.2
Investigational Product Inspection
 
 
 
 
 
 


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4.5.1.3
Dose Preparation Steps
 
 
 
 
 
 
 
 
 
4.5.1.4
MEDI5884 Reconstitution Procedure
 
 
 
 
 
 
 
 
 
 
 Calculations
1.
 
 


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3.
 
4.5.1.6
Subcutaneous Dose Preparation:
1.
 
 
 
 
3.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5.1.7
Treatment Administration
 
 
 
 


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4.5.1.8
Monitoring of Dose Administration
 
 
 
 
4.5.1.9
Reporting Product Complaints
 
 
 
 
MedImmune contact information for reporting product complaints:
Email: productcomplaints@medimmune.com
Phone: +1-301-398-2105
+1-877-MEDI-411 (+1-877-633-4411)
Fax:
+1-301-398-8800
Mail:
MedImmune
Attn: Product Complaint Department
One MedImmune Way,
Gaithersburg, MD USA 20878
4.5.2
Additional Study Medications
 
 


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4.5.3
Labeling……….
 
4.5.4
Storage……….
4.5.5
Treatment Compliance
 
4.5.6
Accountability
 
 
 
 
4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
An IXRS will be used for randomization to a treatment group and assignment of blinded
investigational product. A subject is considered randomized into the study when the 
investigator notifies the IXRS that the subject meets eligibility criteria and the IXRS provides 
the assignment of blinded investigational product kit numbers to the subject.
 
 
 
Investigational product (MEDI5884 or placebo) must be administered the same day 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


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4.6.2
Methods to Ensure Blinding
This is a double-blind study in which MEDI5884 and placebo are visually distinguishable
until SC doses are prepared. 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 order to maintain the blind, an unblinded pharmacist will be responsible for dose 
preparation. Volume matched placebo injections will be prepared as per Table 4.5.1.6-1. 
Once prepared, MEDI5884 and placebo are indistinguishable. A blinded qualified designee 
will administer investigational product to subjects via SC injection.
The investigational product manager/unblinded study personnel must ensure that only the 
unblinded team members (ie, study pharmacist) have access to the areas of the pharmacy 
where the investigational product is being prepared. An independent investigational product 
monitor will also be unblinded to perform investigational product accountability. In the event 
that treatment allocation for a subject becomes known to the investigator or other study 
personnel involved in the management of the study subject, the sponsor must be notified 
immediately. If the identity of a treatment needs to be unblinded for a subject in order to treat 
that individual subject for an AE, the investigator must notify the sponsor immediately. The 
site will maintain a written plan detailing which staff members are blinded/unblinded and the 
process of investigational product administration used to maintain the blind.
4.6.2.1
Unblinding in the Event of a Medical Emergency 
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product allocation. Instructions for unblinding an individual subject’s 
investigational product allocation are contained in the IXRS manual. In general, unblinding 
should only occur if management of the medical emergency would be different based on the 
subject having received investigational product. In most cases, the management of a medical 
emergency would be the same whether the investigational product was received by the 
subject or not. In such cases, the identity of the investigational product should remain 
blinded. 
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. 


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4.6.2.2
Unblinding for the Interim Analysis
MedImmune personnel will be unblinded at the interim analysis; study subjects, the 
investigator, and site staff who are involved in the treatment or clinical evaluation of subjects 
will remain blinded until the end of study.
4.6.2.3
Unblinding for Pharmacokinetic and Immunogenicity Analysis
A small number of clinical bioanalytical personnel, who will not be involved in the treatment 
or clinical evaluation of subjects, will be unblinded to subject treatment allocation to analyze 
PK and immunogenicity samples. Local standard operating procedures will govern 
maintenance of the blind and information on treatment allocation will not be communicated 
outside of these personnel.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of Screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.7.2. Specifically, subjects should receive full supportive care during the 
study, including transfusions of blood and blood products, and treatment with antibiotics, 
anti-emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, and in 
accordance with their institutional guidelines.
Subjects must be on high-intensity statin (≥40-mg atorvastatin or ≥20-mg rosuvastatin for 
non-Asian subjects; ≥10-mg rosuvastatin for Asian subjects), at a stable dose for ≥30 days 
prior to Screening and intend to remain at a stable dose throughout the study duration.
4.7.2
Prohibited Concomitant Medications
Current or previous use of lipid-lowering medications within 
 prior to Screening, 
except for statins and/or <100-mg/day niacin, and/or 10-mg/day ezetimibe, and/or <2-g/day 
fish oil, is prohibited. Enrolled subjects should intend to maintain their prescribed dose of 
lipid-lowering medications through the course of the study; however, subjects whose 
lipid-lowering medications have been changed should stay in the study and may be dosed in 


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accordance with the study, but these medication changes must be recorded in the 
Concomitant Medication eCRF.
Current or previous use of systemic corticosteroids within 
 prior to Screening is 
prohibited. Topical, intra-articular, intranasal, inhaled, and ophthalmic steroid therapies are 
allowed.
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
4.8
Statistical Evaluation
4.8.1
General Considerations
Data will be provided in listings sorted by treatment group and subject number. Tabular 
summaries will be presented by treatment group. Categorical data will be summarized by the 
number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics, including mean, standard deviation, median, minimum, 
and maximum. Baseline values will be defined as the last valid assessment prior to the first 
administration of investigational product unless otherwise specified. Details of endpoint 
analyses will be described in the statistical analysis plan.
Analysis Populations
The As-treated Population includes all subjects who receive any investigational product 
analyzed according to the treatment they actually receive.
The PK Population includes subjects who received any amount of MEDI5884 with at least 
one detectable posttreatment serum concentration measurement.
4.8.2
Sample Size
 
 
 
 
 
 
 
 
 


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4.8.3
Safety……….
4.8.3.1
Analysis of Adverse Events
Safety analysis will be based on the As-treated Population. Adverse event collection begins 
after the subject signs the informed consent document and lasts until the end of the study. 
TEAEs and TESAEs will be coded by the most updated version of the Medical Dictionary 
for Regulatory Activities (MedDRA), and the type, incidence, severity and relationship to 
investigational product will be summarized by MedDRA System Organ Class and Preferred 
Term. Adverse events leading to discontinuation, AEs leading to death, and deaths will also 
be summarized. Specific AEs will be counted once for each subject for calculating 
percentages. In addition, if the same AE occurs multiple times within a particular subject, the 
highest severity and level of relationship observed will be reported. All TEAEs and TESAEs 
will be summarized overall, as well as categorized by MedDRA System Organ Class and 
Preferred Term. Injection site reactions, regardless of being recorded as AEs or not, will also 
be summarized.
4.8.3.2
Analysis of Clinical Laboratory Parameters, Vital Signs, and 
Electrocardiograms
Clinical laboratory data and vital signs will be summarized at each time point by treatment 
group. Change from Baseline to each postbaseline time point in these data will also be 
summarized, where appropriate. ECG parameters will also be assessed and summarized by 
treatment group descriptively.
4.8.4
Efficacy……….
No efficacy data are being collected in this study.
4.8.5
Analysis of Immunogenicity and Pharmacokinetics 
4.8.5.1
Immunogenicity Analysis
ADA incidence rate and titer will be tabulated for each treatment group and the placebo 
group. Samples confirmed positive for ADA may be further characterized and summarized 
similarly.


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4.8.5.2
Pharmacokinetic Analysis
Descriptive statistics of serum MEDI5884 concentration data will be provided. Individual 
and mean serum concentration-time profiles of MEDI5884 per treatment group and/or visit 
will be generated. Non-compartmental PK data analysis will be performed and PK 
parameters such as Cmax, AUC, t1/2 will be generated.
Additional PK and PK/PD analysis may be conducted when appropriate.
4.8.6
Pharmacodynamic Analysis
PD analysis will be based on the As-treated Population. The primary PD endpoints, change 
from Baseline to 
in apoB and percent change from Baseline to 
 in HDL-C,
will be summarized by treatment group. Statistical comparisons of these endpoints between 
each MEDI5884 treatment group and placebo will be performed using an analysis of 
covariance (ANCOVA) by adjusting baseline value and treatment group with last-
observation-carried-forward approach to handle missing data. A one-sided upper 95% 
confidence interval comparing each MEDI5884 treatment group versus placebo for change 
from Baseline to 
 in apoB will be provided. 
 
 
 
 
 
 
 
 
4.8.7
Interim Analysis
An interim analysis is planned after all subjects have completed their 
 visit.


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


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•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in this situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse.
5.3
Definition of Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the investigational product and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or nonserious. 
The rapid reporting of AESIs allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of this investigational product.
Hepatic function abnormality meeting the definition of Hy’s Law is considered an AESI. See
Section 5.6.2 for the definition and reporting of AESIs of hepatic function abnormality. 
5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets 
criteria of an SAE and therefore requires immediate notification to the sponsor (see 
Section 5.5). See Section 5.2 for the definition of SAEs and Section 10.3 for guidelines for 
assessment of severity and relationship. 
If an AE evolves into a condition that meets the regulatory definition of “serious,” it will be 
reported on the SAE Report Form.
5.4.1
Time Period for Collection of Adverse Events
Adverse event collection begins after the subject signs the informed consent document and 
lasts until the end of the study. 
All SAEs will be recorded from the time of informed consent.


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For nontreatment-emergent AEs (ie, AEs that occur during the period from the time informed 
consent is signed but prior to the subject receiving investigational product), only AEs 
associated with protocol-related procedures should be reported. After the start of treatment, 
all TEAEs (Section 5.1) should be reported.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
MedImmune retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
5.5
Reporting of Serious Adverse Events
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs during the study, then investigators or other site personnel must inform the 
appropriate sponsor representative(s) within 1 day, ie, immediately but no later than 24 hours 
after becoming aware of the event.
The designated sponsor representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor’s patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform sponsor 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, 
an automated email alert is sent to inform the designated sponsor representative(s).
If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed. 


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5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose
An overdose is defined as a subject receiving a dose of investigational product greater than
that specified in the current study 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 study, then the 
investigator or other site personnel inform appropriate sponsor representatives immediately, 
or no later than 24 hours after becoming aware of the event.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site.
For overdoses associated with an SAE, the standard reporting timelines apply; see 
Section 5.5. For other overdoses, reporting must occur within 30 days.
5.6.2
Hepatic Function Abnormality 
Cases in which a subject may show elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN 
may need to be reported as SAEs. Please refer to Section 10.5 for further instruction on cases 
of increases in liver biochemistry and evaluation of Hy’s Law. 
5.6.3
Pregnancy
5.6.3.1
Maternal Exposure
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational product should be discontinued immediately and the 
pregnancy reported to the Sponsor.
The designated sponsor representative will work with the investigator to ensure that all 
relevant information is provided within 1 or 5 calendar days for SAEs (see Section 5.5) and 
within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.


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Any subject who becomes pregnant during the study will be followed so that pregnancy 
outcome can be determined and reported to the sponsor and the regulatory authorities.
5.6.3.2
Paternal Exposure
Nonsterilized male study subjects who are sexually active with a female partner of 
childbearing potential must use condom and spermicide from 
 through the end of the 
study follow-up period. 
Male subjects should refrain from fathering a child or donating sperm from 
 through 
the end of the study follow-up period.
Pregnancy of the subject’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) should if possible be followed up and documented. 
The outcome of any conception occurring from 
 through the end of the study follow-up 
period should be followed up and documented. Information on the pregnancy of a subject’s 
partner must be obtained directly from the subject’s partner. Therefore, prior to obtaining 
information about the pregnancy, the Investigator must obtain the consent of the subject’s 
partner.
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 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 staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:


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•
Provide information and support to the investigator(s)
•
Confirm that facilities remain acceptable
•
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the laboratory manual and that study drug accountability checks are 
being performed
•
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts)
•
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.
6.2.2
Study Agreements
The Principal Investigator at the center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this protocol and the Clinical Study Agreement, the terms of protocol 
shall prevail with respect to the conduct of the study and the treatment of subjects and in all 
other respects, not relating to study conduct or treatment of subjects, the terms of the Clinical 
Study Agreement shall prevail.
Agreements between MedImmune and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through their last protocol-specified visit/assessment (including telephone contact) 
regardless of the number of doses of investigational product that were received. 


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Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Section 4.1.5 and 4.1.6).
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 electronic data capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded in the eCRFs as specified in the study protocol 
and in accordance with the eCRF instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the Principal Investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Subject Data Protection
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc. will only be collected with the subject’s informed consent. The Informed Consent 
Form will incorporate (or, in some cases, be accompanied by a separate document 


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incorporating) wording that describes how subject data will be collected, used, and 
distributed in compliance with relevant data protection and privacy legislation.
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. MedImmune will not provide individual genotype results 
to subjects, any insurance company, any employer, their family members, general physician 
or any other third party, unless required to do so by law.
7.2
Ethics and Regulatory Review
The IRB responsible for each site must review and approve the final study protocol, 
including the final version of the Informed Consent Form and any other written information 
and/or materials to be provided to the subjects. The IRB must also approve all advertising 
used to recruit subjects for the study. The investigator is responsible for submitting these 
documents to the applicable IRB, and distributing them to the study site staff.
The opinion of the IRB must be given in writing. The investigator must provide a copy of the 
written approval to MedImmune before enrolment of any subject into the study. 
MedImmune should approve any substantive modifications to the Informed Consent Form 
that are needed to meet local requirements.
If required by local regulations, the protocol must be re-approved by the IRB 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, 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. MedImmune will provide this information to the Principal Investigator so 
that he/she can meet these reporting requirements.
7.3
Informed Consent
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. MedImmune will develop a core 
informed consent form for use by all investigators in the clinical study. MedImmune must 


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approve any modifications to the informed consent form that are needed to meet local 
requirements.
The Principal Investigator(s) at each center will:
•
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study
•
Ensure each subject is notified that they are free to discontinue from the study at any time
•
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
•
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study
•
Ensure the original, signed Informed Consent Form(s) is/are stored in the Investigator’s 
Study File
•
Ensure a copy of the signed Informed Consent Form 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 informed consent form that is approved by an IRB
7.4
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and MedImmune.
Substantial changes must be documented in a study protocol amendment. MedImmune will 
distribute amended versions of the protocol to the principal investigator(s). Before 
implementation, amended protocols must be approved by relevant IRB (see Section 7.2) and 
according to local requirements, the national regulatory authority approval. The IRB must 
also approve revisions to the informed consent form, advertising, and any other written 
information and/or materials resulting from the change to the protocol.
If local regulations require, any unsubstantial changes will be communicated to or approved 
by each IRB.
7.5
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB may perform 
audits or inspections at the center, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 


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analyzed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements. The investigator will contact MedImmune 
immediately if contacted by a regulatory agency about an inspection at the site.


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8
REFERENCES
Aim-High Investigators, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-
Nickens P et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin 
therapy. N Engl J Med. 2011;365(24):2255-67.
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al. Effects of 
torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109-22.
Bhatt A, Rohatgi A. HDL Cholesterol Efflux Capacity: Cardiovascular Risk Factor and 
Potential Therapeutic Target. Curr Atheroscler Rep. 2016;18(1):2.
Contois JH, McConnell JP, Sethi AA, Csako G, Devaraj S, Hoefner DM et al. 
Apolipoprotein B and cardiovascular disease risk: position statement from the AACC 
Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clin Chem. 
2009;55(3):407-19.
Emerging Risk Factor Collaboration, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray 
KK et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 
2009;302(18):1993-2000.
Heinecke JW. The not-so-simple HDL story: A new era for quantifying HDL and 
cardiovascular risk? Nat Med. 2012;18(9):1346-7.
Hps Timi Reveal Collaborative Group, Bowman L, Hopewell JC, Chen F, Wallendszus K, 
Stevens W et al. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N 
Engl J Med. 2017;377(13):1217-27.
Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K et al. 
Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J 
Med. 2011;364(2):127-35.
Mora S, Wenger NK, Demicco DA, Breazna A, Boekholdt SM, Arsenault BJ et al. 
Determinants of residual risk in secondary prevention patients treated with high- versus low-
dose statin therapy: the Treating to New Targets (TNT) study. Circulation. 
2012;125(16):1979-87.
Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, Sherliker P, 
Emberson J et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a 


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meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. 
Lancet. 2007;370(9602):1829-39.
Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE et al. HDL cholesterol 
efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371(25):2383-93.
Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J et al. Effects of 
dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 
2012;367(22):2089-99.
WHO. Top 10 Causes of Death 2017 [23June2017]. Available from: 
http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed on:


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9
CHANGES TO THE PROTOCOL
9.1
Protocol Amendment 4, 29May2018
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. 
Table 9.1-1
Summary of Revisions to the Protocol (Amendment 4)
Key Details of the Amendment
Reason for Amendment
Amendment 4 (29May2018)
Protocol Synopsis
Updated to align with changes to main body.
Section 3.1.1 (Overview)Table 4.2.2-1 
(Schedule of Randomized Treatment 
Period and Follow-up Procedures), 
Section 4.2.3 (Additional Follow-up)
Text and footnote added to reflect additional follow-up visits if a 
subject’s triglyceride level exceeded 1000 mg/dL at the last visit 
and is in response to feedback from the FDA.  
Section 4.1.6 (Discontinuation of 
Investigational Product)
Text added to exclude from dosing any subject whose pre-dose 
triglyceride value was ≥1000 mg/dL. This amendment is 
occurring after all subjects have completed dosing, but the 
amendment is recorded for clarity of the protocol. The exclusion 
was previously instituted by means of a memorandum to sites 
dated 16Mar2018 that was subsequently approved by the IRB.
FDA = Food and Drug Administration
9.2
Protocol Amendment 3, 27Feb2018
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. Changes to the protocol were made for clarification and to improve 
minor administrative/language inconsistencies throughout. Changes are summarized in
Table 9.2-1.
Table 9.2-1
Summary of Revisions to the Protocol (Amendment 3)
Key Details of the Amendment
Reason for Amendment
Amendment 3 (27Feb2018)
Protocol Synopsis
Updated to align with changes to main body.
Usage of greater than / greater than or 
to equal language and symbols revised 
throughout document
Revised throughout for accuracy/clarity: 

For ADA, follow-up if assessment value > baseline value

For ApoB, no dosing if value ≥ baseline value + 30 
mg/dL

For LDL, additional visits required if value ≥ baseline 
value + 30 mg/dL
Section 1.1 (Introduction Disease 
Background)
Text added for clarity: 
World Health Organization (WHO) definition was added (first use 
in text body) and added to List of Abbreviations. 


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Table 9.2-1
Summary of Revisions to the Protocol (Amendment 3)
Key Details of the Amendment
Reason for Amendment
Amendment 3 (27Feb2018)
Section 1.1 (Introduction Disease 
Background)
Text deleted: 
Subjects will be encouraged to maintain a healthy lifestyle, 
including diet and exercise, during the study period.
Section 3.1.1 (Study Design, 
Overview) 
The term “up to” was deleted for accuracy/clarity: 
 
 
 
 
 
 
 
 
Section 4.1.2 (Inclusion Criteria)
Text revised for accuracy: 
Criterion 7: 
 prior to Screening.
Section 4.1.5 (Withdrawal from the 
Study)
Text revised throughout for accuracy/clarity: 
Subjects who withdraw consent will be asked about the reason(s) 
and about the presence or absence of any adverse events (AEs).
The statement “subjects must withdraw if unblinded” was 
removed.
Section 4.1.7 (Replacement of 
Subjects)
Text revised for clarity: 
Subjects who do not complete dosing per randomization for any 
reason other than for safety (which includes subjects who 
withdrew due to an AE or by having met withdrawal criteria for 
withdrawal of investigational product (Section 4.1.6) may be 
replaced if deemed necessary by the medical monitor to ensure 
that safety and PK data are collected from a sufficient number of 
subjects and to maintain the balance of the study.
Section 4.2.1, Enrollment/Screening 
Period
Text revised to the following: 
Table 4.2.1-1 shows all procedures to be conducted at Screening. 
Whenever vital signs, 12-lead ECGs, and blood draws are 
scheduled for the same nominal time, the assessments should 
occur in the following order: 12-lead ECG, vital signs, and then 
blood draws. 
Two sentences deleted: 
Assessments should be performed in the order shown in the table.
The timing of the first 2 assessments should be such that it allows 
the blood draw (eg, PK blood sample) to occur at the proper 
nominal time.
Section 4.2.2 (Randomized Treatment 
Period and Follow-up)
Text revised for clarity: 
Table 4.2.2-1 shows all procedures to be conducted at the 
treatment and follow up periods. 


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Table 9.2-1
Summary of Revisions to the Protocol (Amendment 3)
Key Details of the Amendment
Reason for Amendment
Amendment 3 (27Feb2018)
The last sentence, (assessments should be performed in the order 
shown in the table), was deleted.
Section 4.2.2 (Table 4.2.2-1, Schedule 
of Randomized Treatment Period and 
Follow-up Procedures)
Table note (a) added for clarity: 
a Subjects should dose within dosing windows; however, to 
minimize data loss, subjects who are unable to return within 
dosing windows but are otherwise able and eligible to dose outside 
the window may be dosed with the permission of the sponsor. In 
such cases, subsequent visits may need to be adjusted to maintain 
their relationship to dosing but wherever possible, visits should 
conform to those in Table 4.2.2-1.
Note: All subsequent table notes (sequential lettering
corresponding to each correct note) were updated within the table 
and in the list of table notes to remain accurate.
Section 4.3.2.3 (Vital Signs)
Text added for clarity: 
Predose vital signs should not be clinically significantly different 
from the subject’s screening value according to the judgment of 
the investigator. All vital sign measurements will be measured 
with the subject in a supine position having rested for at least 
10 minutes before each reading, and should be taken before any 
blood draws scheduled in close proximity.
Section 4.3.2.4 (Electrocardiogram)
Additional text added for clarity: 
Predose triplicate digital ECG on 
 should be collected at 
3 different time points (3 × 3 replicates) prior to dosing; each 
triplicate must be separated by at least 5 minutes, and subjects 
with predose ECGs showing clinically significant abnormalities, 
according to the judgment of the investigator, should not be dosed.
Section 4.3.2.5 (Injection Site Reaction 
Assessment)
Text revised for clarity:
Measurements <¼ inch at the largest diameter should be recorded 
as 0 inches. Measurements ≥¼ inch but <1 inch would result in a 
subject recording “yes” to injection site reaction, but the reaction 
would not be graded (< Grade 1). 
Section 4.3.2.5 (Table 4.3.2.5-1)
Table title revised for clarity: 
Tables for Clinical Abnormalities: Local Reactions to Injectable 
Product as Reported by Subjects in their Injection Site Reaction 
Assessments.
Section 4.3.2.5 (Injection Site Reaction 
Assessment)
Text revised for clarity: 
Injection site reaction data are recorded separately by patient 
reported injection site reaction assessments and also by 
investigator reported injection site reactions. These data will be 
reported separately and may not be identical.
Section 4.3.3 (Clinical Laboratory 
Tests)
Text revised for clarity (removed as a table note and added into
table text): 
Urine microscopy and urine casts (as required if dipstick at central 
laboratory is abnormal).


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Table 9.2-1
Summary of Revisions to the Protocol (Amendment 3)
Key Details of the Amendment
Reason for Amendment
Amendment 3 (27Feb2018)
Section 4.5.1.3 (Dose Preparation 
Steps) 
Section 4.5.1.6 (Subcutaneous Dose 
Preparation)
Text revised where applicable for clarity/accuracy:
A 2- or 3-mL polypropylene or polycarbonate syringe with an 18-,
19-, or 20-G 1½ inch needle should be used to extract 1.3 mL of 
sterile water from the single use vial for reconstitution of 
MEDI5884. 
Section 4.5.2 (Additional Study 
Medications)
Section 4.7.1 (Permitted Concomitant 
Medications)
Section 4.7.2 (Prohibited Concomitant 
Medications)
Text revised for accuracy: 
Stable dose for 
 prior to screening was revised to 
 was added to body text.
9.3
Protocol Amendment 2, 28Nov2017
Text revisions resulting from this amendment are incorporated in the body of Protocol
Amendment 2. Changes to the protocol were made in response to feedback from the Food 
and Drug Administration, for the purpose of clarification, and to correct previous oversights. 
Changes are summarized in Table 9.3-1.
Table 9.3-1
Summary of Revisions to the Protocol (Amendment 2)
Key Details of the Amendment
Reason for Amendment
Amendment 2 (28Nov2017)
Protocol Synopsis
Updated to align with changes to main body.
Section 3.1.1 (Overview), Figure 3.1.1-1 (Study 
Flow Diagram), and Table 4.2.2-1 (Schedule of 
Randomized Treatment Period and Follow-up 
Procedures)
Text and footnote updated to reflect addition of 
follow-up visits or if a subject’s directly measured 
LDL-C at the last visit is ≥ Baseline + 30 mg/dL in 
response to feedback from the FDA.
The requirement for additional ADA follow-up if a 
subject’s ADA level is not at or below Baseline at 
the last visit was clarified.
The schedule of procedures was amended to reflect 
the addition of LDL-C follow-up.
Section 3.2.1 (Dose Rationale)
Abbreviations in footnotes and figure titles amended 
to correct previous oversights. 
Section 3.2.2 (Rationale for Study Population), 
Section 4.1.2 (Inclusion Criteria), 
Section 4.5.2 (Additional Study Medications), and 
Section 4.7.1 (Permitted Concomitant Medications)
The requirement to be at a stable dose of 
high-intensity statin was reduced from 
 
prior to Screening to 
 prior to Screening, to 
aid recruitment. 
Relevant text was updated to reflect this.
Section 4.1.3 (Exclusion Criteria)
Criterion 5b amended to LDL-C >100 mg/dL (by 
direct measure) in response to feedback from the 
FDA.


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Table 9.3-1
Summary of Revisions to the Protocol (Amendment 2)
Key Details of the Amendment
Reason for Amendment
Amendment 2 (28Nov2017)
Criterion 9 amended to clarify that current or 
previous use of 10-mg/day ezetimibe and/or
<2-g/day fish oil within 
 prior to 
 is not 
exclusionary.
Section 4.1.4 (Subject Enrollment and 
Randomization)
Text amended to clarify the circumstances under 
which a subject may be rescreened.
Section 4.1.6 (Discontinuation of Investigational 
Product)
Discontinuation criterion 6 was amended from “ALT 
or AST >3 × ULN” to “ALT or AST ≥3 × ULN” to 
correct a previous oversight.
Section 4.1.6 (Discontinuation of Investigational 
Product) and Table 4.2.2-1 (Schedule of Randomized 
Treatment Period and Follow-up Procedures)
A discontinuation criterion based on increased apoB 
levels was added in response to feedback from the 
FDA.
A visit on 
 was added to measure apoB for a 
decision regarding dosing at 
.
Section 4.2.1 (Enrollment/Screening Period) and 
Table 4.2.1-1 (Schedule of Screening Procedures)
New section created to present the schedule of 
screening procedures separately for clarity.
Section 4.2.2 (Randomized Treatment Period and 
Follow-up) and Table 4.2.2-1 (Schedule of 
Randomized Treatment Period and Follow-up 
Procedures)
Study procedures that occurred during Screening 
only were removed due to redundancy.
Section and table titles were updated to better reflect 
the contents.
The definition of a day for Visits 2 to 5 was added to 
the footnotes for clarification.
A telephone visit (V9) was added to for the capture 
of injection site reaction symptoms and 
measurements from subjects and footnote a was 
added to reflect this.
Footnote i added to clarify that the results of HDL-C, 
apoA1 and calculated (Friedewald) LDL-C will not 
be provided to the sites.
Footnote k added to clarify that subjects should be 
closely observed for 1 hour postdose on 
 
.
Table 4.2.2-1 (Schedule of Randomized Treatment 
Period and Follow-up Procedures) and 
Section 4.3.2.5 (Injection Site Reaction Assessment)
Text added to provide detail on subject’s 
measurement of injection site reactions over the 24 
hours after investigational product administration in 
response to feedback from the FDA.
Footnote l was added to schedule of procedures to 
reflect this.
Section 4.2.3 (Additional Follow-up)
Text added to reflect the addition of LDL-C 
follow-up visits.
Section 4.3.3 (Clinical Laboratory Tests) and Section 
4.5.1.5 (Monitoring of Dose Administration)
Text added to specify that tryptase should be 
collected within 30 minutes for anaphylaxis or 
anaphylaxis-like reactions, if feasible, in response to 
feedback from the FDA.
Table 4.3.7-1 (Estimate of Blood Volume to Be 
Collected)
Table updated to reflect changes to the study design.


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Table 9.3-1
Summary of Revisions to the Protocol (Amendment 2)
Key Details of the Amendment
Reason for Amendment
Amendment 2 (28Nov2017)
Section 4.5.1.3 (Dose Preparation Steps)
Text added to clarify instructions for the MEDI5884 
reconstitution process.
Section 4.5.2 (Additional Study Medications)
Text added to clarify that any change in statin type or 
dose must be recorded in the Concomitant 
Medication section of the electronic case report 
form.
Section 4.6.2.1 (Unblinding in the Event of a 
Medical Emergency)
The text “If a subject’s investigational product 
allocation is unblinded to the blinded staff, the 
subject should be discontinued from investigational 
product” was removed to correct a previous 
oversight.
Section 4.7.2 (Prohibited Concomitant Medications)
Text updated to reflect the change to Exclusion 
Criterion 9 and to clarify that subjects whose 
lipid-lowering medications have been changed 
should stay in the study and may be dosed in 
accordance with the study, but these medication 
changes must be recorded in the Concomitant 
Medication eCRF.
Section 4.8.3.1 (Analysis of Adverse Events)
Text amended to clarify that injection site reactions, 
regardless of being recorded as AEs or not, will also 
be summarized.
ADA = antidrug antibody; AEs = adverse events; ALT = alanine transaminase; apoA1 = apolipoprotein A1; 
apoB = apolipoprotein B; AST = aspartate transaminase; eCRF = electronic case report form; FDA = Food 
and Drug Administration; HDL = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein; 
ULN = upper limit of normal. 
9.4
Protocol Amendment 1, 05Oct2017
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. The Original Protocol (03Oct2017) was not submitted to a regulatory agency 
or IRB. Changes to the protocol are summarized in Table 9.4-1.
Table 9.4-1
Summary of Revisions to the Protocol (Amendment 1)
Key Details of the Amendment
Reason for Amendment
Amendment 1 (05Oct2017)
 


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10 APPENDICES


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10.1
Appendix 1 - Signatures


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Sponsor Signature(s)
A Phase 2a, Randomized, Double-blind, Placebo-controlled, Parallel-designed Study to 
Evaluate the Safety, Pharmacokinetics, and Pharmacodynamic Effects of MEDI5884 in 
Subjects with Stable Coronary Heart Disease.
I agree to the terms of this protocol.
Signature and date: Electronic Signature is attached
Clinical Therapeutic Area Head
One MedImmune Way, Gaithersburg MD, 20878, USA
Telephone number: -1-301-398-0645


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10.2
Appendix 2 – Contraception Guidance
For females of childbearing potential:
•
Females of childbearing potential are defined as those who are not surgically sterile (ie, 
surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy) or those who are not postmenopausal defined as 12 months with no 
menses without an alternative medical cause and have a follicle-stimulating hormone 
level in the laboratory’s normal range for post-menopausal phase at Screening.
•
A highly effective method of contraception is defined as one that results in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly. The acceptable 
methods of contraception are described in Table 10.2-1.
•
Female subjects must refrain from egg cell donation and breastfeeding while on study 
and for 90 days after the final dose of investigational product.
Table 10.2-1
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.
10.3
Appendix 3 - Additional Safety Guidance
10.3.1
Further Guidance on the Definition of a Serious Adverse Event (SAE)
10.3.1.1
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
10.3.1.2
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.


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10.3.1.3
Important Medical Event or Medical Intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result 
in death, hospitalization, disability or incapacity but may jeopardize the subject or may 
require medical intervention to prevent one or more outcomes listed in the definition of 
serious. These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; 
medical judgment must be used.
Examples of such events are:
•
Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment
•
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine
•
Intensive treatment in an emergency room or at home for allergic bronchospasm
•
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization
•
Development of drug dependency or drug abuse
10.3.1.4
Assessment of Severity
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below.
Grade 1
An event of mild intensity that is usually transient and may 
require only minimal treatment or therapeutic intervention. The 
event does not generally interfere with usual activities of daily 
living.
Grade 2
An event of moderate intensity that is usually alleviated with 
additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm 
to the subject.


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Grade 3
A severe event that requires intensive therapeutic intervention. 
The event interrupts usual activities of daily living, or 
significantly affects the clinical status of the subject.
Grade 4
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death or with physical or mental 
disabilities that affect or limit the ability of the subject to 
perform activities of daily living (eating, ambulation, toileting, 
etc).
Grade 5
Death as a result of an event.
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the regulatory definition of an SAE and would be 
considered a nonserious event, whereas a Grade 2 seizure resulting in a hospital admission 
would be considered an SAE.
10.3.1.5
Assessment of Relationship
Relationship to Investigational Product
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. The following factors should be considered when deciding if there is 
a “reasonable possibility” that an AE may have been caused by the investigational product.
•
Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product?
•
Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and 
toxicology) or products of the same pharmacological class? OR could the AE be 
anticipated from its pharmacological properties? 
•
De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect investigational product?
•
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, or other host or environmental factors.


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


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10.4
Appendix 4 - National Institute of Allergy and Infectious Diseases
and Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report --
Second National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death. They recognize 3 categories of anaphylaxis, with criteria designated to capture from 
80% of cases (category 1) to >95% of all cases of anaphylaxis (for all 3 categories). 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
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 mm Hg or greater than 30% decrease from that 
person’s Baseline


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10.5
Appendix 5 - Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
10.5.1
Introduction
This appendix describes the process to be followed to identify and appropriately report cases 
of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries. 
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets 
potential Hy’s Law criteria at any point during the study.
The investigator participates, together with MedImmune clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than drug-induced liver injury (DILI) caused by the 
investigational product. 
The investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law
cases and for reporting AEs and SAEs according to the outcome of the review and 
assessment in line with standard safety reporting processes.
10.5.2
Definitions
10.5.2.1
Potential Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).
10.5.2.2
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.


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10.5.3
Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any subject who meets any of the following identification 
criteria in isolation or in combination:
•
ALT ≥3 × ULN
•
AST ≥3 × ULN
•
TBL ≥2 × ULN
In cases where a subject may meet any of the abnormal laboratory 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
•
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 10.5.2) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
10.5.4
Follow-up
10.5.4.1
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.


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10.5.4.2
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
The medical monitor contacts the investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data. Subsequent to 
this contact the investigator will:
•
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated
•
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the medical monitor. This includes deciding which the tests available in the Hy’s 
Law laboratory kit should be used.
•
Complete the Liver CRF Modules as information becomes available.
•
If at any time (in consultation with the medical monitor) the potential Hy’s Law case 
meets serious criteria, report it as an SAE using standard reporting procedures.
10.5.5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where potential Hy’s Law
criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the medical 
monitor will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting potential Hy’s Law criteria other than DILI 
caused by the investigational product. 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.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
•
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
•
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF accordingly 
and follow the sponsor’s standard processes


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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:
•
Report an SAE (report term ‘Hy’s Law’) according to 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 3 weeks 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:
•
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above
•
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are met. Update the SAE report according to the outcome of 
the review
10.6
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: D7870C00002-protocol-amendment-4
Document Title:
D7870C00002-protocol-amendment-4
Document ID:
Doc ID-003842343
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
31-May-2018 15:45 UTC
Management Approval
31-May-2018 13:12 UTC
Author Approval
30-May-2018 12:48 UTC
Author Approval
30-May-2018 14:07 UTC
Content Approval
30-May-2018 18:03 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
MedImmune 
Statistical Analysis Plan for Protocol D7870C00002 
MEDI5884 
 
14DEC2017; Final version 1.0 
CONFIDENTIAL AND PROPRIETARY 
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SAP template version 3.0 
Statistical Analysis Plan 
A Phase 2a Randomized, Double-blind, Placebo-controlled, Parallel-
designed Study to Evaluate the Safety, Pharmacokinetics, and 
Pharmacodynamic Effects of MEDI5884 in Subjects with Stable Coronary 
Heart Disease 
Protocol Number: D7870C00002 


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Statistical Analysis Plan for Protocol D7870C00002 
MEDI5884 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION ...........................................................................................................5 
2 
STUDY OVERVIEW .....................................................................................................5 
2.1 
Study Objectives ...................................................................................................5 
2.1.1Primary Study Objective(s) ..........................................................................5 
2.1.2Secondary Study Objectives .........................................................................5 
2.1.3Exploratory Study Objectives .......................................................................5 
2.2 
Study Design .........................................................................................................5 
2.3 
Treatment Assignment and Blinding ....................................................................6 
2.4 
Sample Size...........................................................................................................7 
3 
STATISTICAL METHODS ...........................................................................................7 
3.1 
General Considerations .........................................................................................7 
3.2 
Analysis Populations.............................................................................................8 
3.3 
Study Subjects.......................................................................................................8 
3.3.1Subject Disposition and Completion Status .................................................8 
3.3.2Demographics and Baseline Characteristics .................................................8 
3.3.3Study Drug Exposure ....................................................................................8 
3.3.4Concomitant Medications .............................................................................9 
3.4 
Efficacy Analyses .................................................................................................9 
3.5 
Pharmacodynamic Endpoint(s) and Analyses ......................................................9 
3.5.1.1 
Secondary Pharmacodynamic Endpoint(s) .................................9 
3.5.1.2 
Analysis of Secondary Pharmacodynamic Endpoint(s) ..............9 
3.5.1.3 
Exploratory Pharmacodynamic Endpoint(s) ...............................9 
3.5.1.4 
Analysis of Exploratory Pharmacodynamic Endpoint(s) .........10 
3.6 
Other Additional Analyses..................................................................................10 
3.7 
Safety Analyses...................................................................................................11 
3.7.1Adverse Events and Serious Adverse Events .............................................11 
3.7.2Adverse Events of Special Interest .............................................................12 
3.7.3Deaths and Treatment Discontinuations due to Adverse Events ................12 
3.7.4Clinical Laboratory Evaluation ...................................................................12 
3.7.4.1 
Physical Examinations ..............................................................12 
3.7.4.2 
Vital Signs .................................................................................12 
3.7.4.3 
Electrocardiogram .....................................................................13 
3.8 
Immunogenicity ..................................................................................................13 
3.9 
Pharmacokinetics ................................................................................................13 
4 
INTERIM ANALYSIS..................................................................................................14 
5 
REFERENCES ..............................................................................................................14 
6 
VERSION HISTORY ...................................................................................................14 


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LIST OF TABLES 
Table 3.2-1 
Analysis Populations ..............................................................................8 
 
 


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List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ADA 
antidrug antibody 
AE 
Adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
apoA1 
Apolipoprotein A1 
apoB 
Apolipoprotein B 
ATC 
anatomical therapeutic chemical 
BMI 
Body mass index 
CHD 
coronary heart disease 
CI 
Confidence interval 
ECG 
Electrocardiogram 
EL 
endothelial lipase 
HDL-C 
HDL Cholesterol (High density lipoprotein – cholesterol) 
HDL-PL 
HDL phospholipids 
hsCRP 
High-sensitivity C-reactive protein 
IXRS 
Interactive voice/web response system 
LDL-C 
LDL Cholesterol (Low density lipoprotein – cholesterol) 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PR 
ECG interval measured from the onset of the P wave to the onset of the QRS 
complex 
QRS 
ECG interval measured from the onset of the QRS complex to the J point 
QT 
ECG interval measured from the onset of the QRS complex to the offset of the 
T-wave 
QTc 
cardiac QT interval corrected for heart rate 
QTcB 
cardiac QTc interval corrected for heart rate by the formula of Bazett 
QTcF 
cardiac QTc interval corrected for heart rate by the formula of Fridericia 
RR 
The time between corresponding points on 2 consecutive R waves on the ECG 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SOC 
MedDRA system organ class 
TEAE 
Treatment emergent adverse event 
TESAE 
Treatment emergent serious adverse event 
VLDL-C 
VLDL Cholesterol (Very low density lipoprotein – cholesterol) 
WHO-DD 
World Health Organization Drug Dictionary 


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1 
INTRODUCTION 
This document describes the statistical analysis for protocol D7870C00002 (Amendment 2, 
28Nov2017), a trial of MEDI5884 in a Phase 2a randomized, double-blind, placebo-
controlled, parallel-design study to evaluate the safety, PK, pharmacodynamics (PD), and 
immunogenicity of multiple subcutaneous (SC) doses of MEDI5884 in subjects with stable 
CHD who are currently receiving high-intensity statin therapy. This document details the 
statistical summaries relating to each study objective and describes the general conventions 
and definitions that will be used. In addition, a set of table, listing, and figure templates and 
specifications is planned to be created in a statistical programming plan (SPP) to complement 
this document. 
2 
STUDY OVERVIEW 
2.1 
Study Objectives 
2.1.1 
Primary Study Objective(s) 
Evaluate the safety and tolerability of repeated monthly dosing with MEDI5884 in subjects 
with stable CHD 
2.1.2 
Secondary Study Objectives 
x Establish the PK profile of MEDI5884 following repeat dosing 
x Evaluate the effect of MEDI5884 on HDL-C and apoB 
x Assess immunogenicity 

2.1.3 
Exploratory Study Objectives 
x Further evaluate the effect of MEDI5884 on lipids, lipoproteins, apolipoproteins, and 
cholesterol efflux 
x Evaluate the effect of MEDI5884 on EL mass and biomarkers of EL activity 
2.2 
Study Design 
This is a Phase 2a randomized, double-blind, placebo-controlled, parallel-design study to 
evaluate the safety, PK, PD, and immunogenicity of multiple SC doses of MEDI5884 in 
subjects with stable CHD who are currently receiving high-intensity statin therapy. At least 
120 subjects are planned to be randomized across approximately 25 study sites in the United 
States of America to evaluate up to 5 dose levels of MEDI5884 via SC injection (50, 100, 


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200, 350, or 500 mg) compared to placebo (Figure 2.2-1). Subjects will be dosed once 
monthly for 3 months and will be randomized in a 1:1:1:1:1:1 ratio to receive MEDI5884 
(50, 100, 200, 350, or 500 mg) or placebo (volume matched for 50, 100, 200, 350, or 500 mg 
MEDI5884). Subjects will be followed for 90 days post last dose (up to Day 151). 
 
Figure 2.2-1 
Study Flow Diagram 
2.3 
Treatment Assignment and Blinding 
An (Interactive voice/web response system) IXRS will be used for randomization to a 
treatment group and assignment of blinded investigational product. A subject is considered 
randomized into the study when the investigator notifies the IXRS that the subject meets 
eligibility criteria and the IXRS provides the assignment of blinded investigational product 
kit numbers to the subject. 
Subjects will be randomized in a 1:1:1:1:1:1 ratio to receive MEDI5884 (50, 100, 200, 350, 
or 500 mg) or placebo (volume matched to 50, 100, 200, 350, or 500 mg MEDI5884). 
This is a double-blind study in which MEDI5884 and placebo are visually distinguishable 
until SC doses are prepared. Neither the subject nor any of the investigator or sponsor staff 


MedImmune 
Statistical Analysis Plan for Protocol D7870C00002 
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who are involved in the treatment or clinical evaluation of the subjects will be aware of the 
treatment received (ICH E9). 
In order to maintain the blind, an unblinded pharmacist will be responsible for dose 
preparation including preparation of volume matched placebo injections. 
Once prepared, MEDI5884 and placebo are indistinguishable. A blinded qualified designee 
will administer investigational product to subjects via SC injection. 
2.4 
Sample Size 
A total of at least 120 subjects is planned for the study with a minimum of 20 subjects in 
each treatment group. The sample size of 20 in each treatment group will provide > 80% 
power to rule out 10 mg/dL increase from baseline in apoB at Day 91 for the comparison of 
each MEDI5884 treatment group versus placebo at a one-sided alpha of 10% without 
multiplicity adjustment, assuming a t-distribution for the placebo adjusted change from 
baseline in apoB at Day 91 and a common standard deviation of 14 mg/dL. In addition, this 
sample size will provide 95% power to detect a 30% increase from baseline in HDL-C at Day 
91 for the comparison of each MEDI5884 treatment group versus placebo at a two-sided 
alpha of 5% without multiplicity adjustment, assuming a t-distribution for the placebo 
adjusted change from baseline in HDL-C at Day 91 and a common standard deviation of 
25%. If the observed placebo adjusted increase from baseline in HDL-C is 30%, the 95% 
confidence interval of this point estimate is (13.4%, 46.6%) based on the same assumption. 
3 
STATISTICAL METHODS 
3.1 
General Considerations 
Data will be provided in listings sorted by treatment group and subject number. Tabular 
summaries will be presented by treatment group. Categorical data will be summarized by the 
number and percentage of subjects in each category. Continuous variables will be 
summarized by descriptive statistics, including mean, standard deviation, median, minimum, 
and maximum. Baseline values will be defined as the last valid assessment prior to the first 
administration of investigational product unless otherwise specified. 
When last observation carried forward (LOCF) is used to impute for missing post-baseline 
data, only post-baseline data will be carried forward (e.g., baseline data will not be carried 
forward). 


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All statistical tests will be 2-sided at an alpha = 0.05 significance level unless stated 
otherwise. 
Data analyses will be conducted using the SAS® System Version 9.3 or higher (SAS Institute 
Inc., Cary, NC). 
3.2 
Analysis Populations 
The analysis populations are defined in Table 3.2-1. 
Table 3.2-1 
Analysis Populations 
Population 
Description 
As-treated 
population 
Subjects who receive any study investigational product will be included in the as-treated 
population and subjects will be analyzed according to the treatment they actually 
received. 
PK population 
Subjects who received any amount of MEDI5884 with at least one detectable post 
treatment serum concentration measurement 
ADA evaluable 
population 
Subjects who have non-missing baseline ADA data and at least one non-missing post-
treatment ADA assessment 
 
3.3 
Study Subjects 
3.3.1 
Subject Disposition and Completion Status 
A summary of subject eligibility and randomization as well as treatment group received 
(including summary of subjects randomized but not treated) will be provided. In addition, 
disposition of subjects throughout the study will be provided with respect to completion of 
treatment, discontinuation of treatment, and discontinuation of study. 
3.3.2 
Demographics and Baseline Characteristics 
Demographic information related to sex, age, race, weight, height, and body mass index 
(BMI) will be presented by treatment group and for all subjects combined. A summary of 
baseline disease characteristics may include, but not be limited to, total cholesterol, HDL-
cholesterol, LDL-cholesterol (direct and Friedewald equation), apoB, apoA1, and 
background statin. 
3.3.3 
Study Drug Exposure 
The number of study drug (investigational product) doses received will be summarized by 
treatment group.  


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3.3.4 
Concomitant Medications 
Concomitant medications (administered during or after treatment) will be coded using the 
current WHO Drug Dictionary. Concomitant medications will be summarized using 
frequency count and percentage by the highest anatomical therapeutic chemical (ATC) class 
and preferred term. All concomitant medications will be presented in a data listing. 
3.4 
Efficacy Analyses 
There are no efficacy endpoints in this study. 
3.5 
Pharmacodynamic Endpoint(s) and Analyses 
All pharmacodynamic analyses will be based on the As-treated population. 
3.5.1.1 
Secondary Pharmacodynamic Endpoint(s) 
x Change in apoB (mg/dL) from baseline to Day 91 
x Percent change in HDL-C from baseline to Day 91 
3.5.1.2 
Analysis of Secondary Pharmacodynamic Endpoint(s) 
PD analysis will be based on the As-treated population. The secondary PD endpoints, change 
from baseline to Day 91 in apoB and percent change from baseline to Day 91 in HDL-C, will 
be summarized by treatment group. Statistical comparisons of these endpoints between each 
MEDI5884 treatment group and placebo will be performed using an analysis of covariance 
(ANCOVA) by adjusting baseline value and treatment group with last-observation-carried 
forward (LOCF) approach to handle any missing data. A one-sided upper 95% confidence 
interval comparing each MEDI5884 treatment group to placebo for change from baseline to 
Day 91 in apoB will be provided. There will be no adjustment for multiple comparisons or 
multiple endpoints. 
3.5.1.3 
Exploratory Pharmacodynamic Endpoint(s) 
x Change in total cholesterol, non-HDL-C, LDL-C (direct and Friedewald equation), 
VLDL-C, and triglycerides from baseline to Day 91 
x Change in free fatty acids and apoA1 (mg/dL) from baseline to Day 91 
x Change in lipoprotein particle size and number from baseline to Day 91 
x Change in cholesterol efflux from baseline to Day 91 
x Change in hsCRP from baseline to Day 91 


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x Baseline and change from baseline for EL mass and biomarkers of EL activity, 
including serum total phospholipids 
EL mass and biomarkers of EL activity, including total phospholipids, are exploratory 
endpoints and assays for these parameters may be performed and reported separately. 
3.5.1.4 
Analysis of Exploratory Pharmacodynamic Endpoint(s) 
Exploratory PD endpoints, including change from baseline to Day 91 in total cholesterol, 
non-HDL-C, LDL-C (direct and Friedewald equation), VLDL-C, and triglycerides, free fatty 
acids, apoA1, lipoprotein particle size and number, cholesterol efflux, hsCRP, total 
phospholipids, HDL-PL, etc. will be analyzed similarly to the analysis of primary PD 
endpoints.  
For ANCOVA, if the data are not normally distributed, the analyses will be conducted on 
rank-transformed data. Descriptive statistics at each visit will be provided by treatment group 
for PD endpoints. 
3.6 
Other Additional Analyses 
The dose-response profile for HDL-C may be explored using the multiple comparison 
procedure – modelling (MCP-Mod) method (Bretz et al, 2005). The MCP-Mod method is a 
unified approach combining the advantages of MCP and modeling methods. The analysis 
contains two main steps: 
• MCP step: calculation of optimal contrasts, critical value, contrast test statistics and p-
values, and selection of a set of significant models; 
• Modelling step: model fitting, model selection/model averaging, and dose estimation. 
A set of candidate dose-response models, including linear log, EMax, sigmoid EMax, and 
logistic, and their parameters may be considered. In addition, as a sensitivity analysis, 
secondary PD endpoints, including change in apoB from baseline to Day 91 and percent 
change in HDL-C from baseline to Day 91 and potentially change in other PD markers, may 
be summarized similar to the analysis in section 3.5.1.2 for in the as-treated population who 
did not have any major protocol violation that would be expected to alter their laboratory 
response to treatment. The violations that would exclude a subject from this population will 
be determined by the medical monitor prior to unblinding. Relevant events could include 
premature discontinuation of drug or change in background lipid medications 


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3.7 
Safety Analyses 
All safety analyses will be based on the As-treated population. The primary safety endpoints 
are the safety and tolerability of MEDI5884 as measured by the incidence of TEAEs and 
TESAEs. Investigators are to record clinically important changes in physical examination, 
laboratory values, 12-lead ECGs, and vital signs as AEs.  In addition, numeric values from 
clinical laboratory tests, ECGs and vital signs will be summarized descriptively.  Other safety 
parameters, such as descriptive ECG readings and physical examination entries will be 
provided as listings.    
The evaluations will be descriptive in nature, and observed differences will be evaluated for 
medical relevance. No formal statistical comparisons will be performed for the safety 
summaries. 
3.7.1 
Adverse Events and Serious Adverse Events 
Treatment emergent AEs (TEAEs) and Treatment emergent serious AEs (TESAEs) are 
events that had an onset after the first dose of investigational product. TEAEs and TESAEs 
will be coded with the most updated version of the Medical Dictionary for Regulatory 
Activities (MedDRA), and the incidence, severity and relationship to investigational product 
will be summarized by treatment group and MEDI5884 overall for each MedDRA system 
organ class and preferred term reported. Adverse events leading to discontinuation, AEs 
leading to death, and deaths will also be summarized. Specific AEs will be counted once for 
each subject when 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. All 
TEAEs and TESAEs will be summarized overall, as well as categorized by MedDRA system 
organ class and preferred term. Injection site assessments (redness, swelling, and pain) 
regardless reported as AEs or not will also be summarized. 
Subjects with potential immunogenicity related TEAEs for immune complex diseases, 
allergic reactions, and injection site reactions according to Standardized MedDRA Queries 
(SMQ) will be summarized. The US Food and Drug Administration has requested that safety 
data be analyzed for this study according to the following SMQs:  Systemic lupus 
erythematosus (broad and narrow terms); vasculitis (broad and narrow terms); Guillain-Barre 
syndrome (narrow terms) and allergic reactions (narrow SMQs for anaphylactic reaction, 
angioedema, severe cutaneous adverse reaction, anaphylactic/anaphylactoid shock conditions 
and hypersensitivity). Injection site reactions will be assessed using the following high level 
MedDRA (HLT) terms: administration site reactions, application and instillation site 


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reactions, infusion site reactions, and injection site reactions. These terms will be updated to 
the current version of MedDRA.  
3.7.2 
Adverse Events of Special Interest 
The following AESI has been identified specifically for this protocol: 
x Hepatic function abnormality meeting the definition of Hy’s law 
The AESIs will be summarized by treatment group and MEDI5884 overall, as well as by 
MedDRA system organ class and preferred term. 
3.7.3 
Deaths and Treatment Discontinuations due to Adverse Events 
Death and AEs resulting in permanent discontinuation from the study drug will be 
summarized by treatment group and MEDI5884 overall as well as by MedDRA system organ 
class and preferred term. 
3.7.4 
Clinical Laboratory Evaluation 
The hematology and serum chemistry parameters as well as their changes from baseline will 
be summarized with descriptive statistics by treatment group at each of the scheduled visits. 
In addition, hematology and serum chemistry values will also be classified as low, normal, or 
high with respect to the laboratory reference range for the parameter.  The shift from baseline 
category to each post-baseline visit category for each parameter will be summarized at each 
post-baseline visit by treatment group as well as for MEDI5884 overall. 
The urinalysis categorical results will be classified as normal or abnormal with respect to the 
laboratory reference range for the parameter. The shift from baseline category to the post-
baseline category will be summarized by treatment group and MEDI5884 overall at each 
post-baseline visit. 
3.7.4.1 
Physical Examinations 
Subjects with abnormalities in each body system examined will be presented for each 
scheduled evaluation in data listings. 
3.7.4.2 
Vital Signs 
Vital sign parameters (systolic and diastolic blood pressure, pulse rate, respiration rate, and 
temperature) will be summarized with descriptive statistics for each scheduled evaluation by 


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treatment group and MEDI5884 overall. Change from baseline to each post baseline 
evaluation will also be summarized.  In addition, changes from pre-dose to 1 hour post-dose 
will be summarized for each dosing visit. 
3.7.4.3 
Electrocardiogram 
The following ECG parameters will be summarized:  Heart rate, RR, PR, QRS and QT 
intervals as well as derived parameters QT corrected interval parameters, QTcB (Bazett’s 
formula) and QTcF (Fridericia’s formula).  The results at each visit: Baseline (average of the 
3 triplicate ECG averages taken on Day 1) and at each post-baseline visit (average of ECG 
triplicate) will be summarized as well as the change from baseline. In addition, the number of 
subjects having the following notable ECG interval values will be summarized. 
x Maximum QTcF and QTcB intervals ! 450 ms, > 480 ms, > 500 ms  
x Maximum uncorrected QT intervals ! 500 ms 
x Maximum changes from baseline in QTcF and QTcB ! 30, >60 and ! 90 ms  
The percent of subjects with an abnormal ECG evaluation and specific ECG abnormalities 
observed at each visit will be summarized by treatment group and MEDI5884 overall.  
3.8 
Immunogenicity 
The immunogenicity analyses will be based on the ADA evaluable population. ADA 
incidence rate and titer will be tabulated for each treatment group. Samples confirmed 
positive for ADA will be tested and analyzed for nAb titer and summarized similarly. For 
overall post-baseline summary, persistent positive is defined as positive at ≥2 post-baseline 
assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline 
assessment; transient positive is defined as negative at last post-baseline assessment and 
positive at only one post-baseline assessment or at ≥2 post-baseline assessments (with <16 
weeks between first and last positive). 
3.9 
Pharmacokinetics 
The pharmacokinetic analyses will be based on the PK population. Descriptive statistics of 
serum MEDI5884 concentration data will be provided. Individual and mean serum 
concentration-time profiles of MEDI5884 for each treatment group will be generated. Non-
compartmental PK data analysis will be performed and PK parameters such as Cmax, AUC0-
inf, t1/2 will be generated. 


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4 
INTERIM ANALYSIS 
An interim analysis is planned after all subjects have completed their Day 111 visit. 
MedImmune personnel will be unblinded at the interim analysis; study subjects, the 
investigator, and site staff who are involved in the treatment or clinical evaluation of subjects 
will remain blinded until the end of study. 
5 
REFERENCES 
Bretz F, Pinheiro J, Branson M. Combining Multiple Comparisons and Modelling 
Techniques in Dose-Response Studies.  Biometrics 2005; 61:738-748 
6 
VERSION HISTORY 
Version 
Date 
Summary of Changes 
Reason for Change 
1.0 
14DEC2017 
Initial document 
Initial document