Conditions: Hypertriglyceridemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 383
Healthy volunteers: no

Brief summary:
This study is a randomised, double-blind phase III long-term study to evaluate efficacy and safety of 12 weeks and 52 weeks of AZD0585 administration compared to placebo in patients with hyperlipidemia accompanied by hypertriglyceridemia .

Detailed description:

Arms:
arm 1: AZD0585 1g × 2 capsules and AZD0585 placebo 1g × 2 capsules once daily arm 2: AZD0585 1g × 4 capsules once daily arm 3: AZD0585 placebo 1g × 4 capsules once daily

Interventions: intervention 1: AZD0585 intervention 2: AZD0585 placebo
Intervention descriptions: intervention 1: 1g soft capsule intervention 2: 1g soft capsule

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
Drug Substance
AZD0585
Study Code
D5884C00002
Edition Number
1
Date
3 April 2015
A Randomised, Double-blind, Placebo controlled, Parallel Group, Phase III 
Long-term Study to Evaluate Efficacy and Safety of 12 Weeks and 52 
Weeks of AZD0585 Administration, Respectively, in Patients with 
Hyperlipidemia Accompanied by Hypertriglyceridemia (TG in the Range 
150-499 mg/dL)
Sponsor:
AstraZeneca KK, 3-1, Ofuka-cho, Kita-ku Osaka 530-0011, Japan
The following Amendment(s) and Administrative Changes have been made to this protocol since the date 
of preparation:
Amendment No.
Date of Amendment
Local Amendment 
No:
Date of Local Amendment
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local 
Administrative Change


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
2(52)
This submission document contains confidential commercial information, disclosure of which is prohibited 
without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
3(52)
PROTOCOL SYNOPSIS
A Randomised, Double-blind, Placebo controlled, Parallel Group, Phase III 
Long-term Study to Evaluate Efficacy and Safety of 12 Weeks and 52 
Weeks of AZD0585 Administration, Respectively, in Patients with 
Hyperlipidemia Accompanied by Hypertriglyceridemia (TG in the Range 
150-499 mg/dL)
National Co-ordinating Investigator
Study site(s) and number of subjects planned
This study will include 375 patients to be randomised at about 25 sites.  All sites are presented 
in Supplement A.
Study period
Phase of development
Estimated date of first subject enrolled
June 2015
Phase III
Estimated date of last subject completed
May 2017
Study design
This is a randomised, multicentre, double-blinded, placebo controlled, parallel group study.  
The eligible patients will be randomised to any of the following 3 cohorts.
!
AZD0585 2 g
!
AZD0585 4 g
!
Placebo


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
4(52)
Objectives
Primary Objective:
Outcome Measure:
To demonstrate the short-term (up to 12 
weeks) efficacy of AZD0585 2 g and 4 g 
compared to placebo (corn oil) in Japanese 
patients with hyperlipidemia accompanied by 
hypertriglyceridemia (TG in the range 150-
499 mg/dL)
Placebo-corrected percent change in serum TG level 
from baseline to the Week 12 Endpoint.
To evaluate the long-term (up to 52 weeks) 
safety of AZD0585 administration in Japanese
patients with hyperlipidemia accompanied by 
hypertriglyceridemia (TG in the range 150-
499 mg/dL)
Adverse events (AEs), brief physical findings/clinical 
assessments, ECG assessments, vital signs and
laboratory evaluations.
Secondary Objective:
Outcome Measure:
To assess the effect of each dose of AZD0585 
on fasting serum lipid profile
Percent change in each serum lipid level from 
baseline to Week 12 Endpoint in serum lipid profile 
including total cholesterol (TC), HDL-C, LDL-C, 
VLDL-C and non-HDL-C.
To assess the effects of each dose of AZD0585
in parameters shown as outcome measure for 
the objective
∀
Apolipoprotein (Apo) A-I, Apo A-II, Apo B, Apo
B48, Apo C-II, Apo C-III, and Apo E based on 
percent changes from baseline to Week 12.
∀
Plasma fatty acids profile: EPA, DHA, 
arachidonic acid (AA) and EPA/AA ratio based on 
percent changes from baseline to Week 12.
∀
Small dense LDL and LDL-C/Apo B ratio based 
on percent changes from baseline to Week 12.
∀
Lipoprotein(a) [Lp(a)], remnant like particles 
cholesterol (RLP-C), proprotein convertase 
subtilisin kexin 9 (PCSK9) and high sensitivity 
C-reactive protein (hs-CRP) based on percent 
changes from baseline to Week 12.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
5(52)
Exploratory Objective:
Outcome Measure:
To assess the time-course of efficacy-related 
parameters profile up to Week 52 and explore 
the efficacy characteristics of long-term use of 
AZD0585 2 g/4 g vs. placebo.
∀
Fasting serum lipid profile including TG, TC, 
HDL-C, LDL-C, VLDL-C and non-HDL-C.
∀
Apo A-I, Apo A-II, Apo B, Apo B48, Apo C-II, 
Apo C-III, and Apo E.
∀
Plasma fatty acids profile: EPA, DHA, AA, and 
EPA/AA ratio.
∀
Small dense LDL and LDL-C/Apo B ratio.
∀
Lp(a), RLP-C, PCSK9 and hs-CRP.
Target subject population
Japanese patients with hyperlipidemia accompanied by hypertriglyceridemia (TG in the range 
150-499 mg/dL) aged 20 years and over.
Duration of treatment
52 weeks.
Investigational product, dosage and mode of administration
The following investigational product(s) will be used in this study.
∀
AZD0585 1 g soft gelatine capsules
All subjects will need to take 4 capsules from assigned bottle, once daily just after breakfast.
Statistical methods
Primary analyses will be carried out by analysis of covariance (ANCOVA) model including 
percent change from baseline in TG at Week 12 Endpoint as a response variable, treatment 
and baseline statin use as factors and baseline TG as a covariate.  The primary analysis will be 
carried out on full analysis set (FAS).
Least square means and 95%CI for each treatment as well as treatment difference to placebo 
will be provided from the model.  P-values will be provided for comparison of AZD0585 each 
dose vs. placebo.
The primary objective of this study is to demonstrate the superiority of AZD0585 2 g and 4 g 
when compared with placebo using the percent change from baseline in TG to Week 12 as a 
primary efficacy variable.  In order to protect family wise error rate to be 5%, superiority of 
AZD0585 2 g vs. placebo and superiority of AZD0585 4 g vs. placebo will be tested based on 
Hochberg procedure using two-sided significance level of 0.05. If a p-value for each 
hypothesis is less than 0.05/2 = 0.025, the corresponding hypothesis claimed to be 
demonstrated. If both p-values are less than 0.05, then the both hypotheses are claimed to be 
demonstrated.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
6(52)
All analyses other than analysis of the primary efficacy endpoint will be interpreted 
descriptively. Consequently, no adjustments for multiplicity will be necessary for such 
analyses. Ninety-five percent confidence intervals will be calculated, where appropriate, as 
measures of study precision. P-values may be calculated but are to be regarded as descriptive.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
7(52)
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................3
TABLE OF CONTENTS.........................................................................................7
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................11
1.
INTRODUCTION .................................................................................................14
1.1
Background and rationale for conducting this study .............................................14
1.2
Rationale for study design, doses and control groups............................................15
1.3
Benefit/risk and ethical assessment........................................................................16
1.4
Study Design..........................................................................................................17
2.
STUDY OBJECTIVES..........................................................................................19
2.1
Primary objective...................................................................................................19
2.2
Secondary objectives .............................................................................................19
2.3
Exploratory objectives ...........................................................................................20
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................20
3.1
Inclusion criteria ....................................................................................................20
3.2
Exclusion criteria ...................................................................................................21
3.3
Subject enrolment and randomisation....................................................................23
3.4
Procedures for handling incorrectly enrolled or randomised subjects...................23
3.5
Methods for assigning treatment groups................................................................24
3.6
Methods for ensuring blinding...............................................................................24
3.7
Methods for unblinding..........................................................................................24
3.8
Restrictions ............................................................................................................25
3.9
Discontinuation of investigational product............................................................25
3.9.1
Procedures for discontinuation of a subject from investigational product ............26
3.10
Criteria for withdrawal...........................................................................................26
3.10.1
Screen failures........................................................................................................26
3.10.2
Withdrawal of the informed consent......................................................................26
3.11
Discontinuation of the study..................................................................................27


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
8(52)
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................27
4.1
Screening period ....................................................................................................31
4.2
Treatment period....................................................................................................31
4.3
Withdrawal visit.....................................................................................................32
5.
STUDY ASSESSMENTS .....................................................................................32
5.1
Efficacy assessments..............................................................................................33
5.2
Safety assessments.................................................................................................33
5.2.1
Laboratory safety assessments...............................................................................33
5.2.2
Physical examination .............................................................................................34
5.2.2.1
Brief Physical Findings..........................................................................................34
5.2.2.2
Clinical Assessments .............................................................................................35
5.2.3
ECG........................................................................................................................35
5.2.4
Vital signs ..............................................................................................................35
5.3
Other assessments (Not Applicable)......................................................................35
5.4
Pharmacokinetics (Not Applicable).......................................................................35
5.5
Pharmacodynamics (Not Applicable)....................................................................35
5.6
Pharmacogenetics (Not Applicable) ......................................................................35
5.7
Biomarker analysis (Not Applicable) ....................................................................35
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................35
6.1
Definition of adverse events ..................................................................................36
6.2
Definitions of serious adverse event......................................................................36
6.3
Recording of adverse events ..................................................................................36
6.3.1
Time period for collection of adverse events.........................................................36
6.3.2
Follow-up of unresolved adverse events................................................................36
6.3.3
Variables ................................................................................................................36
6.3.4
Causality collection................................................................................................37
6.3.5
Adverse events based on signs and symptoms.......................................................38
6.3.6
Adverse events based on examinations and tests...................................................38
6.4
Reporting of serious adverse events.......................................................................38
6.5
Overdose ................................................................................................................39
6.6
Pregnancy...............................................................................................................39
6.6.1
Maternal exposure..................................................................................................39
6.6.2
Paternal exposure...................................................................................................40
6.7
Management of investigational product related toxicities (Not Applicable).........40
6.8
Study governance and oversight ............................................................................40
6.8.1
Steering Committee ...............................................................................................40


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
9(52)
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................41
7.1
Identity of investigational product(s).....................................................................41
7.2
Dose and treatment regimens.................................................................................41
7.3
Labelling ................................................................................................................41
7.4
Storage ...................................................................................................................41
7.5
Compliance ............................................................................................................41
7.6
Accountability........................................................................................................42
7.7
Concomitant and other treatments .........................................................................42
7.8
Post Study Access to Study Treatment (Not Applicable)......................................43
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................43
8.1
Statistical considerations........................................................................................43
8.2
Sample size estimate..............................................................................................43
8.3
Definitions of analysis sets ....................................................................................43
8.3.1
Efficacy analysis set...............................................................................................43
8.3.2
Safety analysis set..................................................................................................43
8.4
Outcome measures for analyses.............................................................................44
8.4.1
Primary efficacy variable.......................................................................................44
8.4.2
Secondary efficacy variables .................................................................................44
8.5
Methods for statistical analyses .............................................................................44
8.5.1
Analysis of the primary variable (s).......................................................................44
8.5.2
Analysis of the secondary variable(s)....................................................................45
8.5.2.1
Efficacy variables...................................................................................................45
8.5.2.2
Safety variables......................................................................................................46
8.5.3
Subgroup analysis ..................................................................................................46
8.5.4
Interim analysis......................................................................................................46
8.5.5
Sensitivity analysis.................................................................................................46
8.5.6
Exploratory analysis...............................................................................................47
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................47
9.1
Training of study site personnel.............................................................................47
9.2
Monitoring of the study .........................................................................................47
9.2.1
Source data.............................................................................................................48
9.2.2
Study agreements...................................................................................................48
9.2.3
Archiving of study documents...............................................................................48
9.3
Study timetable and end of study...........................................................................48
9.4
Data management...................................................................................................48
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................49


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
10(52)
10.1
Ethical conduct of the study...................................................................................49
10.2
Subject data protection...........................................................................................49
10.3
Ethics and regulatory review..................................................................................50
10.4
Informed consent ...................................................................................................50
10.5
Changes to the protocol and informed consent form.............................................51
10.6
Audits and inspections ...........................................................................................51
11.
LIST OF REFERENCES.......................................................................................51
LIST OF TABLES
Table 1
Study Plan.................................................................................................28
Table 2
Laboratory Safety Variables.....................................................................34
Table 3
Identity of investigational product(s) .......................................................41
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................18
LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional Safety Information 
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
11(52)
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
AA
Arachidonic acid
AE
Adverse event
AP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Apo
Apolipoprotein
Apo A-I
Apolipoprotein A-I
Apo A-II
Apolipoprotein A-II
Apo B
Apolipoprotein B
Apo B48
Apolipoprotein B48
Apo C-II
Apolipoprotein C-II
Apo C-III
Apolipoprotein C-III
Apo E
Apolipoprotein E
AST
Aspartate aminotransferase
BMI
Body Mass Index
BP
Blood pressure
CSA
Clinical Study Agreement
CVD
Cardiovascular disease
DHA
Docosahexaenoic acid
eCRF
Electronic Case Report Form
EE
Ethyl ester
EPA
Eicosapentaenoic acid
FAS
Full analysis set
FDA
Food and Drug Administration
FFA
Free fatty acid


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
12(52)
Abbreviation or 
special term
Explanation
GCP
Good Clinical Practice
Unless otherwise noted, ‘GCP’ shall mean ‘the International Conference on 
Harmonisation Tripartite Guideline for Good Clinical Practice’ (ICH GCP) 
and the Japanese ‘Good Clinical Practice for Trials on Drugs (Ministry of 
Health, Labour and Welfare [MHLW] Ordinance No. 28, 27 March 1997, 
partially revised by MHLW Ordinance and their related notifications’ (GCP 
Ordinance).
Hb
Haemoglobin
HbA1c
Haemoglobin A1c
HDL-C
High-density lipoprotein cholesterol
HR
Heart rate
hs-CRP
high sensitivity C-reactive protein
ICH
International Conference on Harmonisation
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
Investigators
Principal Investigator + Sub-investigator
IRB
Institutional Review Board
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
JAS
Japan Atherosclerosis Society
LDL
Low-density lipoprotein
LDL-C
Low-density lipoprotein cholesterol
Lp(a)
Lipoprotein(a)
non-HDL-C
Non-high-density lipoprotein cholesterol
OTC
Over-the-counter
PCSK9
Proprotein Convertase Subtilisin Kexin 9
PI
Principal Investigator
PPS
Per protocol set
PT
Prothrombin time
PTT
Partial thromboplastin time
RLP-C
Remnant like particles cholesterol
SAE
Serious adverse event


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
13(52)
Abbreviation or 
special term
Explanation
TC
Total cholesterol
TG
Triglycerides
TLC
Therapeutic Lifestyle Changes
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
US
United States
VLDL-C
Very low-density lipoprotein cholesterol
WBDC
Web Based Data Capture


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
14(52)
1.
INTRODUCTION
1.1
Background and rationale for conducting this study
AZD0585 capsules (hereinafter referred to as AZD0585), which was developed by Omthera 
Pharmaceuticals, Inc., is a complex mixture of 1 g of omega-3 free fatty acid (FFA) derived 
from fish oils, and primarily composed of eicosapentaenoic acid (EPA: 
 
and docosahexaenoic acid (DHA: 
 Omega-3 fatty acids are well-known 
to lower serum triglycerides (TG) levels by reducing the amount of hepatic TG secretion and 
by enhancing the rate of TG clearance from circulation. In Japan, Epadel® (S300, S600, S900 
and capsules 300; hereinafter referred to as Epadel®) and Lotriga® granular capsule 2 g 
(hereinafter referred to as Lotriga®), drugs containing omega-3 fatty acid like AZD0585, are 
approved for the indication of hyperlipidemia.  Epadel is composed mostly of EPA ethyl ester
(EE) and Lotriga is composed of EPA EE and DHA EE.
AZD0585 was initially developed for an indication to enhance the remission of Crohn’s 
Disease (Investigational New Drug application No. 65,440). While investigating this 
indication in two large, placebo-controlled, randomised, double-blind, Phase III trials 
(AZD0585 Program in Crohn’s Disease [EPIC]-1 in Europe and Canada, and EPIC-2 in North 
America and Europe), it was recognized that AZD0585 lowered TG levels in patients with TG 
levels in the slightly elevated range.  Since then, in overseas AZD0585 has been clinically 
developed for the indication of hypertriglyceridemia.
AZD0585 containing omega-3 fatty acid as FFA, unlike the existing drugs containing omega-
3-acid EE, does not require hydrolysis at absorption from the small intestine to the systemic 
circulation, and provides favourable bioavailability regardless of taking meals containing fat. 
Actually, in the clinical pharmacology study of AZD0585 (ECLIPSE-2), the bioavailability of 
AZD0585 4 g per day and Lovaza®4 g per day administered up to 14 days with low-fat diet 
(evaluated by plasma total EPA, DHA and total1 EPA + total DHA levels) was significantly 
higher compared to Lovaza®, a drug containing omega-3-acid EE.
In two Phase III studies (EVOLVE (OM-EPA-003) and ESPRIT (OM-EPA-004)) conducted 
out of Japan, consistent dose-dependent TG-lowering response with AZD0585 treatment was 
observed and clinical benefit on improving lipid parameters was demonstrated in both studies.
In EVOLVE study conducted with severe hypertriglyceridemia, TG levels were between ≥500
mg/dL and <2000 mg/dL after a washout period of lipid-altering medications other than 
statins and ezetimibe, median baseline TG level was 694 mg/dL. Treatment with AZD0585 
led to statistically significant reductions in fasting TG levels (median % changes from baseline 
in TG were -10%, -25%, and -31% for placebo, AZD0585 2 g, and AZD0585 4 g, 
respectively; p<0.01 and p<0.001 for AZD0585 2 g and 4 g vs. placebo, respectively).  
                                                
1 “total” = the combined unesterified and esterified forms of EPA or DHA




Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
16(52)
this study. Although placebo was extra virgin olive oil for both EVOLVE and ESPRIT 
studies, corn oil is used for placebo instead of extra virgin olive oil in this study, because it is 
reported that no statistically significant changes were observed in human plasma TG 
concentrations by corn oil and extra virgin olive oil (Sirtori et al 1986, Lichtenstein et al 1993).
This study is a randomised, double-blinded, placebo controlled, parallel group study designed 
to evaluate the efficacy of 12 weeks and safety of 52 weeks of AZD0585 treatment, 
respectively, in Japanese subjects with hyperlipidemia accompanied by hypertriglyceridemia 
(TG in the range 150-499 mg/dL). The effect of 2 g or 4 g dose of AZD0585 once daily 
on %TG reduction will be evaluated by comparing with that of 4 g dose of placebo (corn oil).  
In addition, a long-term safety of 2 g or 4 g dose of AZD0585 once daily will be evaluated by 
comparing with the placebo control in a double-blinded fashion so that the relationship 
between AZD0585 administration and AEs including abnormalities in safety parameters such 
as clinical laboratory test can be better assessed with some insights of AZD0585
dose-dependency on the AEs.
An interim analysis is planned in this study. The data of interim analysis will be cut off when
the last subject goes through Visit 11. An interim analysis will include all patients’ data 
available until data cut-off even if patients withdraw prior to Visit 11 including analysis at 
Week 12 Endpoint for primary efficacy endpoint as well as safety evaluation up to Visit 11.
1.3
Benefit/risk and ethical assessment
AZD0585 contains omega-3-acid as FFA and has an advantage of greater bioavailability over 
existing omega-3-acid EE alternatives because absorption of EEs is significantly dependent on 
stimulated intestinal hydrolysis (food-activated) for mucosal uptake (Ikeda et al 1995, Small 
1991, El Boustani et al 1987, Hazra et al 1999, Lawson and Hughes 1988a, Lawson and 
Hughes 1988b, Beckermann et al 1990, Hansen et al 1998).
The meal-fat independency of the AZD0585 formulation is important for full treatment effects, 
as patients with hypertriglyceridemia are advised to restrict fat intake in order to reduce TG 
and the associated risk of pancreatitis or CVD events (NCEP 2002).
The total intake of EPA plus DHA in subjects will not exceed 3 g per day since the planned 
4 g per day dose of AZD0585 contains approximately 75% EPA plus DHA.  This dose level is 
in agreement with the 1997 FDA ruling of 3 g per day as Generally Recognized as Safe for 
this aggregate amount (FDA 1997).  In a previous Phase I study with AZD0585 in healthy 
adult male Japanese subjects (D5881C00005), 4 g AZD0585 was safe and well tolerated 
following single- and multiple-dose and once-daily administration up to 14 days.
Additionally, AZD0585 4 g daily dose was safe and well tolerated for up to 3 years in subjects 
with Crohn’s disease. Therefore it is considered that 52-week treatment period is applicable 
for this study.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
17(52)
The patients who are allocated to placebo group continue placebo treatment for 52 weeks. 
From ethical point of view, patients are allowed to use lipid lowering drugs and/or 
supplements except for omega-3-acid after Visit 8.
1.4
Study Design
This is a randomised, double-blinded, placebo controlled, study employing 3 arm parallel 
groups to evaluate efficacy of 12 weeks and safety of 52 weeks of AZD0585 administration in 
patients with hyperlipidemia accompanied by hypertriglyceridemia (TG in the range 
150-499 mg/dL).
Total 375 subjects will be randomised to 3 cohorts, A) placebo, B) Epanova 2 g, and C) 
Epanova 4 g, at a ratio of 1:2:2, respectively.  The efficacy will be evaluated as placebo-
corrected percent change TG reduction at 12 weeks from the baseline TG level (see Section 
8.1).  The safety will be evaluated as AEs and other safety parameters (vital sign, clinical 
laboratory test, etc) during 52-week treatment period.
A.
Placebo (corn oil) 4 g once daily (n=75)
B.
AZD0585 2 g (+placebo 2 g) once daily (n=150)
C.
AZD0585 4 g once daily (n=150)
Randomisation will be stratified by the following factors to ensure equal representation across 
all treatment groups;
∀
Current use of statin (yes vs. no) at baseline
∀
Baseline TG level <300 or ≥300 mg/dL
Stratified randomisation will be conducted so that approximately 50% or more of total 
randomised patients are statin users.




Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
19(52)
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To demonstrate the short-term (up to 12 
weeks) efficacy of AZD0585 2 g and 4 g 
compared to placebo (corn oil) in Japanese 
patients with hyperlipidemia accompanied by 
hypertriglyceridemia (TG in the range 150-
499 mg/dL)
Placebo-corrected percent change in serum TG level 
from baseline to Week 12 Endpoint.
To evaluate the long-term (up to 52 weeks) 
safety of AZD0585 administration in Japanese
patients with hyperlipidemia accompanied by 
hypertriglyceridemia (TG in the range 150-
499 mg/dL)
AEs, brief physical findings/clinical assessments, 
ECG assessments, vital signs and laboratory 
evaluations.
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To assess the effect of each dose of AZD0585
on fasting serum lipid profile
Percent change in each serum lipid level from 
baseline to Week 12 Endpoint in serum lipid profile 
including total cholesterol (TC), HDL-C, LDL-C, 
VLDL-C and non-HDL-C.
To assess the effects of each dose of AZD0585
in parameters shown as outcome measure for 
the objective
∀
Apolipoprotein (Apo) A-I, Apo A-II, Apo B, Apo
B48, Apo C-II, Apo C-III, and Apo E based on 
percent changes from baseline to Week 12.
∀
Plasma fatty acids profile: EPA, DHA, AA and 
EPA/AA ratio based on percent changes from 
baseline to Week 12.
∀
Small dense LDL and LDL-C/Apo B ratio based 
on percent changes from baseline to Week 12.
∀
Lp(a), RLP-C, PCSK9 and hs-CRP based on 
percent changes from baseline to Week 12.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
20(52)
2.3
Exploratory objectives  
Exploratory Objective:
Outcome Measure:
To assess the time-course of efficacy-related 
parameters profile up to Week 52 and explore 
the efficacy characteristics of long-term use of 
AZD0585 2 g/4 g vs. placebo.
∀
Fasting serum lipid profile including TG, TC, 
HDL-C, LDL-C, VLDL-C and non-HDL-C.
∀
Apo A-I, Apo A-II, Apo B, Apo B48, Apo C-II, 
Apo C-III, and Apo E.
∀
Plasma fatty acids profile: EPA, DHA, AA, and 
EPA/AA ratio.
∀
Small dense LDL and LDL-C/Apo B ratio.
∀
Lp(a), RLP-C, PCSK9 and hs-CRP.
3.
SUBJECT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
1.
Japanese men or women, ≥20 years of age.
2.
Subjects must meet all of the following criteria;
(a)
Fasting TG level: average of Visit 2 and Visit 3 must be in the range 150 -
499 mg/dL
(b) %TG change between Visit 2 and Visit 3 must be within 30%
(c) %LDL-C change between Visit 2 and Visit 3 must be within 25%
If subjects do NOT meet one of above criteria but the average values are very close 
to inclusion cut-offs, and are quite willing to join the study and the investigators 
decide that an additional test is appropriate, an additional Visit (Visit 3a) is allowed 
between Visit 3 and 4. To be included after Visit 3a the subjects must meet all the 
following criteria; 
(d) Fasting TG level: average of Visit 2, 3 and 3a must be in the range 150-
499 mg/dL


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
21(52)
(e) %TG change between Visit 2 and the average of Visit 3 and 3a must be within 
30%
(f) %LDL-C change between Visit 2 and the average of Visit 3 and 3a must be 
within 25% 
3.
Subjects must be willing and able to give written informed consent by signing an 
Institutional Review Board (IRB)-approved Informed Consent Form prior to 
admission to this study and follow the restrictions and procedures outlined for the 
study.
4.
If a statin is prescribed, the patient should be on an optimal statin dose for achieving 
LDL-C goals based on Japan Atherosclerosis Society (JAS) guideline 2012 or on a 
maximally tolerated statin dose (i.e., without muscles aches/weakness, liver or 
muscle enzyme elevations). Statin dose must have been stable for at least 4 weeks 
prior to screening.
5.
Subjects who is willing to follow the diet and/or exercise therapy recommended by 
JAS guideline 2012 during the study.
3.2
Exclusion criteria
Subjects must not be randomised in the study if any of the following exclusion criteria are 
fulfilled:
1.
Allergy or intolerance to omega-3 fatty acids and omega-3-acid ethyl esters.
2.
Use of fibrates, bile acid sequestrants, or niacin or its analogues (greater than 
200 mg/day) or any drug for the purpose of lowering plasma cholesterol (except for 
statin) during screening.
3.
Use of any EPA or DHA products, fish oil, or medications (e.g., Lotriga®, Epadel®) 
or investigational drugs (e.g., AMR101) containing EPA or DHA within 8 weeks 
prior to randomisation.
4.
Use of any supplement for the purpose of lowering plasma cholesterol during 
screening (e.g., red rice yeast supplements).
5.
Use of weight loss drugs (including over-the-counter [OTC] preparations), 
supplements or programs during screening.
6.
Use of anticoagulants (e.g. warfarin, coumarin, heparin, enoxaparin or Prazaxa®) 
during screening.
7.
Use of oral or injected corticosteroids (other than intranasal or inhaled steroids used 
for allergies/asthma) during screening.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
22(52)
8.
Use of tamoxifen, estrogens, progestins, or testosterone, that has not been stable for 
>4 weeks at Visit 1, or is unstable during screening.
9.
Known lipoprotein lipase impairment or deficiency, or Apo C-II deficiency or 
familial dysbetalipoproteinemia.
10.
Current or history of pancreatitis.
11.
Type I diabetes mellitus, use of insulin, or haemoglobin A1c (HbA1c) >10% at 
Visit 1.
12.
Poorly controlled hypertension (resting blood pressure [BP] ≥160 mmHg systolic 
and/or ≥100 mmHg diastolic) at two consecutive visits prior to randomisation at 
Visit 4.
13.
Uncontrolled hypothyroidism, thyroid stimulating hormone (TSH) >1.5 x upper 
limit of normal (ULN) or Cushing’s syndrome at Visit 1.
14.
Within six months prior to Visit 1 or current significant nephritic syndrome, 
pulmonary, hepatic, biliary, gastrointestinal or immunologic disease.
15.
Current or history of cancer (except non-melanoma skin cancer, or carcinoma in 
situ of cervix) within the previous five years.
16.
Female patients who is considered of childbearing potential if she is not surgically 
sterile or if her last menstrual period was <12 months prior to Visit 1 meet any 
following criteria:
∀
Have a positive pregnancy test
∀
Be breast feeding
∀
Be planning to be pregnant during the study period
∀
Cannot use acceptable methods of contraception
Acceptable methods of contraception for this study include use of double barrier 
contraception, intrauterine device or abstinence, all oral, hormonal or selective 
estrogen receptor modulator contraceptives as long as dose and type is stable for 3 
months prior to Visit 1.
17.
Creatine kinase >5.0 times ULN; AST or ALT >2.5 times ULN at Visit 2.
18.
Current or within 12 months prior to Visit 1 of drug or alcohol abuse.
19.
Exposure to any investigational agent within 4 weeks prior to Visit 1.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
23(52)
20.
Any other condition the investigators believe would interfere with the subject’s 
ability to provide informed consent, comply with study instructions, or which might 
confound the interpretation of the study results or put the subject at undue risk.
21.
Patients who are at known risk for bleeding including congenital disorder of 
coagulation system, recent severe external injury and/or any known conditions that 
will require surgery during the study period.
22.
Involvement in the planning and/or conduct of the study (applied to both 
AstraZeneca staff and/or staff at the study site)
23.
Previous participation in a clinical study with AZD0585.
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4.
3.3
Subject enrolment and randomisation
The Principal Investigator (PI) will ensure:
1.
Signed informed consent is obtained from each potential subject before any study 
specific procedures are performed.
2.
The eligibility of each subject is determined see Sections 3.1 and 3.2.
3.
Each potential subject is assigned a unique enrolment number, beginning with “E”.
4.
Each eligible subject is assigned a unique randomisation code.
Randomisation will be performed before the first dose treatment at Visit 4.
Randomisation codes will be assigned strictly sequentially as subjects become eligible for 
randomisation.
If a subject withdraws his participation in the study, then his/her enrolment/randomisation 
code cannot be reused.
3.4
Procedures for handling incorrectly enrolled or randomised 
subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Subjects who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomised or initiated on treatment, and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigators should inform the AstraZeneca Study Team
Physician immediately, and a discussion should occur between the AstraZeneca Study Team
Physician and the investigators regarding whether to continue or discontinue the patient from 


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
24(52)
treatment.  The AstraZeneca Study Team Physician must ensure all decisions are 
appropriately documented.
3.5
Methods for assigning treatment groups
Patients will be randomised to placebo, AZD0585 2g and AZD0585 4 g with the ratio of 1:2:2.
Randomisation will be stratified by concomitant statin use (yes / no) at baseline and baseline 
TG value (<300, ≥300 mg/dL).
Stratified randomisation will be conducted so that approximately 50% or more of total 
randomised patients are statin users.
3.6
Methods for ensuring blinding
The treatment allocation in this study will be double-blind. To ensure the blinding of the 
treatments, matching AZD0585 placebo capsules will be used. Each pack will be labelled 
with a unique kit ID number that will be used to assign the treatment to the patient but will not 
indicate treatment allocation to the investigators or patient.
An un-blinded interim report will be provided based on Visit 11 data, in order to submit Japan 
New Drug Application. Investigators and patients will be kept blinded to randomized 
treatment up-to study closure.
The plasma fatty acids profile (EPA, DHA, AA and EPA/AA ratio) data from Visit4 or later 
and the serum TG values between Visit4 and Visit8 will also be kept double-blinded until the 
interim database lock. These data will not be disclosed to Investigators and patients up-to 
study closure.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
subject, will be available to the Investigator(s) or pharmacists from the interactive voice 
response system (IVRS) / interactive web response system (IWRS). Routines for this will be 
described in the IVRS/IWRS user manual that will be provided to each site.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomisation. The 
Investigators documents and reports the action to AstraZeneca, without revealing the 
treatment given to subject to the AstraZeneca representative.
AstraZeneca representatives who are independent to the study evaluation at the Patient Safety 
Department retains the right to break the code for serious adverse event (SAE) that are 
unexpected and are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. Treatment codes will not be 
broken for the planned analyses of data until all decisions on the evaluability of the data from 
each individual subject have been made and documented.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
25(52)
3.8
Restrictions
Subjects will be instructed as follows for a specified period during the study:
1.
Any new prescription medications or OTC preparations, supplements must be 
reported to study site staff during study period.
2.
Continue existing therapy (if applicable) with antihypertensive agents at current 
dosages unless needed by the Investigators discretion during study period.
3.
Fast overnight for at least 8 hours prior to each study visit, i.e., no food or beverage 
except water.
4.
Withhold alcohol and refrain from intense exercise 24 hours prior to each study 
visit.
5.
Do not donate blood for the duration of the study.
6.
Statin dose should not be changed up to Visit 8 unless needed for safety reason at
investigators discretion.  Do not take lipid lowering drug except for statin up to 
Visit 8.  Thereafter any lipid lowering drugs and/or supplements are allowed except 
for omega-3.
7.
Subjects should not take investigational products on the morning of the study visit.
Subjects bring study drug to each study visit and take investigational products just 
after the nearest meal after study procedure of the study visit.
8.
Subjects must make every attempt to adhere to the dietary and physical activity 
changes and goals as discussed with the Investigator(s) during study period.
9.
Women of child-bearing potential must immediately contact the Investigators if 
they suspect they might be pregnant and if they have changed, or plan to change 
their birth control method during study period.
The sponsor or designee should be contacted if the investigator is informed of any restriction 
violations.  The sponsor will decide whether a subject with restriction violations will be 
allowed to continue study participation.
3.9
Discontinuation of investigational product
Subjects may be discontinued from investigational product in the following situations:
∀
Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment
∀
AE
∀
Severe non-compliance with the study protocol, as judged by the investigator(s) or
AstraZeneca


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
26(52)
3.9.1
Procedures for discontinuation of a subject from investigational product
At any time, subjects are free to discontinue investigational product or withdraw from the 
study (i.e., investigational product and assessments – see Section 3.10), without prejudice to 
further treatment.  A subject that decides to discontinue investigational product will always be 
asked about the reason(s) and the presence of any AEs.  If possible, they will be seen and 
assessed by an Investigator(s).  AEs will be followed up (see Section 6); diary cards and all 
study drugs should be returned by the subject. If the patient discontinues the study during the 
treatment period (by Visit 18), the test and evaluations planned at Visit 18 should be 
performed unless the patient refuses the procedure.
If a subject is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
Subjects may be withdrawn from the study in the following situations:
∀
Subject decision.  The subject is at any time free to withdraw from study
∀
AE
∀
Severe non-compliance with the study protocol, as judged by the investigator(s) or
AstraZeneca
∀
Incorrect enrolment of the patient
∀
Patient falls into exclusion criteria, e.g., pregnancy
∀
Death
∀
Patient lost to follow up
3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (i.e., patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (not randomised
patients).
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The Investigators will follow up AEs outside of the clinical study. 
If a subject withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn subjects will not be replaced.
If possible, they will be seen and assessed by investigators.  Unresolved AEs will be followed 
up (see Sections 6.3.2); investigational products should be returned by the subject.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
27(52)
3.11
Discontinuation of the study
AstraZeneca may terminate the entire study prematurely if concerns for safety arise within this 
study or in any other study with AZD0585.
4.
STUDY PLAN AND TIMING OF PROCEDURES


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
28(52)
Table 1
Study Plan
Screening period
Treatment period
With-
drawal 
visit a
Week
-8
-4
-2
0
4
8
10
12
16
20
24
28
32
36
40
44
48
52
Visit
1
2
3
3a b
4 c
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Visit window (days)
±
3
±
3
±
2
0
±
2
±
2
±
2
±
2
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
Informed Consent
X
Eligibility Review
Randomisation
X
Demography
X
Medical History/Surgical
History, Prior Medications
Brief Physical Findings d
X
X
X
X
Clinical Assessments e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Sign
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Lipid Panel (TG, TC, 
LDL-C, HDL-C, non-HDL-C, 
VLDL-C)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting special lipid markers 
(RLP-C, Apo B and Apo B48)
X
X
X
X
X
X
X
Fatty acids profile (EPA, DHA, 
AA, and EPA/AA ratio)
X
X
X
X
X
X
X
Small dense LDL
X
X
X
X
X
X


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
29(52)
Table 1
Study Plan
Screening period
Treatment period
With-
drawal 
visit a
Week
-8
-4
-2
0
4
8
10
12
16
20
24
28
32
36
40
44
48
52
Visit
1
2
3
3a b
4 c
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Visit window (days)
±
3
±
3
±
2
0
±
2
±
2
±
2
±
2
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
Apo except Apo B
(A-I, A-II, C-II, C-III and E)
X
X
X
X
X
X
hs-CRP
X
X
X
X
X
X
Fasting special lipid markers 
(Lp(a), PCSK9)
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
X
X
X
X
X
X
Thromboplastin time (PT), 
Partial thromboplastin time
(PTT)
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
Assessment of renal function 
(Estimated glomerular filtration 
rate [eGFR], Albumin 
Creatinine Ratio [ACR])
X
TSH
X
Urine Pregnancy Test
X
X
X
X


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
30(52)
Table 1
Study Plan
Screening period
Treatment period
With-
drawal 
visit a
Week
-8
-4
-2
0
4
8
10
12
16
20
24
28
32
36
40
44
48
52
Visit
1
2
3
3a b
4 c
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Visit window (days)
±
3
±
3
±
2
0
±
2
±
2
±
2
±
2
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
±
7
ECG
X
X
X
X
X
X
X
Diet Counselling on 
Therapeutic Lifestyle Changes
(TLC) diet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Question Adherence to TLC 
diet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Investigational 
Product
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess Investigational Product 
Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs/SAEs  f
Concomitant and other 
treatments
a
If a patient withdraws before completion of 52 weeks of treatment, withdrawal visit should be carried out to evaluate the patient’s safety.
b
If the investigators decide that an additional test is appropriate, Visit 3a is allowed.  See section 3.1, 2nd inclusion criterion for details.
c
All examinations to be completed before randomisation.
d
Brief physical findings consisting of an evaluation of general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, 
eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including spine and extremities) and neurological systems.
e
Clinical assessments: Subjects will be questioned regarding the occurrence and nature of any symptoms and signs. Weight will be measured at each 
time; however, height will be measured only at Visit 1 to determine the body mass index (BMI).
f
SAEs will be recorded from the time of informed consent (Visit 1), and non-serious AEs will be collected from time of randomisation (Visit 4).


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
31(52)
4.1
Screening period
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening. Investigators will obtain signed informed consent from a potential subject
before starting screening period. Each subject should meet all of the inclusion criteria and 
none of the exclusion criteria for this study.  Under no circumstances can there be exceptions 
to this rule.
Screening period takes 8 weeks. Concomitant medications for hyperlipidemia except for 
statins are not allowed to use.
Subjects will take 3 study visits during screening period (Visit 1, Visit 2 and Visit 3). TG, 
LDL-C and other laboratory data will be measured at each visit, then only the subjects with 
TG and LDL-C values within acceptable ranges of variability will be randomised (see 
Sections 3.1).  In case repeat of Visit 3 test (Visit 3a) is performed between Visit 3 and 4 at 
investigators discretion, eligibility should be re-evaluated with using Visit 3a data (see Section 
3.1).
The following assessments and procedures should be performed during screening period as 
per Table 1.
∀
Demography (date of birth, sex, race and ethnicity)
∀
Medical history/Surgical history and prior medications
∀
Brief physical findings
∀
Clinical assessments (occurrence and nature of any symptoms and signs, body 
weight, height)
∀
Vital signs (BP and pulse)
∀
Clinical Chemistry/Haematology/Urinalysis
∀
ECG
∀
Urine pregnancy test for women of childbearing potential
∀
Diet counselling on TLC diet/Question adherence to TLC diet
∀
AEs must be captured from time of consent.  However, screening period of the 
study only SAEs will be collected.
∀
Concomitant and other treatments
The investigators should adhere to the study plan, procedures and perform tests/observations 
in accordance with the protocol.
4.2
Treatment period
The following assessments and procedures should be performed during treatment period as 
per Table 1.
∀
Brief physical findings


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
32(52)
∀
Clinical assessments (occurrence and nature of any symptoms and signs, body 
weight)
∀
Vital signs (BP and pulse)
∀
Clinical Chemistry/Haematology/Urinalysis
∀
ECG
∀
Urine pregnancy test for women of childbearing potential
∀
Diet counselling on TLC diet/Question adherence to TLC diet
∀
Dispense investigational product
∀
Assess investigational product compliance
∀
AEs
∀
Concomitant and other treatments
The Investigators should adhere to the study plan, procedures and perform tests/observations 
in accordance with the protocol.
4.3
Withdrawal visit
The following assessments and procedures should be performed if subjects withdraw from the 
study before they complete 52 weeks treatment, i.e., Visit 18 (see Table 1).
∀
Brief physical findings
∀
Clinical assessment (occurrence and nature of any symptoms and signs, body 
weight)
∀
Vital signs (BP and pulse)
∀
Clinical Chemistry/Haematology/Urinalysis
∀
Urine pregnancy test for women of childbearing potential
∀
ECG
∀
Question adherence to TLC diet
∀
Assess investigational product compliance
∀
AEs
∀
Concomitant and other treatments
The Investigators should adhere to the study plan, procedures and perform tests/observations 
in accordance with the protocol.
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
33(52)
The investigators will ensure that data are recorded on the Electronic Case Report Form 
(eCRF) as specified in the study protocol and in accordance with the instructions provided.
The PI 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 (CSA). The 
PI will sign the completed eCRF.  A copy of the completed eCRF will be archived at the study 
site.
5.1
Efficacy assessments
Blood samples will be taken at the times indicated in the Study Plan (see Table 1).
The samples are measured by SRL Medisearch Inc. The detailed procedure of sampling, 
handling and shipping is described in the standard operating procedure made by AstraZeneca.
The valuables for efficacy assessment are as follows;
∀
Fasting serum TG
∀
Fasting serum lipid profile: TC, LDL-C*, VLDL-C, HDL-C and non-HDL-C* 
(*direct method)
∀
Apolipoprotein: Apo A-I, Apo A-II, Apo B, Apo B48, Apo C-II, Apo C-III, and Apo
E
∀
Plasma fatty acids profile: EPA, DHA, AA, and EPA/AA ratio
∀
Small dense LDL and LDL-C/Apo B ratio
∀
Lp(a), RLP-C, PCSK9 and hs-CRP
The plasma fatty acids profile (EPA, DHA, AA and EPA/AA ratio) data from Visit 4 or later 
and the serum TG values between Visit 4 and Visit 8 must not be disclosed to Investigators 
and patients until the study closure.
In addition, the plasma fatty acids profile data from Visit 4 or later and the serum TG values 
between Visit 4 and Visit 8 will be kept double-blinded until the interim database lock.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation,
and urinalysis will be taken at the times indicated in the Study Plan (see Table 1).
Blood samples will be measured by SRL Medisearch Inc.
The detailed procedure of sampling, handling and shipping is described in the standard 
operating procedure made by AstraZeneca.  In addition, the PI ensures that samples are 
labelled and shipped in accordance with the Laboratory Manual and the Biological Substance, 
Category B Regulations (materials containing or suspected to contain infectious substances 


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
34(52)
that do not meet Category A criteria), see Appendix C ‘International Airline Transportation 
Association (IATA) 6.2 Guidance Document’.  Any samples identified as Infectious Category 
A materials are not shipped and no further samples will be taken from the subject unless 
agreed with AstraZeneca and appropriate labelling, shipment and containment provisions are 
approved.
Urinalysis will be performed at each study site by dipstick provided by SRL Medisearch Inc.
The following laboratory variables will be measured:
Table 2
Laboratory Safety Variables
Haematology/Haemostasis
Clinical Chemistry
B-Haemoglobin (Hb)
S-Creatinine
B-Leukocyte count
S-Bilirubin, total
B-Leukocyte differential count (absolute count)
S-Alkaline phosphatise (AP)
B-Platelet count
S-AST
B-Haematocrit 
S-ALT
P-PT
S-Albumin
P-PTT
S-Potassium
Urinalysis
S-Calcium, total
U-Hb
S-Sodium
U-Protein/Albumin
S-Creatine kinase (CK)
U-Glucose
S-TSH
U-Pregnancy
B-HbA1c
P-Glcouse
S-LDL-C
S-Apo B
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at site
as source data for laboratory variables.  For information on how AEs based on laboratory tests 
should be recorded and reported, see Section 6.3.
5.2.2
Physical examination
5.2.2.1
Brief Physical Findings
A brief physical findings will be performed and include an assessment of the following: 
general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, 


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
35(52)
eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including spine and 
extremities) and neurological systems.
5.2.2.2
Clinical Assessments
Subjects will be questioned by investigators at every visit regarding the occurrence and nature 
of any symptoms and signs. Body weight will be measured at each time, however, height will 
be measured only at Visit 1 to determine the BMI.
5.2.3
ECG
For timing of assessments refer to the Study Plan (Table 1).
A 12-lead ECG will be performed after patient has been supine at rest for at least 5 minutes.
All ECGs will be evaluated for heart rate, QT interval, ECG interval measured from the onset 
of the QRS complex to the onset of the P wave (PR), ECG interval measured from the onset of 
the QRS complex to the J point (QRS), and the time between corresponding points on 2 
consecutive R waves on ECG (RR) intervals from the 12-lead ECG, and the Investigators will 
judge the overall interpretation as normal or abnormal.  If abnormal, it will be decided as to 
whether or not the abnormality is clinically significant and the reason for the abnormality will 
be recorded. ECG will be measured using the same recording device during this study as 
much as possible.
All ECG readings will be stored as source documents as a paper printout if the data will not be 
able to kept electronically.
5.2.4
Vital signs
BP and pulse will be measured by standard BP recording device using at study site(s) with an 
appropriate cuff size.  BP and pulse will be measured using the same recording device during 
this study as much as possible.
For timings of assessments refer to the Study Plan (Table 1).
5.3
Other assessments (Not Applicable)
5.4
Pharmacokinetics (Not Applicable)
5.5
Pharmacodynamics (Not Applicable)
5.6
Pharmacogenetics (Not Applicable)
5.7
Biomarker analysis (Not Applicable)
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
36(52)
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, ECG).  In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, including screening periods, 
even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A SAE is an AE occurring during any study phase (i.e., screening and treatment), that fulfils 
one or more of the following criteria:
∀
Results in death
∀
Is immediately life-threatening
∀
Requires in-patient hospitalisation or prolongation of existing hospitalisation
∀
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions
∀
Is a congenital abnormality or birth defect
∀
Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs will be collected from randomisation (Visit 4) until Visit 18 (or Visit 19).
SAEs will be recorded from the time of informed consent (Visit 1) until Visit 18 (or Visit 19).
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF.  
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collected for each AE:


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
37(52)
∀
AE (verbatim)
∀
The date when the AE started and stopped
∀
Maximum Intensity
∀
Whether the AE is serious or not
∀
Investgators causality rating against the investigational product (yes or no)
∀
Action taken with regard to investigational product
∀
AE caused subject’s withdrawal from study (yes or no)
∀
Outcome
In addition, the following variables will be collected for SAEs:
∀
Date AE met criteria for serious AE
∀
Date Investgators became aware of serious AE
∀
AE is serious due to
∀
Date of hospitalisation
∀
Date of discharge
∀
Probable cause of death
∀
Date of death
∀
Autopsy performed
∀
Causality assessment in relation to Study procedure(s)
∀
Description of AE
Intensity rating scale:
1.
mild (awareness of sign or symptom, but easily tolerated)
2.
moderate (discomfort sufficient to cause interference with normal activities)
3.
severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The PI will assess causal relationship between investigational product and each AE, and 
answer “yes” or “no” to the question “Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?”


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
38(52)
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: “Have you had any health problems since you were last asked?”, or 
revealed by observation will be collected and recorded in the eCRF.  When collecting AEs, 
the recording of diagnoses are preferred (when possible) to recording a list of signs and 
symptoms.  However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests, vital signs, ECGs and other safety 
assessments will be summarised in the clinical study report.  Deterioration as compared to 
baseline in protocol-mandated laboratory values, vital signs, ECGs and other safety 
assessments should therefore only be reported as AEs if they fulfil any of the SAE criteria or 
are the reason for discontinuation of treatment with the investigational product.
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result 
or vital sign will be considered as additional information.  Wherever possible the reporting 
investigator uses the clinical, rather than the laboratory term (e.g., anaemia versus low Hb 
value).  In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives promptly, or no later than 24 hours of when he or 
she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca patient safety data entry site within one 
calendar day of initial receipt for fatal and life threatening events and within five calendar 
days of initial receipt for all other SAEs.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
39(52)
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 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
promptly, or no later than 24 hours of when he or she becomes aware of it.
Once the investigator or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site personnel how to 
proceed.
6.5
Overdose
There are no human data on overdosing and no known antidote.
It will be considered the taking investigational product that is ≥ 5 capsules per day to be the 
overdose.
∀
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
∀
An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must be provided to the AstraZeneca Patient Safety data entry 
site within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
40(52)
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives promptly, or no later than 24 hours of 
when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
6.6.2
Paternal exposure
There are no restrictions against fathering a child when treated with AZD0585.
If paternal exposure pregnancy occurs in the course of the study, then investigators or other 
centre personnel should inform appropriate AstraZeneca representatives within 24 hours as 
described in the maternal exposure Section 6.6.1.
6.7
Management of investigational product related toxicities (Not 
Applicable)
6.8
Study governance and oversight
6.8.1
Steering Committee
A Steering Committee will be set up in this clinical study.  The Steering Committee charter 
will be prepared to detail responsibilities.  The Steering Committee constitutions are presented 
in Supplement A.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
41(52)
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Table 3
Identity of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
AZD0585 capsule
1 g soft gelatine capsules
Catalent Germany Eberbach GmbH
(encapsulation)
Catalent Germany Schondorf GmbH
(capsule coating / bulk packing)
AZD0585 capsule 
placebo
1 g soft gelatine capsules
(corn oil)
Catalent Germany Eberbach GmbH
(encapsulation)
Catalent Germany Schondorf GmbH
(capsule coating / bulk packing)
7.2
Dose and treatment regimens
Patients start treatment of AZD0585 administration at Visit 4 (Randomisation).
Eligible patients will be randomly assigned to 1 of 3 treatment groups: AZD0585 2 g with 
placebo (corn oil) 2 g once daily, or AZD0585 4 g once daily, or placebo (corn oil) 4 g once 
daily. The capsules of AZD0585 and placebo are identical in appearance of 1 g soft gelatine
capsules, and all patients will need to take 4 capsules once daily just after breakfast.
7.3
Labelling
Labels will be prepared in accordance with Good Clinical Practice (GCP) Ordinance.  Details 
are specified in the document “explaining the reconstitution procedures and other handling 
procedures for the investigational products”.
7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  
A description of the appropriate storage conditions is specified in the document “explaining 
the reconstitution procedures and other handling procedures for the investigational products”.
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
42(52)
The investigator(s) will check drug accountability.  If the patient’s compliance rate is low due 
to missing doses, etc, the investigator(s) will instruct the patient to comply with the treatment.
7.6
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
Study drug will not be distributed to the study site until the contract is concluded between the 
study site and AstraZeneca. The Investigational Product Storage Manager is responsible for 
managing the study drug from receipt by the study site until the return of all unused study 
drug to AstraZeneca.  AstraZeneca will provide the study documents ‘Procedures for drug 
accountability’ and ‘explaining the reconstitution procedures and other handling procedures 
for the investigational products’ which describes the specific requirements.  The 
Investigator(s) is responsible for ensuring that the subject has returned all unused study drug.
7.7
Concomitant and other treatments
Concomitant use of following medications or therapies is not allowed during study period.
∀
Fibrates, bile acid sequestrants, or niacin or its analogues (greater than 200 mg/day)
or any drug for the purpose of lowering plasma cholesterol (except for statin) from 
the screening to Visit 8.
∀
Any EPA or DHA products, fish oil, or medications (e.g., Lotriga®, Epadel®) or 
investigational drugs (e.g., AMR101) containing EPA or DHA during study period.
∀
Any supplement for the purpose of lowering plasma cholesterol (e.g., red rice yeast 
supplements) from the screening to Visit 8.
∀
Weight loss drugs (including OTC preparations) or programs during study period.
∀
Ketoconazole, erythromycin, clarithromycin, cyclosporine, itraconazole, or protease 
inhibitors during study period only for statin users.
∀
Any anticoagulants (e.g., warfarin, coumarin, heparin, Prazaxa® or enoxaparin)
during study period.
∀
Oral or injected corticosteroids (other than intranasal or inhaled steroids used for 
allergies/asthma) during study period.
∀
Grapefruit juice >750 mL/day during study period only for statin users.
∀
Insulin during study period.
Concomitant use of tamoxifen, estrogens, progestins, and testosterone are allowed during 
study period without change of the dose regimen, if the treatment of those drugs is stable 
during screening.
Fixed dose statin can be used until Visit 8. No limit is set to use statin after Visit 8.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
43(52)
7.8
Post Study Access to Study Treatment (Not Applicable)
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
∀
All personnel involved with the analysis of the study will remain blinded until 
database lock and protocol violators identified.
∀
Analyses will be performed by AstraZeneca or its representatives.
8.2
Sample size estimate
A common standard deviation of 24% is assumed for primary efficacy variable (percent 
change from baseline to Week 12 Endpoint in serum TG). One hundred and fifty patients in 
both of AZD0585 2 g and AZD0585 4 g and 75 patients in placebo will ensure the power for 
detecting 12.5% difference of AZD0585 each dose vs. placebo to be at least 92%, based on t-
test with two-sided significance level of 0.05/2= 0.025.
In the above calculation, it was assumed that a total of 375 patients are to be randomised to 
placebo, AZD0585 2 g, AZD0585 4 g with ratio of 1:2:2 and that proportion of randomised
patients not contributing primary analysis at Week 12 Endpoint is negligible.
In addition, the above sample size is expected to be sufficient to provide long term safety data 
of more than 100 Japanese patients treated by AZD0585 2 g or by AZD0585 4 g for 1 year.
8.3
Definitions of analysis sets
Randomised set: all patients who received randomisation number.
8.3.1
Efficacy analysis set
Full Analysis Set (FAS): all randomised set who had both any baseline and any post-baseline 
efficacy measurements.  Patients will be analyzed according to their randomised treatment.  
FAS will be considered primary analysis set used for all efficacy evaluation.
Per Protocol Set (PPS): all patients in FAS who completed the first 12-week treatment period 
without any significant protocol deviations affecting primary efficacy evaluations.  All criteria 
to exclude patients from the PPS will be made prior to the unblinding of the study. Patients 
will be analyzed according to their randomised treatment.  Analyses on PPS will be of 
supportive purpose and limited to primary and important secondary efficacy variables.
8.3.2
Safety analysis set
Safety set: all patients who took at least on dose of double-blind study medication. Patients 
will be analyzed according to actual medication received.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
44(52)
8.4
Outcome measures for analyses
8.4.1
Primary efficacy variable 
Primary efficacy variable is percent change from baseline to the Week 12 Endpoint in serum 
TG.
8.4.2
Secondary efficacy variables
∀
Percent change from baseline to the Week 12 Endpoint in TC
∀
Percent change from baseline to the Week 12 Endpoint in HDL-C
∀
Percent change from baseline to the Week 12 Endpoint in non-HDL-C
∀
Percent change from baseline to the Week 12 Endpoint in LDL-C
∀
Percent change from baseline to the Week 12 Endpoint in VLDL-C
∀
Percent change from baseline to Week 12 in Apo A-I
∀
Percent change from baseline to Week 12 in Apo A-II
∀
Percent change from baseline to Week 12 in Apo B
∀
Percent change from baseline to Week 12 in Apo B48
∀
Percent change from baseline to Week 12 in Apo C-II
∀
Percent change from baseline to Week 12 in Apo C-III
∀
Percent change from baseline to Week 12 in Apo E
∀
Percent change from baseline to Week 12 in EPA
∀
Percent change from baseline to Week 12 in DHA
∀
Percent change from baseline to Week 12 in AA
∀
Percent change from baseline to Week 12 in EPA/AA ratio
∀
Percent change from baseline to Week 12 in Small dense LDL
∀
Percent change from baseline to Week 12 in LDL-C/Apo B ratio
∀
Percent change from baseline to Week 12 in Lp(a)
∀
Percent change from baseline to Week 12 in RLP-C
∀
Percent change from baseline to Week 12 in PCSK9
∀
Percent change from baseline to Week 12 in hs-CRP
8.5
Methods for statistical analyses
8.5.1
Analysis of the primary variable (s)
Primary analyses will be carried out by analysis of covariance (ANCOVA) model including 
percent change from baseline in TG at Week 12 Endpoint as a response variable, treatment 
and baseline statin use as factors and baseline TG as a covariate. The primary analysis will be 
carried out on FAS.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
45(52)
Least square means and 95%CI for each treatment as well as treatment difference to placebo 
will be provided from the model. P-values will be provided for comparison of AZD0585 each 
dose vs. placebo.
As a sensitivity analysis, log-transformed TG at Week 12 Endpoint will also be analyzed by 
ANCOVA model including treatment and baseline statin use as factors and log-transformed 
baseline TG as a covariate.  Least square means and 95%CI for treatment difference to 
placebo will be back transformed and presented as relative treatment difference to placebo in 
percent change from baseline of TG.
Definition of Endpoint and baseline & missing values
Baseline is defined as average of Week -4, -2 and 0.
Week 12 Endpoint is defined as an average of measurements Week 10 and Week 12. 
If patients drop out before Week 12, average of the last two consecutive post-treatment values 
will be used for Week 12 Endpoint evaluation. If only one post-baseline measurement is 
available, it will be employed for Endpoint evaluation.  Data obtained after Week 12 visit will 
not be used for evaluation of Week 12 Endpoint. 
It is assumed that most patients will complete 12-week treatment without major deviations and 
the above approach would provide approximately unbiased estimates for treatment effects. 
However, further sensitivity checks may be planned and documented in Statistical Analysis 
Plan.
Confirmatory Hypothesis Family & Multiplicity
The primary objective of this study is to demonstrate the efficacy of AZD0585 2 g and 4 g 
when compared with placebo using the percent change from baseline in TG to Week 12 as a 
primary efficacy variable. In order to protect family wise error rate to be 5%, superiority of 
AZD0585 2 g vs. placebo and superiority of AZD0585 4 g vs. placebo will be tested based on 
Hochberg procedure using two-sided significance level of 0.05. If a p-value for each 
hypothesis is less than 0.05/2 = 0.025, the corresponding hypothesis claimed to be 
demonstrated. If both p-values are less than 0.05, then the both hypotheses are claimed to be 
demonstrated.
All analyses other than analysis of the primary efficacy endpoint will be interpreted 
descriptively. Consequently, no adjustments for multiplicity will be necessary for such 
analyses. Ninety-five percent confidence intervals will be calculated, where appropriate, as 
measures of study precision. P-values may be calculated but are to be regarded as descriptive.
8.5.2
Analysis of the secondary variable(s)
8.5.2.1
Efficacy variables
Percent change from baseline to the Week 12 Endpoint in TC, HDL-C, LDL-C, VLDL-C 
and non-HDL-C


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
46(52)
Analyses will be carried out by ANCOVA model including percent change from baseline at 
Week 12 Endpoint as a response variable, treatment and baseline statin use and baseline TG 
strata (<300, ≥300 mg/dL) as factors, and the corresponding baseline values as a covariate.
Percent change from baseline to Week 12 in Apo A-I, Apo A-II, Apo B, Apo B48, Apo
C-II, Apo C-III, Apo E
Percent change from baseline to Week 12 in EPA, DHA, AA, EPA/AA ratio
Percent change from baseline to Week 12 in Small dense LDL, LDL-C/Apo B ratio
Percent change from baseline to Week 12 in Lp(a), RLP-C, PCSK9, hs-CRP
Analyses will be carried out by ANCOVA model including percent change from baseline at 
Week 12 as a response variable, treatment and baseline statin use and baseline TG strata 
(<300, ≥300 mg/dL) as factors, and the corresponding baseline values as a covariate.
8.5.2.2
Safety variables 
Safety for AZD0585 2 g and 4 g will be mainly evaluated via AEs, brief physical 
findings/clinical assessments, laboratory measurements, vital signs and ECGs.
The analysis of safety was based on the safety analysis set. Safety data obtained during the
treatment period were evaluated descriptively by treatment group. No formal statistical 
hypothesis testing will be performed. Details will be specified in Statistical Analysis Plan.
8.5.3
Subgroup analysis
Subgroup analyses for primary efficacy variable and selected secondary variables will be 
carried out to explore internal consistency.  Descriptive summary would be provided by 
gender, by age (<65, ≥65 years), by concurrent statin use at baseline, by baseline TG level 
(<300, ≥300 mg/dL) and by other clinically relevant factors if appropriate.
8.5.4
Interim analysis
An interim analysis will include all patients’ data available until data cut-off, including 
primary/secondary analysis at Week 12 Endpoint for efficacy as well as safety evaluation 
based on 24-week or longer exposure to study drug.  Sponsor will be unblinded at the time of 
interim analysis but investigators, patients and site-staff will not be informed of assigned 
treatment in order to maintain integrity as much as possible.  Data cut off date is defined as a 
day when 24 weeks have passed after Last Subject In (LSI).  This interim analysis will be 
documented as an interim clinical study report.
8.5.5
Sensitivity analysis
Primary analysis will be repeated for PPS.  Also, several exploratory analyses based on 
different missing handling may be carried out for the purpose of sensitivity check. Details 
will be specified in Statistical Analysis Plan.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
47(52)
8.5.6
Exploratory analysis
For efficacy and pharmacodynamic parameters, baseline and post-baseline measurements up
to Week 52 will be summarized by treatment group. In addition, percent change from 
baseline to Week 52 Endpoint will also be presented.  Week 52 Endpoint will be defined as 
last non-missing measurement after start of treatment.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC
system(s) utilised.
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved.
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
∀
Provide information and support to the Investigator(s)
∀
Confirm that facilities remain acceptable
∀
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that 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 original records for each subject (e.g., 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 AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the site needs information and advice about the study conduct.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
48(52)
9.2.1
Source data
Source data are any data generated as a result of the subject’s inclusion in the study (including 
run-in and/or follow up related to the study) and includes all related medical examinations and 
other records. Original data recorded on the eCRFs and regarded as source data are listed in 
the CSA.
9.2.2
Study agreements
The PI at each/the site should comply with all the terms, conditions, and obligations of the 
CSA, or equivalent, for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to 
the conduct of the study and the treatment of subjects and in all other respects, not relating to 
study conduct or treatment of subjects, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or subjects are enrolled.
9.2.3
Archiving of study documents
The PI follows the principles outlined in the CSA.
9.3
Study timetable and end of study
Planned duration of the study:
Study period: June 2015 - May 2017
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with AZD0585.
9.4
Data management
Data management will be performed by Cognizant Technology Solution and AstraZeneca
Data Management Centre staff according to the Data Management Plan.
The data collected through third party sources will be obtained and reconciled against study 
data.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the International Conference on Harmonisation (ICH) Medical Dictionary for 
Regulatory Affairs (MedDRA).  Medications will be classified according to the AstraZeneca 
Drug Dictionary.  Classification coding will be performed by the Medical Coding Team of 
Cognizant Technology Solution.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
49(52)
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
SAE Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
Data Management of genotype data
N/A
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
Management of external data
Data Management determines the format of the data to be received from external vendors and 
coordinates the flow of data to the clinical database.  Data Management will assure that the 
data collection tools (e.g., IVRS/IWRS, etc) are tested and validated. External data 
reconciliation will be done with the clinical database as defined in the Data Management plan.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with GCP, applicable regulatory requirements and 
the AstraZeneca policy on Bioethics and Human Biological Samples.
10.2
Subject data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
50(52)
10.3
Ethics and regulatory review
An IRB should 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 head of the study site will ensure the distribution of these documents to the 
applicable IRB, and the PI to the Investigators and study site staff.
The opinion of the IRB should be given in writing. The head of the study site should submit a 
notification of direction/determination as well as the IRB written approval to AstraZeneca and 
the PI before enrolment of any subject should into the study.
The IRB should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds one year. The PI should submit progress reports to the IRB via the head 
of the study site at the time of the protocol re-approval.
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority with notification 
provided, according to local regulations.  AstraZeneca will handle the distribution of any of 
these documents to the national regulatory authorities.
AstraZeneca will provide Regulatory Authorities, IRB, the head of the study site and the PI
with safety updates/reports according to local requirements.
The head of the study site should submit a written report to the IRB providing the details of all 
safety relative information reported by AstraZeneca.
10.4
Informed consent
The PI at each site will:
∀
Ensure each subject is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study
∀
Ensure each subject is notified that they are free to discontinue from the study at 
any time
∀
Ensure that each subject is given the opportunity to ask questions and allowed time 
to consider the information provided
∀
Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study
∀
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
51(52)
∀
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 Ethics Committee.
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the PI and 
AstraZeneca.  If it is necessary for the study protocol to be amended, the amendment should 
be submitted to the Head of the Study Site and be approved by its IRB.  If applicable, 
AstraZeneca should submit a notification to the regulatory authority before it is implemented.  
If a protocol amendment requires a change to a particular site’s Informed Consent Form, then 
AstraZeneca and the site's IRB should be notified by the PI.  Approval of the revised Informed 
Consent Form by AstraZeneca and by the IRB is required before the revised form is used.  If 
an administrative change is required, such a change should be notified to or approved by each 
IRB according to local requirements.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the site, including source data verification.  The purpose 
of an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analysed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements.  The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the site.
11.
LIST OF REFERENCES
Beckermann et al 1990
Beckermann B, Beneke M, Seitz I. Comparative bioavailability of eicosapentaenoic acid and 
docasahexaenoic acid from triglycerides, free fatty acids and ethyl esters in volunteers. 
Arzneimittelforschung 1990;40:700-4.
El Boustani et al 1987
El Boustani S, Colette C, Monnier L, Descomps B, Crastes de Paulet A, Mendy F. Enteral 
absorption in man of eicosapentaenoic acid in different chemical forms. Lipids 1987;22:711-4.
FDA 1997
FDA 1997. Substances Affirmed as Generally Recognized as Safe: Menhaden Oil (Final rule). 
Fed Reg (U.S.) 62(108):30751-30751-7


Clinical Study Protocol
Drug Substance AZD0585
Study Code D5884C00002
Edition Number 1
Date 3 April 2015
52(52)
Hansen et al 1998
Hansen JB, Grimsgaard S, Nilsen H, Nordøy A, Bønaa KH. Effects of highly purified 
eicosapentaenoic acid and docosahexaenoic acid on fatty acid absorption, incorporation into 
serum phospholipids and postprandial triglyceridemia. Lipids 1998;33:131-8.
Hazra et al 1999
Hazra A, Tripathi SK, Ghosh A. Pharmacology and therapeutic potential of the n3 
polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in 
fish oils. Indian J Pharmacol 1999;31:247-64.
Ikeda et al 1995
Ikeda I, Sasaki E, Yasunami H, Nomiyama S, Nakayama M, Sugano M, et al. Digestion and 
lymphatic transport of eicosapentaenoic and docosahexaenoic acids given in the form of 
triacylglycerol, free acid and ethyl ester in rats. Biochim Biophys Acta 1995;1259:297-304.
Lawson and Hughes 1988a
Lawson LD, Hughes BG. Human absorption of fish oil fatty acids as triacylglycerols, free 
acids, or ethyl esters. Biochem Biophys Res Commun 1988;152:328-35.
Lawson and Hughes 1988b
Lawson LD, Hughes BG. Absorption of eicosapentaenoic acid and docosahexaenoic acid from 
fish oil triacylglycerols or fish oil ethyl esters coingested with a high-fat meal. Biochem 
Biophys Res Commun 1988;156:960-3.
Lichtenstein et al 1993
Lichtenstein AH, Ausman LM, Carrasco W, Jenner JL, Gualtieri LJ, Goldin BR, et al. Effects 
of canola, corn, and olive oils on fasting and postprandial plasma lipoproteins in humans as 
part of a National Cholesterol Education Program Step 2 diet. Arterioscler Thromb. 1993 Oct;
13(10):1533-42.
NCEP 2002
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and 
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of 
the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, 
and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. 
Circulation 2002;106:3143-421.
Sirtori et al 1986
Sirtori CR, Tremoli E, Gatti E, Montanari G, Sirtori M, Colli S, et al. Controlled evaluation of 
fat intake in the Mediterranean diet: comparative activities of olive oil and corn oil on plasma 
lipids and platelets in high-risk patients. Am J Clin Nutr. 1986 Nov; 44(5):635-42.
Small 1991
Small, DM. The effects of glyceride structure on absorption and metabolism. Annu Rev Nutr 
1991;11:413-34.























SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D5884C00002
Edition Number
2.0
Date
19 September 2016
A Randomised, Double-blind, Placebo controlled, Parallel Group, Phase III 
Long-term Study to Evaluate Efficacy and Safety of 12 Weeks and 52 
Weeks of AZD0585 Administration, Respectively, in Patients with 
Hyperlipidemia Accompanied by Hypertriglyceridemia (TG in the Range 
150-499 mg/dL)






Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
4
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
SIGNATURE OF STUDY STATISTICIAN ..........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN....................................3
TABLE OF CONTENTS.........................................................................................4
LIST OF ABBREVIATIONS..................................................................................6
AMENDMENT HISTORY .....................................................................................8
1.
STUDY DETAILS...................................................................................................9
1.1
Study objectives.......................................................................................................9
1.1.1
Primary objectives ...................................................................................................9
1.1.2
Secondary objectives ...............................................................................................9
1.1.3
Exploratory objectives ...........................................................................................10
1.2
Study design...........................................................................................................10
1.3
Number of subjects ................................................................................................11
2.
ANALYSIS SETS .................................................................................................12
2.1
Definition of analysis sets......................................................................................12
2.2
Violations and deviations.......................................................................................12
3.
ANALYSIS VARIABLES ....................................................................................13
3.1
Primary Efficacy variable ......................................................................................13
3.2
Secondary efficacy variables .................................................................................13
3.2.1
Fasting lipids..........................................................................................................13
3.2.2
Secondary variables other than fasting lipids ........................................................13
3.3
Exploratory efficacy variables ...............................................................................14
3.4
Primary Safety variables........................................................................................14
4.
ANALYSIS METHODS .......................................................................................15
4.1
General principles ..................................................................................................15
4.1.1
Objectives and hypotheses.....................................................................................15
4.1.1.1
Primary Efficacy Objective....................................................................................15
4.1.1.2
Primary Safety Objective.......................................................................................15
4.1.2
Definitions..............................................................................................................15
4.1.2.1
Baseline..................................................................................................................15
4.1.2.2
Endpoints ...............................................................................................................16
4.1.2.3
Percent change from baseline and change from baseline ......................................16


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
5
4.1.2.4
Study Day...............................................................................................................16
4.1.2.5
Visit windows and Unscheduled/Discontinuation visits........................................17
4.2
Analysis methods...................................................................................................17
4.2.1
Study population ....................................................................................................17
4.2.1.1
Disposition .............................................................................................................17
4.2.1.2
Demographic and other baseline characteristics....................................................17
4.2.1.3
Medical/surgical histories and current medical conditions....................................17
4.2.2
Efficacy..................................................................................................................17
4.2.2.1
Analysis of primary efficacy variable....................................................................17
4.2.2.2
Analysis of secondary efficacy variables...............................................................20
4.2.2.3
Analysis of exploratory efficacy variables ............................................................20
4.2.3
Safety .....................................................................................................................21
4.2.3.1
Extent of exposure .................................................................................................21
4.2.3.2
Adverse events.......................................................................................................22
4.2.3.3
Safety Laboratory evaluation.................................................................................22
4.2.3.4
Vital signs ..............................................................................................................23
4.2.3.5
Physical examination .............................................................................................23
4.2.3.6
Electrocardiograms ................................................................................................23
5.
INTERIM ANALYSES.........................................................................................24
6.
CHANGES OF ANALYSIS FROM PROTOCOL ...............................................24
7.
REFERENCES (NOT APPLICABLE) .................................................................24
8.
APPENDIX (NOT APPLICABLE).......................................................................24
LIST OF TABLES
Table 1
List of important protocol deviations .......................................................12
Table 2
Transformation of quantities from log-transformed analysis...................18
Table 3
Subgroup analyses of primary efficacy variable ......................................19
Table 4
Liver enzyme abnormalities .....................................................................23
Table 5
Categorical evaluation of QTcF ...............................................................24
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................11


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
6
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AA
Arachidonic acid
AE
Adverse Event
ALP
Alkaline phosphatise
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
Apo
Apo-lipoprotein
AST
Aspirate transferase
AT
Aminotransferase; short for ALT or AST
BMI
Body Mass Index 
CI
Confidence Interval
DAE
AE leading to Discontinuation
DHA
Docosahexaenoic Acid
ECG
Electrodiagram
EPA
Eicosapentaenoic Acid
FAS
Full Analysis Set
HDL-C
High-density lipoprotein cholesterol
hs-CRP
High-sensitivity C-reactive protein
LDL-C
Low-density lipoprotein cholesterol
Lp(a)
Lipoprotein(a)
LS
Least squares
MAR
Missing At Random
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multipile imputation
MMRM
Mixed model with repeated measures
OC
Observed Case
PCSK9
Proprotein convertase subtilisin/kexin type 9
PD
Protocol Deviation
PT
Preferred Term
QTcF
QT interval corrected by Fridericia Formula (
3
/
QT
RR
!
)


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
7
Abbreviation or 
special term
Explanation
RLP-C
Remnant lipoprotein cholesterol
SAE
Serious Adverse Event
SMQ
Standard MedDRA Query
SOC
System Organ Class
TBIL
Total bilirubin
TC
Total cholesterol
TG
Triglyceride
ULN
Upper limits of normal
VLDL-C
Very-low-density lipoprotein cholesterol


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
8
AMENDMENT HISTORY
Date
Brief description of change
19Sep2016
Concomitant medications: summary of all prior/concomitant medications are 
changed to summary of all prior/concomitant medications excluding lipid 
lowering medications.
Adverse events: the following two summaries are now taken out based on 
consideration of relevance for study report. 
-
Most common AEs (i.e., reported by ≥ 2 % of subjects in any treatment 
group based on Preferred Terms)
-
AEs by treatment period ( by Day 1-84, Day 85-168, Day 169-252, Day 
253-336, Day 337- end of study )


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
9
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objectives
Primary Objective:
Outcome Measure:
To demonstrate the short-term (up to 12 weeks)
efficacy of AZD0585 2 g and 4 g compared to 
Placebo (corn oil) in Japanese patients with 
hyperlipidemia accompanied by 
hypertriglyceridemia (TG in the range 150-
499 mg/dL)
Placebo-corrected percent change in serum TG level 
from baseline to Week 12 Endpoint.
To evaluate the long-term (up to 52 weeks) safety 
of AZD0585 administration in patients with 
hyperlipidemia accompanied by 
hypertriglyceridemia (TG in the range 150-
499 mg/dL)
Adverse events, brief physical findings/clinical 
assessments, ECG assessments, vital signs and
laboratory evaluations.
1.1.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To assess the effect of each dose of AZD0585 on 
fasting serum lipid profile
Percent change in each serum lipid level from 
baseline to Week 12 Endpoint in serum lipid profile 
including total cholesterol (TC), LDL-C, VLDL-C, 
HDL-C and non-HDL-C.
To assess the effects of each dose of AZD0585 in 
parameters shown as outcome measure for the 
objective
∀
Apolipoprotein (Apo) A-I, Apo A-II, Apo B, Apo
B48, Apo C-II, Apo C-III, and Apo E based on 
percent changes from baseline to Week 12.
∀
Plasma fatty acids profile: EPA, DHA, AA and 
EPA/AA ratio up to Week 12.
∀
Small dense LDL and LDL-C/Apo B ratio based 
on percent changes from baseline to Week 12.
∀
Lp(a), RLP-C, PCSK9 and hs-CRP up to Week 
12.


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
10
1.1.3
Exploratory objectives
Exploratory Objective:
Outcome Measure :
To assess the time-course of efficacy-related 
parameters profile up to Week 52 and explore the 
efficacy characteristics of long-term use of 
AZD0585 2 g/4 g vs. Placebo.
∀
Fasting serum lipid profile including TG, TC, 
LDL-C, VLDL-C, HDL-C and non-HDL-C.
∀
Apo A-I, Apo A-II, Apo B, Apo B48, Apo C-II, 
Apo C-III, and Apo E.
∀
Plasma fatty acids profile: EPA, DHA, AA, and 
EPA/AA ratio.
∀
Small dense LDL and LDL-C/Apo B ratio.
∀
Lp(a), RLP-C, PCSK9 and hs-CRP.
1.2
Study design
This is a randomised, double-blinded, placebo controlled, study employing 3 arm parallel 
groups to evaluate efficacy of 12 weeks and safety of 52 weeks of AZD0585 administration in 
patients with hyperlipidemia accompanied by hypertriglyceridemia (TG in the range 150-
499 mg/dL).
Total 375 subjects will be randomised to 3 cohorts, A) Placebo, B) AZD0585 2 g, and C) 
AZD0585 4 g, at a ratio of 1:2:2, respectively.  The efficacy will be evaluated as placebo-
corrected percent change TG reduction at 12 weeks from the baseline TG level.  The safety 
will be evaluated as adverse events and other safety parameters (vital sign, clinical laboratory 
test, etc) during 52-week treatment period.
A.
Placebo (corn oil) 4 g once daily (n=75)
B.
AZD0585 2 g (+placebo 2g) once daily (n=150)
C.
AZD0585 4 g once daily (n=150)
Randomisation will be stratified by the following factors to ensure equal representation across 
all treatment groups;
∀
Current use of statin (yes vs. no) at baseline
∀
Baseline TG level <300 or ≥300 mg/dL
In addition to the stratified randomisation the recruitment of patients will monitored so that 
approximately 50% of total randomised patients are statin users.




Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
12
1 year assuming 10-15% drop out rate during 52-week treatment period, in accordance with 
Japan regulatory requirement.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Randomised set: all patients who received randomisation number.
Full Analysis Set (FAS): all randomised set who had both any baseline and any post-baseline 
efficacy measurements.  Patients will be analyzed according to their randomised treatment.  
FAS will be considered primary analysis set used for all efficacy evaluation.
Per Protocol Set (PPS): all patients in FAS who completed the first 12-week treatment period 
without any significant protocol deviations affecting primary efficacy evaluations.  All criteria 
to exclude patients from the PPS will be made prior to the unblinding of the study. Patients 
will be analyzed according to their randomised treatment. Analyses on PPS will be of 
supportive purpose and limited to primary and important efficacy variables. Per Protocol Set 
will be subset of FAS, typically including patients without any important protocol deviations 
listed in Table 1. 
Safety Analysis set (SAF): all patients who took at least on dose of double-blind study 
medication.  Patients will be analyzed according to the actual study medication received. If a 
patient has received different study medications, the study physician and the clinical team will 
determine treatment group on a case-by-case basis, prior to unblinding.
2.2
Violations and deviations
Protocol deviations will be reviewed in a blinded fashion by the study team prior to database 
lock. The important protocol deviations which lead to exclusion from Per-protocol analysis
are listed in the Table 1. All decisions to exclude subjects and/or data from the Full Analysis 
Set to form the Per-Protocol Analysis Set will be agreed by the study team and documented
prior to the unblinding of the study. 
Table 1
List of important protocol deviations
#
Protocol deviations
1
Discontinued study before attending 12-week visit
2
Subjects who took wrong study medication during initial 12-week treatment period  
3
Subjects who were not compliance to study drug ( <  80% or  >  120%) during the initial 12-
week treatment period
4
Subjects  who changed the dose/regimen of statin during the initial 12-week treatment 
period 


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
13
#
Protocol deviations
5
Subjects who newly introduced additional lipid lowering drugs/supplements during the 
initial 12-week treatment period
3.
ANALYSIS VARIABLES
3.1
Primary Efficacy variable
Primary efficacy variable is percent change from baseline to the Week 12 Endpoint in serum 
triglyceride (TG).
3.2
Secondary efficacy variables
Secondary efficacy variables are listed below. 
3.2.1
Fasting lipids
∀
Percent change from baseline to the Week 12 Endpoint in total cholesterol (TC)
∀
Percent change from baseline to the Week 12 Endpoint in high-density lipoprotein-
cholesterol (HDL-C)
∀
Percent change from baseline to the Week 12 Endpoint in non- high-density 
lipoprotein-cholesterol (non-HDL-C)
∀
Percent change from baseline to the Week 12 Endpoint in very-low-density 
lipoprotein-cholesterol (VLDL-C)
∀
Percent change from baseline to the Week 12 Endpoint in low-density lipoprotein-
cholesterol (LDL-C)
3.2.2
Secondary variables other than fasting lipids
∀
Percent change from baseline to Week 12 in Apo-lipoprotein A-I (Apo A-I)
∀
Percent change from baseline to Week 12 in Apo-lipoprotein A-II (Apo A-II)
∀
Percent change from baseline to Week 12 in Apo-lipoprotein B (Apo B)
∀
Percent change from baseline to Week 12 in Apo-lipoprotein B48 (Apo B48)
∀
Percent change from baseline to Week 12 in Apo-lipoprotein C-II (Apo C-II)
∀
Percent change from baseline to Week 12 in Apo-lipoprotein C-III(Apo C-III)
∀
Percent change from baseline to Week 12 in Apo-lipoprotein E (Apo E)
∀
Percent change from baseline to Week 12 in Eicosapentaenoic Acid (EPA)
∀
Percent change from baseline to Week 12 in Docosahexaenoic Acid (DHA)
∀
Percent change from baseline to Week 12 in Arachidonic acid (AA)
∀
Percent change from baseline to Week 12 in EPA/AA ratio


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
14
∀
Percent change from baseline to Week 12 in Small dense LDL
∀
Percent change from baseline to Week 12 in LDL-C/Apo B ratio
∀
Percent change from baseline to Week 12 in Lipoprotein(a) (Lp(a))
∀
Percent change from baseline to Week 12 in Remnant Lipoprotein Cholesterol 
(RLP-C)
∀
Percent change from baseline to Week 12 in Proprotein convertase subtilisin/kexin
type 9 (PCSK9)
∀
Percent change from baseline to Week 12 in High-sensitivity C-reactive protein (hs-
CRP)
3.3
Exploratory efficacy variables
Exploratory efficacy variables are time course from baseline to Week 52 of following 
variables. 
∀
Fasting serum lipid profile including TG, TC, LDL-C, VLDL-C, HDL-C and non-
HDL-C
∀
Apo A-I, Apo A-II, Apo B, Apo B48, Apo C-II, Apo C-III, and Apo E
∀
Plasma fatty acids profile: EPA, DHA, AA, and EPA/AA ratio
∀
Small dense LDL and LDL-C/Apo B ratio
∀
Lp(a), RLP-C, PCSK9 and hs-CRP
3.4
Primary Safety variables
Safety of AZD0585 2g/4g treatment will be analyzed when administered for up to 52 weeks. 
The safety evaluations will include analyses of:
∀
Adverse events
∀
(Safety) Laboratory parameters
∀
Electrodiagram (ECG)
∀
Vital signs
∀
Physical examination and findings


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
15
4.
ANALYSIS METHODS
4.1
General principles
4.1.1
Objectives and hypotheses
4.1.1.1
Primary Efficacy Objective
The primary efficacy objective of this study is to demonstrate the efficacy of AZD0585 2 g
and 4 g when compared with Placebo using the percent change from baseline in TG to Week 
12 Endpoint as a primary efficacy variable.  
The null hypothesis H01, H02  given below will be tested against the alternative hypothesis HA1 , 
HA2.
H01:
μE2 - μP = 0,
H02:
μE4 - μP = 0  
HA1: 
μE2 - μP ≠ 0,
HA2: 
μE4 - μP ≠ 0
where μE2, μE4, μp denote true means of AZD0585 2g, AZD0585 4g, Placebo respectively.   
In order to protect family wise error rate (FWER) to be 5%, superiority of AZD0585 2 g vs. 
Placebo and superiority of AZD0585 4 g vs. Placebo will be tested based on Hochberg 
procedure using two-sided significance level of 0.05. If a p-value for each hypothesis is less 
than 0.05/2 = 0.025, the corresponding hypothesis claimed to be demonstrated. If both p-
values (for 2g and 4g dose groups) are less than 0.05, then the both hypotheses are claimed to 
be demonstrated.
All analyses other than analysis of the primary efficacy endpoint will be interpreted 
descriptively. Consequently, no adjustments for multiplicity will be necessary for such 
analyses. Ninety-five percent confidence intervals will be calculated, where appropriate, as 
measures of study precision. P-values may be calculated but are to be regarded as descriptive.
4.1.1.2
Primary Safety Objective 
The other primary objective is to evaluate the safety of long-term (up to 52 weeks) treatment 
by AZD0585 2g and AZD0585 4g. No formal statistical hypothesis test will be carried out for 
this safety primary objective. 
4.1.2
Definitions
4.1.2.1
Baseline
For fasting lipids (TG, TC, HDL-C, non-HDL-C, VLDL-C, and LDL-C), baseline is defined 
as an average of week -4, week -2 (, week -1 if patients attended Visit 3a) and week 0 
measurements. 


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
16
For the other efficacy parameters listed in section 3.2.2 as well as safety parameters, baseline 
value is defined as the last non-missing assessment on or prior to the date of the first dose of 
the study medication. In typical case, week 0 is considered as baseline. 
4.1.2.2
Endpoints
For fasting lipids (TG, TC, HDL-C, non-HDL-C, VLDL-C, and LDL-C), the Week 12 
Endpoint is defined as an average of week 10 and week 12 measurements. For discontinued 
subjects, average of last non-missing two consecutive measurements up to week 12 is used as 
the week 12 Endpoint. If only a single measurement is available for a patient, it is used as the 
week 12 Endpoint.   
For the other secondary efficacy parameters listed in section 3.2.2, if no measurement is 
available at Week 12, the last post-baseline single measurement up to Week 12 will be used if 
appropriate. Such cases will be presented as Week 12 (LOCF).  
For any variables, last non-missing measurement up to Week 24/52 will be employed for 
Week 24/52(LOCF) evaluation if appropriate. 
4.1.2.3
Percent change from baseline and change from baseline
Percent change from baseline to any Week t (protocol-planned visits or Endpoints as defined 
section 4.1.2.2) is defined as follows:
PWeek t =100×(MWeek t - Mbaseline) / Mbaseline .
where:
∀
PWeek t is the percent change from baseline at Week t,
∀
MWeek t is the measurement at Week t,
∀
Mbaseline is the measurement at baseline as defined in section 4.1.2.1.
Change from baseline to any Week t (or Endpoints) is defined as follows : 
CWeek t =MWeek t - Mbaseline .
where CWeek t is the change from baseline at Week t, and MWeek t and Mbaseline  are as defined 
above.
4.1.2.4
Study Day
Study Day is calculated from date of first dose of double-blind medication. The first dose date 
is defined as Day 1 and Study Day for each post-baseline assessment is attributed by Date of 
assessment – Date of first dose + 1.   Study Day for assessment before first dose date will be 
calculated as Date of assessment – Date of first dose. Day 0 will not be used. 


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
17
4.1.2.5
Visit windows and Unscheduled/Discontinuation visits
In principle, all the analysis will be performed based on nominal visit basis as reported in 
eCRF. Unscheduled/discontinuation visit will not be mapped to scheduled visit but will be 
used for Baseline and Endpoint/LOCF derivation and extreme values summary for laboratory 
values.  
4.2
Analysis methods
4.2.1
Study population
4.2.1.1
Disposition
The disposition of subjects for the enrollment period and the double-blind treatment period
(12 week, 24 weeks as well as 52 weeks) will be summarized. 
The disposition summary of enrollment period will include all subjects enrolled (who signed 
informed consent). 
The disposition summary of the treatment period will include all randomized subjects, and be 
presented by treatment group and total. This summary will include subjects completing and 
discontinuing the first 12-week, 24-week as well as 52 week treatment period with reasons for 
discontinuation.
4.2.1.2
Demographic and other baseline characteristics
Demographic and other baseline characteristics will be summarized by treatment group.
For continuous variables, descriptive statistics (n, mean, standard deviation, median, min, 
max) will be presented.  For categorical variables number and proportion of patients in each 
category will be presented. 
Demographic and baseline characteristics will include but not limited to age, gender, body 
weight, height, BMI, concurrent use of statin, baseline TG,  baseline LDL-C and other 
baseline values of selected lipid parameters as well as some co-morbidities. 
4.2.1.3
Medical/surgical histories and current medical conditions
The number (percent) of subjects with medical history findings and current medical conditions
will be summarized by treatment group.
4.2.2
Efficacy
4.2.2.1
Analysis of primary efficacy variable
The primary efficacy variable is the percent change in TG from baseline to week 12 Endpoint. 
The primary efficacy analysis for the percent change in TG will be based on analysis of 
covariance (ANCOVA) model, with fixed categorical effects of treatment, statin usage, as 
well as continuous fixed covariate of baseline TG value. For comparisons of each AZD0585 


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
18
dose vs. Placebo pair-wise comparison, variance estimated from each pair will be employed. 
Primary analysis will be carried out for FAS. 
The model will provide least-squares (LS) mean estimates, standard errors and 2-sided 95% 
confidence intervals (CIs) for mean change at Week 12 Endpoint within and between 
treatments. Unadjusted two sided P-values will be calculated based on the model. 
Confirmatory hypothesis testing will be based on Hochberg procedure as described in section 
4.1.1.1. If a (two-sided) p-value for either dose is less than 0.05/2 = 0.025, superiority of the 
corresponding AZD0585 dose to Placebo will be claimed. If both p-values (for 2g and 4g 
dose groups) are less than 0.05, then superiority of both AZD0585 doses to placebo will be 
claimed. 
Sensitivity analysis of primary efficacy variable
To assess the robustness of the primary efficacy analysis, and to compare the results with 
previous studies, the sensitivity analyses on the primary efficacy variable will be carried out
using the following approaches.  
Per Protocol analysis 
Primary analysis by the same ANCOVA model for percent change in TG from baseline to 
week 12 Endpoint will be repeated for Per-Protocol Set.
Analysis based on log transformation
Change from baseline in log-transformed TG values at Week 12 Endpoint will be analyzed by 
ANCOVA model with fixed categorical effects of treatment, statin usage, as well as 
continuous fixed covariate of log-transformed baseline TG value. LSmeans and 95%CIs for 
each treatment and treatment difference will be back-transformed and presented as mean 
percent change from baseline and as relative treatment difference to Placebo in percent change.
Nominal p-values will also be reported from the models. The detail of transforming quantity 
from analysis in log scale to percent change is provided in the table below: 
Table 2
Transformation of quantities from log-transformed analysis
Quantities
Derivation
Adjusted mean percent change from 
baseline
100 # [exp(Adjusted mean change from baseline in 
natural logarithm) – 1]
Lower confidence limit for adjusted mean 
percent change from baseline
100 # [exp(lower confidence limit for adjusted mean 
change from baseline in natural logarithm) – 1]
Upper confidence limit for adjusted mean 
percent change from baseline
100 # [exp(upper confidence limit for adjusted mean 
change from baseline in natural logarithm) – 1]
Relative difference to Control in adjusted 
mean percent change from baseline.
100 # (exp(difference in adjusted mean change from 
baseline between AZD0585 treatment arm and Control
in natural logarithm) – 1)


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
19
Quantities
Derivation
Lower confidence limit for relative 
difference to Control in adjusted mean 
percent change from baseline
100 # (exp(lower confidence limit for difference in 
adjusted mean change from baseline between 
AZD0585 treatment arm and Control in natural 
logarithm) – 1)
Upper confidence limit for relative 
difference to Control in adjusted mean 
percent change from baseline
100 # (exp(upper confidence limit for difference in 
adjusted mean change from baseline between 
AZD0585 treatment arm and Control in natural 
logarithm) – 1)
Nonparametric analysis
In order to address potential deviation from normality of percent change metric, treatment 
comparison on percent change of TG to Week 12 Endpoint will be conducted by two-sample 
Wilcoxon test. Treatment difference for location (median) shift will be presented with 
Hodges-Lehmann estimators and nonparametric 95%CIs.  
Primary efficacy variable within subgroups
The primary efficacy variable of TG at Week 12 Endpoint will be descriptively summarized
and analyzed similarly for the subgroups defined on the basis of the categorized variables
listed in Table 3. Descriptive summary statistics would include, n, mean, standard deviation, 
minimum, 1st quartile, median, 3rd quartile, maximum.
Table 3
Subgroup analyses of primary efficacy variable
Group variable
Subgroups
Gender
Male, Female
Age
< 65 yrs
>= 65 yrs
Body Mass Index
< 25 kg/m2
>= 25 kg/m2 
Baseline triglyceride
< 300 mg/dL 
>= 300 mg/dL 
Concurrent  use of statin
Yes, No
Baseline LDL-C
< 140 mg/dL
>= 140 mg/dL 
Baseline HDL-C  
< 40 mg/dL
>= 40 mg/dL
Baseline non-HDL-C
< 170 mg/dL
>= 170 mg/dL 


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
20
Group variable
Subgroups
Baseline VLDL-C
< 60 mg/dL 
>= 60 mg/dL 
Comorbidity – established CVD 
Yes, No
Comorbidity – Hypertension 
Yes, No
Comorbidity - Diabetes 
Yes, No
4.2.2.2
Analysis of secondary efficacy variables
Fasting lipids (as defined in section 3.2.1) 
The percent change from baseline of each fasting lipid parameter to the Week 12 Endpoint
will be analyzed by ANCOVA model, with fixed categorical effects of treatment, statin usage, 
baseline TG strata (<300, >= 300 mg/dL) as well as continuous fixed covariate of 
corresponding baseline value. All the analyses will be carried out primarily for FAS and will 
be repeated for PPS.  
The model will provide least-squares (LS) mean estimates, standard errors and 2-sided 95% 
confidence intervals for mean change at Week 12 Endpoint within and between treatments.
Nominal two-sided p-values will also be displayed.
Other secondary efficacy parameters except for fasting lipids (as defined in section 3.2.2) 
The percent change from baseline of each secondary efficacy parameter to Week 12 (LOCF) 
will be analyzed by ANCOVA model, with fixed categorical effects of treatment, statin usage, 
TG strata (<300, >= 300 mg/dL) as well as continuous fixed covariate of corresponding 
baseline value. All the analyses will be carried out for FAS only.  
The model will provide least-squares (LS) mean estimates, standard errors and 2-sided 95% 
confidence intervals for mean percent change at Week 12 (LOCF) within and between 
treatments. Nominal two-sided p-values will also be displayed. 
4.2.2.3
Analysis of exploratory efficacy variables
The time course of continuous efficacy variables will be presented using descriptive summary 
statistics by treatment and visit. For Week 12 Endpoint and Week 52 Endpoint, absolute 
change from baseline and percent change from baseline will also be presented. Descriptive 
summary statistics would include, n, mean, standard deviation, minimum, 1st quartile, median, 
3rd quartile, maximum. 
Descriptive summaries for selected secondary variables (including fasting lipids) will also be 
provided if deemed necessary based on the subgroup defined in Table 3. 


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
21
4.2.3
Safety
For all safety evaluation, safety set will be used. In general, safety will be evaluated for the 
first 12-week treatment period as well as for 24-week or 52-week treatment period 
respectively at interim data base lock as well final data base lock.  
4.2.3.1
Extent of exposure
Study medication
The extent of exposure to study medication is defined as last dose data – first dose date + 1. 
The number and percent of subjects with an extent of exposure within pre-specified day 
ranges will be presented by treatment group. The categorization will be >=1 day, >= 4 weeks, 
>= 8 weeks, >= 12 weeks, >= 24 weeks, >= 36 weeks, >= 48 weeks and >= 52 weeks. The 
mean, standard deviation (SD), median and range of the number of days of exposure will also 
be presented.
Concomitant statin at baseline
Concurrent use of statin at baseline will be identified as those used at randomization day. 
Number of patients treated by statin at baseline will be summarized by treatment group, 
broken down by statin generic name.   
General prior and concomitant medications
Prior medication will be defined as any medication taken before first dose of study drug. 
Concomitant medication will be defined as any medication taken on or after first dose of study 
medications. Medication which started before first dose of study drug and continued during 
study treatment will be counted in both prior medication and concomitant medication. 
Prior and concomitant medications will be summarized using the Safety Set by drug class and 
(generic) drug name. A summary table by drug class and generic drug name will be generated 
for each of the following:
∀
all prior medication (excluding lipid lowering medication)
∀
all concomitant medication (excluding lipid lowering medication) taken during the 
first 12-week treatment period
∀
all concomitant medication (excluding lipid lowering medications) taken during the 
first 24-week treatment period
∀
all concomitant medication (excluding lipid lowering medications) taken during the 
whole treatment period (up to 52 weeks)
∀
prior lipid lowering medication
∀
concomitant lipid lowering medication during first 12-week treatment period


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
22
∀
concomitant lipid lowering medication during first 24-week treatment period
∀
concomitant lipid lowering medication during the whole treatment period (up to 52 
weeks)   
The WHO dictionary is used to code the non-study medication.
4.2.3.2
Adverse events
Treatment-emergent adverse events (TEAEs, i.e. adverse events with onset on or after first 
dose of study drug) will be summarized for safety evaluation. Adverse events occurring before
start of study drug will only be listed. 
Adverse events (AEs) will be classified by Primary System Organ Class (SOC) and Preferred 
Term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Summaries of AEs will use the version of MedDRA that is current at the time of database 
lock.
All adverse events
All AEs with onset during the first 12-week (+2 days) treatment period, 24-week (+7 days) 
treatment period and with onset during the whole study treatment period will be summarized. 
The following items will be summarized by system organ class, preferred term and treatment 
group. 
∀
Any AEs
∀
Deaths
∀
Serious AEs (SAEs)
∀
AEs leading to study drug discontinuation (DAEs)
∀
AEs by maximum intensity
∀
AEs related to study drug
4.2.3.3
Safety Laboratory evaluation
Hematology and Clinical Chemistry
For quantitative variables, descriptive summary statistics (for value at visit and change from 
baseline) will be provided by visit and treatment group. 
Shift tables in categories of low, normal, and high (based on normal range of central 
laboratory) will be summarized by treatment group using the baseline (Week 0) values and the 
highest and lowest values obtained during the first 12 weeks, 24 weeks as well as during the 
whole 52-week study treatment period. Percentages will be based on the number of subjects 


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
23
within each treatment group with each baseline status. In this summary, unscheduled 
measurement will also be counted in.   
Liver enzyme abnormalities
For liver safety, additional summary of proportion of subjects with elevated liver enzymes
will be provided by treatment group. Liver enzyme abnormalities are defined as the Table 4. 
Table 4
Liver enzyme abnormalities
Parameter
Criteria
ALT
>3, >5, >10, >20xULN
AST
>3, >5, >10, >20xULN
AT (ALT or AST) 
>3, >5, >10, >20xULN
TBL
>1.5, >2xULN
ALP
>1.5, >3xULN
AT & TBL
AT > 3xULN & TBL > 1.5xULN, 
AT > 3xULN & TBL > 2 xULN
AT & TBL & ALP
AT > 3xULN & TBL > 2xULN & ALP < 2xULN
ALT = alanine aminotransferase, AST = aspartate aminotransferase, AT = alanine or aspartate aminotransferase, 
TBL = total bilirubin, ULN = upper limits of normal
Urinalysis
For qualitative variables (measured by dipstick test), shift table from baseline to post-baseline 
will be produced by visit and treatment group.   
4.2.3.4
Vital signs
Descriptive summary statistics (for value at visit and change from baseline) will be provided
by visit and treatment group.  
4.2.3.5
Physical examination
All results of physical examination will be listed for each patient.
4.2.3.6
Electrocardiograms
For all continuous measurements (HR, RR, PR, QRS and QT) as well as QTcF (derived by 
QTcF and RR) will be summarized descriptive statistics by treatment group and visit.  
QTcF will be derived as: 
3
QTcF
QT
RR
!


Statistical Analysis Plan 
Study Code D5884C00002
Edition Number 2.0
Date 19 September 2016
24
Abnormal prolongation of QTcF will be summarized by treatment group based on criteria
specified in the Table 5. The extreme (highest) value for a patient during treatment will be 
used this summary.   
Table 5
Categorical evaluation of QTcF
Parameter
Criterion
QTcF
>450 msec
>480 msec
>500 msec
Change from baseline in QTcF 
>30 msec 
>60 msec
Shift table for the investigators assessment on abnormality will also be created by visit and 
treatment group. 
5.
INTERIM ANALYSES
An interim analysis will include all patients’ data available until data cut-off, including 
primary/secondary analysis at Week 12 Endpoint for efficacy as well as safety evaluation 
based on 24-week or longer exposure to study drug.  Sponsor will be unblinded at the time of 
interim analysis but investigators, patients and site-staff will not be informed of assigned 
treatment in order to maintain integrity as much as possible.  Data cut off date is defined as a 
day when 24 weeks have passed after Last Subject In (LSI).  This interim analysis will be 
documented as an interim clinical study report.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
While in the protocol, sensitivity analysis based on log-transformed data was planned to 
model including log-transformed post-baseline TG value as a response variable, it was 
changed to model change from baseline in log-transformed TG value in order to facilitate 
easier transformation of quantity related to the percent change from baseline in each arm. In 
terms of statistical treatment comparison, these two approaches are equivalent.      
7.
REFERENCES (NOT APPLICABLE)
8.
APPENDIX (NOT APPLICABLE)