Clinical trial NCT03577275
Conditions: Dyslipidemias
Sponsor: NorthSea Therapeutics B.V.
Start date: 2018-06-15; Completion date: 2018-09-24
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase 1, single centre, randomised, double blind (except for moxifloxacin), placebo and positive controlled, 4 way crossover study assessing the ECG effects of therapeutic and supratherapeutic doses of icosabutate in healthy male and female subjects.

Detailed description:

Arms: arm 1: Single dose of placebo to match NST-4016 arm 2: Single 400mg dose of active comparator moxifloxacin (open label) arm 3: Likely therapeutic dose of NST-4016 arm 4: Supratherapeutic dose of NST-4016
Interventions: intervention 1: NST-4016 600mg intervention 2: Placebo oral capsule intervention 3: Moxifloxacin 400mg intervention 4: NST-4016 2000mg
Intervention descriptions: intervention 1: Likely maximum therapeutic dose of NST-4016 intervention 2: Placebo for comparison with moxifloxacin and potential NST-4016 effects intervention 3: Active comparator with known effect on QT interval intervention 4: Supratherapeutic dose of NST-4016

Protocol documents:
Prot_000.pdf: 
 
 
TITLE PAGE 
Protocol 
A Randomised, Partially Double-blind, Placebo- and Positive-controlled, 
4-way Crossover Study to Evaluate the Effect of Icosabutate (NST-4016) on 
the QT/QTc Interval in Healthy Subjects 
Protocol Status: Final 
Protocol Date: 11 April 2018 
Investigational Product: icosabutate (NST-4016) 
 
Protocol Reference Number: NST-01 
Covance Study Number: 8383557 
EudraCT Number: 2018-000395-14 
 
 
Sponsor: 
NorthSea Therapeutics BV 
Gooimeer 2-35 
1411, DC Naarden 
The Netherlands 
Study Site: 
Covance Clinical Research Unit (CRU) Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
 
Sponsor Signatory: 
Dr. Patrick Round, MBBS FFPM 
Principal Investigator: 
Dr. Ashley Brooks, MBChB 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
Covance Study: 8383557 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
JM_j 
Dr. Patrick Round, MBBS FFPM 
Chief Medical Officer 
NorthSea Therapeutics BV 
Final, 11 April 2018 
Date 
CONFIDENTIAL 
Protocol Reference: NST -01 
Page 2 of 51 


Protocol 
Covance Study: 8383557 
CONFIDENTIAL 
Protocol Reference: NST-01 
-l~V"ESTIGATOR AGREEI'I'iENT . 
I have read the protocol and agree to conduct the study as described herein. 
Date 
Principal Investigator 
Final, 11 April 2018 
Page 3 of 51 


Protocol 
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STUDY IDENTIFICATION 
Sponsor 
NorthSea Therapeutics BV 
Gooimeer 2-35 
1411, DC Naarden 
The Netherlands 
Sponsor’s Study Contact and 
Medical Contact 
Dr. Patrick Round, MBBS FFPM 
Chief Medical Officer 
NorthSea Therapeutics BV 
Gooimeer 2-35 
1411, DC Naarden 
The Netherlands 
Tel: +44 (0)7979 502 770 
Tel (after hours): +44 (0)7979 502 770 
Study Site 
Covance Clinical Research Unit (CRU) Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
Dr. Ashley Brooks, MBChB 
Principal Investigator 
Covance CRU Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0)113 301 3521 
Tel (after hours): +44 (0)113 301 3500 
Project Physician 
Dr. Hamzah Malik, MD 
Clinical Research Physician 
Covance CRU Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0)113 301 3656 
Clinical Laboratory 
Covance Clinical Pathology Services 
Otley Road 
Harrogate, HG3 1PY 
United Kingdom 
Bioanalytical Laboratory 
Covance Laboratories Europe (CLE) 
Otley Road 
Harrogate, HG3 1PY 
United Kingdom 


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Central Electrocardiogram 
Laboratory 
iCardiac Technologies, Inc. (an ERT company) 
150 Allens Creek Rd 
Rochester 
New York 14618 
United States 
Regulatory and Monitoring 
QRC Consultants Ltd 
Silvaco Technology Centre 
Compass Point Business Park 
Stocks Bridge Way 
Saint Ives 
PE27 5JL 
United Kingdom 
Pharmacovigilance 
Bionical Emas 
63-65 Knowl Piece 
Wilbury Way 
Hitchin, Hertfordshire 
SG4 0TY 
United Kingdom 
Statistician 
Izabela Antys, BSc MSc GradStat 
Covance Biometrics 


Protocol 
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SYNOPSIS 
Title of study: A Randomised, Partially Double-blind, Placebo- and Positive-controlled, 4-way 
Crossover Study to Evaluate the Effect of Icosabutate (NST-4016) on the QT/QTc Interval in 
Healthy Subjects 
Objectives: 
The primary objective of the study is: 
• 
To evaluate the effects of therapeutic and supratherapeutic concentrations of icosabutate on 
the Fridericia’s corrected QT interval (QTcF) in healthy subjects. 
The secondary objectives of the study are: 
• 
To evaluate the effect of therapeutic and supratherapeutic doses of icosabutate on other 
electrocardiogram (ECG) parameters (heart rate [HR], PR and QRS intervals, and T-wave 
morphology) in healthy subjects. 
• 
To evaluate the pharmacokinetics (PK) of single doses of 600 mg and 2000 mg icosabutate 
in healthy subjects. 
• 
To assess the safety and tolerability of single doses of 600 mg and 2000 mg icosabutate in 
healthy subjects. 
Study design: 
This will be a Phase 1, single-centre, randomised, double-blind (except for moxifloxacin), 
placebo- and positive-controlled, 4-way crossover study assessing the ECG effects of therapeutic 
and supratherapeutic doses of icosabutate in healthy male and female subjects. 
Thirty-two subjects will be randomised to a treatment sequence that includes each of the following 
4 treatments, administered as a single oral dose: 
• 
therapeutic dose of icosabutate (600 mg) 
• 
supratherapeutic dose of icosabutate (2000 mg) 
• 
moxifloxacin (400 mg) 
• 
placebo 
Moxifloxacin will be used as a positive control to determine the assay sensitivity of this study, with 
an expected peak QT effect ∆∆QTcF of 10 ms to 15 ms. 
Each subject will participate in 4 dosing periods (ie, Dosing Periods 1 to 4). Subjects will remain in 
the Clinical Research Unit (CRU) from Day -1 until Day 18. Doses will be administered in the 
morning of Days 1, 6, 11, and 16 after an overnight fast of at least 8 hours (not including water). 
Dose administration in each dosing period will be separated by a wash-out period of at least 5 days. 
There will be a Follow-up Visit 7 to 10 days after the final dose administration. 
Number of subjects: 
A total of 32 subjects will be enrolled in order that a minimum of 28 subjects complete the study. 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged between 18 and 55 years (inclusive) with a body mass index 
(BMI) between 18.0 and 33.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test products: 
600 mg icosabutate (3 × 200 mg capsules; therapeutic dose) 
2000 mg icosabutate (10 × 200 mg capsules; supratherapeutic dose) 
Administration route: oral. 
Reference product and mode of administration: 
Reference products: 
Placebo capsules matched to icosabutate 
400 mg moxifloxacin (positive control) 
Administration route: oral 


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Duration of subject participation in the study: 
Planned Screening duration: up to 27 days. 
Planned study duration (Screening to Follow-up Visit): approximately 8 weeks. 
Endpoints: 
Cardiodynamics 
The primary endpoint for this study is the placebo-corrected change-from-baseline QTcF 
(ΔΔQTcF). 
The following are the secondary cardiac endpoints for this study: 
• 
change-from-baseline HR, QTcF, PR, and QRS (ie, ΔHR, ΔQTcF, ΔPR, and ΔQRS, 
respectively) 
• 
placebo-corrected ΔHR, ΔPR, and ΔQRS (ie, ΔΔHR, ΔΔPR, and ΔΔQRS, respectively) 
• 
frequency of T-wave morphology and U-wave presence changes 
 
Continuous 12-lead ECG recordings will be performed from 1 hour predose to approximately 
25 hours postdose in each dosing period (ie, Days 1, 6, 11, and 16). All ECG data will be collected 
using a continuous 12-lead digital recorder, which will be supported by iCardiac Technologies, Inc 
(an ERT company). At the ECG core laboratory, up to 10 replicate ECGs will be extracted at each 
of the following timepoints in each dosing period (ie, Days 1, 6, 11, and 16): -45, -30, 
and -15 minutes predose, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose. 
 
Pharmacokinetics: 
Where data allow, the PK parameters for icosabutate will include area under the plasma 
concentration-time curve from time zero to the time of the last observed concentration (AUC0-t), 
maximum observed plasma concentration (Cmax), and time of the maximum observed plasma 
concentration (Tmax). Additional PK parameters may be determined, if deemed appropriate. Details 
of the parameters, and handling procedures, will be described in the Statistical Analysis Plan (SAP).
For the purposes of establishing assay sensitivity, moxifloxacin plasma concentrations will be 
measured to allow concentration-QTc analysis. 
 
Safety: 
Adverse events, clinical laboratory evaluations (haematology, clinical chemistry, urinalysis), 
12-lead ECGs, vital sign measurements, and physical examinations. 


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Statistical methods: 
Cardiodynamics 
The primary analysis will be based on exposure-response modelling of the relationship between 
icosabutate and Δ∆QTcF with the intent to exclude an effect > 10 ms at clinically relevant 
icosabutate plasma concentrations. 
In addition, the effect of icosabutate on ∆∆QTcF will be evaluated at each postdose timepoint 
(‘by-timepoint’ analysis) using the Intersection Union Test. An analysis of categorical outliers will 
be performed for changes in HR, PR, QRS, QTcF, T-wave morphology and U-wave presence. 
Assay sensitivity will be evaluated by exposure-response analysis of the effect on Δ∆QTcF of 
moxifloxacin using a similar model as for the primary analysis. If the slope of the 
exposure-response relationship is statistically significant at 10% level of significance in a 2-sided 
test and the lower bound of the 2-sided 90% confidence interval (CI) of the predicted QT effect at 
the observed geometric mean Cmax following a single dose of 400 mg moxifloxacin is above 5 ms, it 
will be concluded that assay sensitivity has been demonstrated. 
The ECG core laboratory will be responsible for the analysis of the cardiodynamic data. 
 
Pharmacokinetics: 
Individual plasma concentrations of icosabutate will be listed and summarised using descriptive 
statistics. 
No formal statistical analysis of PK parameters will be performed. 
 
Safety: 
Safety parameters will be listed and summarised using descriptive statistics. No formal statistical 
analysis of safety data is planned. Each adverse event will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF TABLES AND FIGURES........................................................................................11 
LIST OF ABBREVIATIONS ..................................................................................................12 
1. 
INTRODUCTION ...........................................................................................................13 
1.1. 
Overview ................................................................................................................13 
1.2. 
Summary of Non-clinical Pharmacology ...............................................................14 
1.3. 
Summary of Clinical Experience ...........................................................................14 
1.3.1. 
Safety ...........................................................................................................14 
1.3.2. 
Pharmacokinetics .........................................................................................15 
1.4. 
Study Rationale ......................................................................................................16 
1.5. 
Benefit-risk Assessment .........................................................................................16 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................16 
2.1. 
Objectives ..............................................................................................................16 
2.2. 
Endpoints ...............................................................................................................16 
2.2.1. 
Primary Endpoints .......................................................................................16 
2.2.2. 
Secondary Endpoints ...................................................................................17 
3. 
INVESTIGATIONAL PLAN ..........................................................................................17 
3.1. 
Overall Study Design and Plan ..............................................................................17 
3.2. 
Study Start and End of Study Definitions ..............................................................19 
3.3. 
Discussion of Study Design, Including the Choice of Control Groups .................19 
3.4. 
Selection of Doses in the Study .............................................................................20 
4. 
SELECTION OF STUDY POPULATION .....................................................................20 
4.1. 
Inclusion Criteria ...................................................................................................20 
4.2. 
Exclusion Criteria ..................................................................................................21 
4.3. 
Subject Number and Identification ........................................................................23 
4.4. 
Subject Withdrawal and Replacement ...................................................................23 
4.5. 
Study Termination .................................................................................................24 
5. 
STUDY TREATMENTS .................................................................................................24 
5.1. 
Description, Storage, Packaging, and Labelling ....................................................24 
5.2. 
Study Treatment Administration ............................................................................25 
5.3. 
Randomisation .......................................................................................................25 
5.4. 
Blinding..................................................................................................................26 
5.5. 
Treatment Compliance ...........................................................................................26 


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5.6. 
Drug Accountability...............................................................................................26 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................27 
6.1. 
Concomitant Therapies ..........................................................................................27 
6.2. 
Diet .........................................................................................................................27 
6.3. 
Smoking .................................................................................................................27 
6.4. 
Exercise ..................................................................................................................27 
6.5. 
Blood Donation ......................................................................................................28 
6.6. 
Contraception .........................................................................................................28 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................29 
7.1. 
Pharmacokinetic Assessments ...............................................................................29 
7.1.1. 
Sample Collection and Processing ...............................................................29 
7.1.2. 
Analytical Methodology ..............................................................................30 
7.2. 
Cardiodynamic (Continuous) 12-lead Electrocardiogram Recordings ..................30 
7.2.1. 
Electrocardiogram Collection ......................................................................30 
7.2.2. 
QTc Analysis ...............................................................................................30 
7.2.3. 
12-lead Electrocardiogram Extraction Technique .......................................30 
7.2.4. 
High-precision QT Analysis ........................................................................31 
7.3. 
Safety and Tolerability Assessments .....................................................................32 
7.3.1. 
Adverse Events ............................................................................................32 
7.3.2. 
12-lead Safety Electrocardiogram ................................................................32 
7.3.3. 
Vital Signs ....................................................................................................32 
7.3.4. 
Clinical Laboratory Evaluations ..................................................................33 
7.3.5. 
Physical Examination...................................................................................33 
7.3.6. 
Body Weight and Height .............................................................................33 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................33 
8.1. 
Determination of Sample Size ...............................................................................33 
8.2. 
Sample Size Considerations for Assay Sensitivity ................................................34 
8.3. 
Analysis Populations ..............................................................................................34 
8.3.1. 
Safety Population .........................................................................................34 
8.3.2. 
Pharmacokinetic Population ........................................................................34 
8.3.3. 
QT/QTc Population ......................................................................................34 
8.3.4. 
Pharmacokinetic/QTc Population ................................................................34 
8.4. 
Statistical Analyses of Cardiodynamic (Continuous) 12-lead 
Electrocardiogram Data .........................................................................................35 
8.4.1. 
Baseline ........................................................................................................35 
8.4.2. 
Exposure-response Analysis ........................................................................35 
8.4.3. 
Assay Sensitivity ..........................................................................................36 
8.4.4. 
By-timepoint Analysis (Secondary Analysis) ..............................................37 
8.4.5. 
Categorical Analysis ....................................................................................37 
8.5. 
Pharmacokinetic Analyses .....................................................................................37 


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8.6. 
Safety Analysis ......................................................................................................38 
8.7. 
Interim Analysis .....................................................................................................38 
9. 
REFERENCES ................................................................................................................38 
10. APPENDICES .................................................................................................................39 
Appendix 1: Adverse Event Reporting ..............................................................................40 
Appendix 2: Clinical Laboratory Evaluations ...................................................................44 
Appendix 3: Total Blood Volume ......................................................................................45 
Appendix 4: Regulatory, Ethical, and Study Oversight Considerations ............................46 
Appendix 5: Schedule of Assessments ..............................................................................49 
 
LIST OF TABLES AND FIGURES 
Table 1: Treatment Sequences ...............................................................................................18 
Table 2: Number of Capsules to be Administered on Each Respective Dosing Occasion ....25 
Table 3: T-wave Morphology Categories ..............................................................................31 
Table 4: Schedule of Assessments for NST-01 ......................................................................50 
 
Figure 1: Study Schematic .......................................................................................................19 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ΔΔQTcF 
placebo-corrected change-from-baseline QTcF 
ΔQTcF 
change-from-baseline QTcF 
AUC0-t 
area under the plasma concentration-time curve from time zero to the time of 
the last observed concentration 
ApoC3 
apolipoprotein C3 
AUC 
area under the plasma concentration-time curve 
bpm 
beats per minute 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration 
CRO 
Contract Research Organisation 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
EDC 
electronic data capture 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
FSH 
follicle-stimulating hormone 
HDL-C 
high density lipoprotein cholesterol 
HR 
heart rate 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
LDL-C 
low density lipoprotein cholesterol 
LS 
least squares 
NSAID 
non-steroidal anti-inflammatory drug 
OTC 
over-the-counter 
PK 
pharmacokinetic(s) 
PPAR 
peroxisome proliferator-activated receptor 
QTc 
QT interval corrected for heart rate 
QTcF 
Fridericia’s corrected QT interval 
SD 
standard deviation 
SE 
standard error 
Tmax 
time of the maximum observed plasma concentration 
TQT 
thorough QT 
VLDL-TG 
very low density lipoprotein triglyceride 


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1. INTRODUCTION 
1.1. 
Overview 
Elevation in triglycerides is associated with dual risks of acute pancreatitis and accelerated 
atherosclerosis leading to cardiovascular events. Recent genetic studies have strongly 
suggested a causal relationship between triglyceride levels and ischaemic cardiovascular 
disease, in addition to other closely interrelated markers such as triglyceride-rich lipoproteins 
and apolipoprotein C3 (ApoC3). For patients with elevated triglycerides 
(hypertriglyceridemia) who do not adequately respond to dietary and lifestyle restrictions, 
there are relatively few classes of drugs available and each is associated with risks that limit 
their use either alone or in combination. 
Icosabutate is a novel, orally administered, highly potent, semi-synthetic fatty acid for the 
treatment of various dyslipidaemias including severe hypertriglyceridemia, mixed 
dyslipidaemia, and hypercholesterolemia. In severe hypertriglyceridemia, the primary goal of 
therapy is to prevent the development of acute pancreatitis by lowering triglyceride levels. 
Mixed dyslipidaemia is characterised by elevated low density lipoprotein cholesterol 
(LDL-C) and triglycerides, often accompanied by high density lipoprotein cholesterol 
(HDL-C) levels. Elevations of triglyceride signal an increased risk of atherosclerotic 
cardiovascular events even when the LDL-C is well-controlled by statin therapy. The drug 
substance, icosabutate, is a semi-synthetic derivative of the naturally occurring omega-3 fatty 
acid eicosapentaenoic acid. The aim of modifying eicosapentaenoic acid is to potentiate the 
pharmacological effects of naturally occurring omega-3 fatty acids by increasing direct 
hepatic delivery through the portal vein following absorption, reduce the incorporation into 
complex lipids, and increase availability for intracellular signalling. 
Non-clinical and clinical experience with icosabutate has so far indicated large reductions in 
both triglycerides and cholesterol, in addition to ApoC3. There are likely multiple 
contributors to the observed pharmacodynamic effects of icosabutate, a partial peroxisome 
proliferator-activated receptor (PPAR)α-agonist. Peroxisome proliferator-activated receptor-α 
is a nuclear receptor expressed in a number of organs including the liver, muscles, heart, and 
kidneys, and has been recognised as one of the major regulators of glucose and lipid 
metabolism, playing a role in fatty acid transport, fatty acid binding protein expression, fatty 
acid-coenzyme A (CoA) synthesis, microsomal, peroxisomal, and mitochondrial oxidation, 
ketogenesis, fatty acid desaturation, and expression of several apolipoproteins, including 
ApoC3. However, the lipid changes induced by icosabutate are also partially maintained in 
PPARα knock-out mice. Icosabutate increases the hepatic clearance of very low density 
lipoprotein triglyceride (VLDL-TG) without a compensatory increase in hepatic secretion of 
VLDL-TG and with an improvement in hepatic steatosis. This is consistent with the observed 
increase in hepatic fatty acid oxidation by icosabutate, which also reduces expression of 
ApoC3 in animal models and reduces plasma ApoC3 in clinical studies. Expression of 
ApoC3 is regulated by multiple factors including insulin, glucose, and PPARα, and it plays a 
key role in regulating triglyceride metabolism (ie, promoting hepatic VLDL-TG secretion and 
inhibiting peripheral and hepatic clearance of both triglycerides and lipoproteins). Thus, the 
reductions in ApoC3 conferred by icosabutate may be one of the key drivers of its lipid 
effects. 


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1.2. 
Summary of Non-clinical Pharmacology 
The potential cardiovascular effects of icosabutate were evaluated in 4 telemetered male 
beagle dogs. Each animal received a single oral dose of icosabutate at 0 (corn oil), 
100 mg/kg, 550 mg/kg, and 1000 mg/kg in a crossover design with a 6-day interval between 
doses. Blood pressure, heart rate (HR), and electrocardiogram (ECG) parameters were 
measured by telemetry at predose and for up to 12 hours postdose and clinical signs were 
assessed up to 4 hours postdose. 
There were no biologically significant changes noted in the blood pressure, HR, ECG 
intervals or morphology of the ECG waveform at doses of icosabutate up to 1000 mg/kg. 
Furthermore, no clinical signs were observed at 100 mg/kg. There were 2 events of emesis 
following 550 mg/kg icosabutate (1 event at 1.25 hours postdose and 1 event at 2.25 hours 
postdose) and 1 event following 1000 mg/kg icosabutate (1.25 hour postdose). 
At the 550-mg/kg and 1000-mg/kg dose levels, mucoid/liquid faeces were observed. No 
effects on cardiovascular function were observed up to 1000 mg/kg. 
Icosabutate was administered at doses of 20 mg/kg/day, 50 mg/kg/day, and 250 mg/kg/day 
for 52 weeks to male and female dogs in a repeat-dose toxicity study. The reversibility of any 
changes was assessed over a 4-week recovery to 2 male and 2 female animals from each dose 
group. During this study, toxicologically significant findings were predominantly confined to 
the 250-mg/kg/day dose group. Increases in group mean QT, Van de Water corrected QT 
interval (QTcV) and Fridericia’s corrected QT interval (QTcF) were observed in dogs 
administered 250 mg/kg/day for 52 weeks. In addition, 1 male dog presented with several 
ventricular escape complexes at 1.5 hours postdose in Week 25. Based on findings in this 
52-week toxicity study, the no-observed-adverse-effect-level (NOAEL) in this study was 
50 mg/kg/day, which corresponds to respective maximum observed plasma concentration 
(Cmax) and area under the plasma concentration-time curve from time zero to the time of the 
last observed concentration (AUC0-t) values of 23800 ng/mL and 189000 ng·h/mL, 
respectively, in males and 29500 ng/mL and 168000 ng·h/mL, respectively, in females. 
1.3. 
Summary of Clinical Experience 
1.3.1. 
Safety 
As of 24 January 2018, icosabutate has been evaluated in 6 clinical studies, comprising 
4 Phase I and 2 Phase II proof-of-concept trials in the target populations. 
In the First-in-Human study, icosabutate was administered as single doses between 5 mg and 
600 mg, multiples doses of 50 mg to 300 mg twice daily, and 500 mg to 600 mg once daily 
for up to 28 days. Icosabutate was considered to be safe and well-tolerated, with the overall 
incidence of adverse events throughout the study being generally low. There were no 
apparent treatment- or dose-related trends in the number of adverse events reported, or the 
number of subjects reporting adverse events. There were no other findings of clinical 
importance in the clinical laboratory evaluations, vital signs, 12-lead ECGs, telemetry, 
physical examinations, or body weight observed during the study. No dose- or 
treatment-related trends in ophthalmological assessments were observed following single and 
multiple oral doses. 


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In a Phase I high-dose study, single oral doses of 1000 mg, 1400 mg, 2000 mg, and 2800 mg 
icosabutate were considered to be safe and well tolerated by healthy male and female 
subjects. All treatment-related adverse events were mild in severity and the majority were 
gastrointestinal disorders, with incidence tending to increase with increasing dose. There 
were no treatment- or dose-related findings in the clinical laboratory results, vital signs, 
12-lead ECGs, ophthalmological assessments, or physical examinations. 
In all Phase I and II studies combined, 265 subjects have received icosabutate; 150 (57%) 
subjects have reported at least 1 treatment-emergent adverse event, the maximum severity 
being mild in 114 subjects, moderate in 45 subjects, and severe in 1 subject. Of these 
150 subjects, 94 (35%) subjects reported a drug-related treatment-emergent adverse event. 
No serious adverse events have been reported following the administration of icosabutate. 
Three adverse events relating to cardiac or 12-lead ECG findings have been reported in 
icosabutate-treated patients; all events were non-serious and mild, with 1 event not 
considered related to study drug by the Investigator, and 2 events being considered possibly 
related to the study drug by the Investigator. 
One event was reported in the First-in-Human Phase I study in healthy and otherwise healthy 
dyslipidaemic subjects. Following once daily 500 mg icosabutate, 1 subject reported mild 
palpitations considered by the Investigator to be possibly related to the study drug. The event 
resolved after 5 minutes. 
Two events were reported in the Phase II study in patients with mixed dyslipidaemia. One 
patient experienced mild sinus bradycardia, which was considered by the Investigator to be 
not related to study drug. One patient experienced QTc prolongation at the early termination 
visit, which was mild in severity and considered possibly related to the study drug by the 
Investigator. No other cardiac-related adverse events were experienced by this subject. 
1.3.2. 
Pharmacokinetics 
In all Phase I and II studies combined, icosabutate was rapidly absorbed at all dose levels 
with a time of the maximum observed plasma concentration (Tmax) generally within 3 hours 
postdose at the lower doses, and increasing to 3 to 4 hours postdose at the higher doses. 
Following chronic dosing the time taken for the concentration of a substance to reduce to half 
its original value (t½) was approximately 5 hours to 11 hours. Icosabutate is excreted both by 
the kidneys and the liver. Clinical metabolism profiling of clinical plasma samples from 
300 mg twice daily in males and 500 mg once daily at Day 14 has been compared with 
plasma samples from rat and dog after 13-week repeat-dose toxicity studies at 30 mg/kg/day 
and 50 mg/kg/day, respectively. There were no human unique metabolites, whereas 2 major 
human disproportionate metabolites were observed with area under the plasma 
concentration-time curve (AUC) exposure around 10% of total drug-related material. A 
human radiolabelled absorption, metabolism, and excretion (AME) study showed that the 
5 most abundant metabolites in plasma (P1 to P5) accounted for <10% of icosabutate 
exposure and <5% of the total drug-related exposure. The notable plasma metabolites were 
characterised as dehydroxylated icosabutate with the loss of C14H2O, two dehydroxylated 
metabolites of icosabutate hydroxylated icosabutate with the addition of a glucuronide, 
icosabutate +2H +2O and hydroxylated icosabutate. No icosabutate was detected in urine 
samples. Only one metabolite (U4) accounted for >10% of the dose administered. The 


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majority of the remaining components detected in urine accounted for <5% of the total 
administered dose. As faeces was a relatively minor elimination route, all components 
accounted for <5% of the dose administered. Two of the metabolites present in faeces were 
identified as icosabutate +2H +3O and icosabutate +2H+2O. 
1.4. 
Study Rationale 
Regulatory guidance (ICH E14 and FDA E14)1 recommends a thorough QT (TQT) study to 
be performed on new chemical entities in order to define the ECG effects, with a particular 
focus on cardiac repolarisation as measured by the QTc duration. This study is being 
conducted to obtain clear and robust ECG data, using a sufficient sample size, to evaluate the 
effects of icosabutate on cardiac repolarisation. The study will be conducted in healthy male 
and female subjects, who are not at risk of arrhythmias. 
1.5. 
Benefit-risk Assessment 
Healthy subjects in the current study will not receive any health benefit (beyond that of an 
assessment of their medical status) from participating in the study. The risks of participation 
are primarily those associated with adverse reactions to the study drug(s), although there may 
also be some discomfort from collection of blood samples and other study procedures. More 
information about the known and expected benefits, risks, and reasonably anticipated adverse 
events associated with icosabutate may be found in the Investigator Brochure (IB).2 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
• To evaluate the effects of therapeutic and supratherapeutic concentrations of 
icosabutate on the QTcF in healthy subjects. 
The secondary objectives of the study are: 
• To evaluate the effect of therapeutic and supratherapeutic doses of icosabutate on 
other ECG parameters (HR, PR and QRS intervals, and T-wave morphology) in 
healthy subjects. 
• To evaluate the pharmacokinetics (PK) of single doses of 600 mg and 2000 mg 
icosabutate in healthy subjects. 
• To assess the safety and tolerability of single doses of 600 mg and 2000 mg 
icosabutate in healthy subjects. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
The primary endpoint for this study is the placebo-corrected change-from-baseline QTcF 
(ΔΔQTcF). 


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2.2.2. 
Secondary Endpoints 
The secondary endpoints for this study are: 
• change-from-baseline HR, QTcF, PR, and QRS (ie, ΔHR, ΔQTcF, ΔPR, and ΔQRS, 
respectively) 
• placebo-corrected change-from-baseline HR, PR, and QRS (ie, ΔΔHR, ΔΔPR, and 
ΔΔQRS, respectively) 
• frequency of T-wave morphology and U-wave presence changes 
The PK endpoints will include the following plasma PK parameters for icosabutate using 
non-compartmental methods: 
• AUC0-t 
• Cmax 
• Tmax 
Additional PK parameters may be determined, if deemed appropriate. 
The safety and tolerability endpoints will include the monitoring and reporting of adverse 
events, and the incidence and magnitude of clinically significant changes from baseline in 
clinical laboratory values (haematology, clinical chemistry, and urinalysis), vital sign 
measurements (blood pressure, pulse rate, and oral body temperature), 12-lead safety ECG 
results, and physical examination findings. 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a Phase 1, single-centre, randomised, double-blind (except for moxifloxacin), 
placebo- and positive-controlled, 4-way crossover study assessing the ECG effects of 
therapeutic and supratherapeutic doses of icosabutate in healthy male and female subjects. 
Thirty-two subjects will be randomised to 1 of 12 treatment sequences (Table 1), with 
approximately 3 subjects randomised into 8 of the 12 sequences, and 2 subjects randomised 
into 4 of the 12 sequences, and will receive a single oral dose of each of the following 
treatments, with a minimum 5-day wash-out between doses: 
• therapeutic dose of icosabutate (600 mg) 
• supratherapeutic dose of icosabutate (2000 mg) 
• moxifloxacin (400 mg) 
• placebo 
Moxifloxacin will be used as a positive control to determine the assay sensitivity of this 
study, with an expected peak QT effect ∆∆QTcF of 10 ms to 15 ms. 


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Table 1: 
Treatment Sequences 
Treatment 
Sequence 
Dosing Period 
1 
(Day 1) 
2 
(Day 6) 
3 
(Day 11) 
4 
(Day 16) 
1 
icosabutate 
(600 mg) 
icosabutate 
(2000 mg) 
placebo 
moxifloxacin 
(400 mg) 
2 
icosabutate 
(2000 mg) 
moxifloxacin 
(400 mg) 
icosabutate 
(600 mg) 
placebo 
3 
placebo 
icosabutate 
(600 mg) 
moxifloxacin 
(400 mg) 
icosabutate 
(2000 mg) 
4 
moxifloxacin 
(400 mg) 
placebo 
icosabutate 
(2000 mg) 
icosabutate 
(600 mg) 
5 
icosabutate 
(2000 mg) 
placebo 
icosabutate 
(600 mg) 
moxifloxacin 
(400 mg) 
6 
placebo 
moxifloxacin 
(400 mg) 
icosabutate 
(2000 mg) 
icosabutate 
(600 mg) 
7 
icosabutate 
(600 mg) 
icosabutate 
(2000 mg) 
moxifloxacin 
(400 mg) 
placebo 
8 
moxifloxacin 
(400 mg) 
icosabutate 
(600 mg) 
placebo 
icosabutate 
(2000 mg) 
9 
placebo 
icosabutate 
(600 mg) 
icosabutate 
(2000 mg) 
moxifloxacin 
(400 mg) 
10 
icosabutate 
(600 mg) 
moxifloxacin 
(400 mg) 
placebo 
icosabutate 
(2000 mg) 
11 
icosabutate 
(2000 mg) 
placebo 
moxifloxacin 
(400 mg) 
icosabutate 
(600 mg) 
12 
moxifloxacin 
(400 mg) 
icosabutate 
(2000 mg) 
icosabutate 
(600 mg) 
placebo 
Subjects will be screened to assess their eligibility from Day -28 to Day -2. Subjects will be 
admitted to the Clinical Research Unit (CRU) on Day -1 and remain in the CRU until Day 18. 
Each subject will participate in 4 dosing periods, with doses administered in the morning of 
Days 1, 6, 11, and 16 after an overnight fast of at least 8 hours (not including water). Dose 
administration in each dosing period will be separated by a wash-out period of at least 5 days. 
There will be a Follow-up Visit 7 to 10 days after the final dose administration. An overview 
of the study design is shown in Figure 1. 


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Figure 1: 
Study Schematic 
 
Abbreviations: CRU = Clinical Research Unit 
The total duration of study participation for each subject (from Screening through Follow-up 
Visit) is anticipated to be approximately 8 weeks. 
3.2. 
Study Start and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrolment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Discussion of Study Design, Including the Choice of Control Groups 
This study will be randomised and partially double-blind (double-blind with respect to 
icosabutate and placebo; open-label with respect to moxifloxacin) and placebo-controlled in 
order to avoid bias in the collection of data during its conduct. Randomisation eliminates 
confounding by baseline variables and blinding eliminates confounding by concomitant 
interventions and biased safety findings, therefore eliminating the possibility that the 
observed effects of intervention are because of differential use of other treatments or biased 
expectations regarding safety. 
Placebo has been chosen as the control treatment to assess whether any observed effects are 
treatment-related or simply reflect the study conditions. Moxifloxacin has been chosen as the 
positive control to demonstrate assay sensitivity. Moxifloxacin has been shown to produce a 
peak QT interval corrected for heart rate (QTc) prolongation ranging from 10 ms to 15 ms, 
which is above the threshold of regulatory concern.1 
The reading and analysis of ECG data will be fully blinded to treatment and timepoint. 
A crossover design has been chosen to reduce the variability between treatments; each 
subject will serve as his/her own control. 
Healthy subjects will be enrolled to eliminate variables such as concomitant medications and 
diseases known to have an effect on ECG parameters. Male and female subjects will be 
included to eliminate similar known ECG variability effects. 


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3.4. 
Selection of Doses in the Study 
Icosabutate has been tested at single oral doses between 5 mg and 2800 mg and considered to 
be safe and well-tolerated (Section 1.3.1). In a Phase II proof-of-concept study, treatment 
with icosabutate 600 mg resulted in reductions in non-HDL-C compared with placebo that 
were both statistically significant and clinically relevant. Treatment with icosabutate was 
well-tolerated and no safety concerns emerged in this study.2 A total daily dose of 600 mg 
has been chosen to pursue in subsequent clinical trials and to show any cardiac effects at a 
therapeutic dose. 
The supratherapeutic dose of icosabutate was chosen as it produces the highest exposure in 
terms of AUC via the oral route. 
A 400 mg dose has been for moxifloxacin as this is a standard dose used as a positive control 
in TQT studies. At this dose it has been consistently demonstrated to increase QTc ranging 
from 10 ms to 15 ms, which is above the threshold of regulatory concern.1 
A wash-out period of 5 days is considered sufficient for this study because it spans at least 
5 half-lives for icosabutate and moxifloxacin. 
4. SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria at the Screening Visit unless otherwise 
stated: 
1. Males or females, of any race, between 18 and 55 years of age, inclusive, at 
Screening. 
2. Body mass index (BMI) between 18.0 and 33.0 kg/m2, inclusive, at Screening. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory 
evaluations (congenital non-haemolytic hyperbilirubinemia [eg, Gilbert’s syndrome] 
is not acceptable) at Screening or Check-in (Day -1) as assessed by the Investigator 
(or designee). 
4. Females will not be pregnant or lactating, and females of childbearing potential and 
males will agree to use contraception as detailed in Section 6.6. Females of 
non-childbearing potential are defined as permanently sterile (ie, due to hysterectomy, 
bilateral salpingectomy, or bilateral oophorectomy) or post-menopausal (defined as at 
least 12 months post-cessation of menses without an alternative medical cause), 
confirmed by follicle-stimulating hormone (FSH) assessment (>40 mIU/mL) at 
Screening, and will not be required to use contraception. 
5. Able to comprehend and willing to sign an ICF, to comply with all study activities, 
and to abide by the study restrictions. 


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4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
Screening Visit unless otherwise stated: 
1. An uninterpretable or abnormal ECG at Screening and/or Check-in (Day -1), 
indicating a second or third degree atrioventricular block, or 1 or more of the 
following: 
• QRS interval >110 ms; 
• QTcF >430 ms in males and >450 ms in females; 
• PR interval >200 ms; 
• HR <45 beats per minute (bpm); 
• or any rhythm other than sinus rhythm that is interpreted by the Investigator to 
be clinically significant. 
2. History of risk factors for Torsades de Pointes (TdP), including unexplained syncope, 
known long QT syndrome, heart failure, myocardial infarction, angina, or clinically 
significant abnormal laboratory assessments including hypokalaemia, hypercalcemia, 
or hypomagnesemia. Subjects will also be excluded if there is a family history of long 
QT syndrome or Brugada syndrome. 
3. A sustained supine systolic blood pressure >140 mmHg or <90 mmHg, supine 
diastolic blood pressure >90 mmHg or <50 mmHg, or a resting HR of <45 bpm or 
>100 bpm at Screening or Check-in (Day -1). 
• Blood pressure may be repeated once in the supine position. 
• The blood pressure abnormality is considered sustained if either the systolic or the 
diastolic pressure values are outside the above stated limits following 
2 assessments. 
4. Unstable cardiovascular disease, including recent myocardial infarction or cardiac 
arrhythmia. 
5. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
6. History of acquired immunodeficiency syndrome (AIDS) or positive hepatitis panel 
and/or positive human immunodeficiency virus (HIV) test at Screening (Appendix 2). 
7. Significant history of alcoholism or drug/chemical abuse within 2 years prior to 
Screening, in the opinion of the Investigator. 
8. Alcohol consumption of >28 units per week for males and >21 units for females at 
any time in the 6 months prior to first dose (ie, Day 1). One unit of alcohol equals 
½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1 6
ൗ gill (25 mL) of 
spirits. 
9. Positive alcohol breath test result, positive urine drug screen (confirmed by repeat), or 
positive cotinine test at Screening or Check-in (Day -1). 


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10. Clinically significant illness, including viral syndromes within 3 weeks prior to first 
dose (ie, Day 1). 
11. Female subjects who are pregnant (or planning to become pregnant within 90 days 
after the final dose administration) or are currently lactating. 
12. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 3 months (or 5 half-lives, whichever is longer) prior 
to first dose (ie, Day 1). 
13. Have previously completed or withdrawn from this study or any other study 
investigating icosabutate, and have previously received the investigational product. 
14. Use or intend to use any prescription medications/products (including non-steroidal 
anti-inflammatory drugs [NSAIDs] or sucralfate and other medications known to 
prolong the QT/QTc interval), other than hormone replacement therapy, oral, 
implantable, transdermal, injectable, or intrauterine contraceptives, within 14 days (or 
5 half-lives, whichever is longer) prior to first dose (ie, Day 1), unless deemed 
acceptable by the Investigator (or designee). 
15. Use or intend to use any non-prescription/over-the-counter (OTC) 
medications/products including vitamins, minerals, and 
phytotherapeutic/herbal/plant-derived preparations or omega-3 fish oils within 7 days 
prior to first dose (ie, Day 1), unless deemed acceptable by the Investigator (or 
designee). 
16. Use or intend to use slow-release medications/products considered to still be active 
within 14 days (or 5 half-lives, whichever is longer) prior to first dose (ie, Day 1), 
unless deemed acceptable by the Investigator (or designee). 
17. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to first dose (ie, Day 1), unless deemed acceptable by the Investigator (or designee). 
18. Consumption of food and beverages containing poppy seeds, Seville oranges, 
grapefruit, or grapefruit juice, within 7 days prior to Check-in (Day -1; Section 6.2). 
19. Consumption of caffeine- or xanthine-containing products or alcohol within 72 hours 
prior to Check-in (Day -1; Section 6.2). 
20. Use of tobacco- or nicotine-containing products (eg, cigarettes, cigars, chewing 
tobacco, snuff, or nicotine-replacement products) within 30 days prior to first dose 
(Day 1). 
21. Strenuous activity (eg, sports), or intent to participate in strenuous activity from 
4 days before Check-in (Day -1) and throughout the study (until after the final 
Follow-up Visit). 
22. Donation of more than 500 mL blood (or significant blood loss) from 3 months prior 
to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior 
to Screening. 
23. Receipt of blood products within 2 months prior to Check-in (Day -1). 


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24. History of significant hypersensitivity, intolerance, or allergy to any drug compound 
(including moxifloxacin), food, or other substance, unless approved by the 
Investigator (or designee). 
25. Any other medical, psychological, or social condition that, in the opinion of the 
Investigator or the medical monitor, would prevent the subject from fully participating 
in the study, would represent a concern for study compliance, or would constitute a 
safety concern to the subject. 
26. Poor peripheral venous access. 
27. Unable to or may have difficulties swallowing a potentially large number of capsules. 
28. Study site staff or immediate family members of study site staff either directly or 
indirectly involved with the present study. 
29. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
Subjects may previously have been screened on a generic basis to determine their eligibility 
for inclusion in Phase I clinical studies conducted at the CRU. If generic screening was 
performed within the specified study screening window, selected study-specific procedures 
will be repeated either at an additional Screening Visit or on admission to the CRU on 
Day -1. 
4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number immediately after the first dose occasion, at the time of their 
randomisation. Assignment of subject numbers will be in ascending order and no numbers 
will be omitted (eg, Subjects 101, 102, 103, etc). Replacement subjects (Section 4.4) will be 
assigned a subject number corresponding to the number of the subject he/she is replacing plus 
1000 (eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File (SMF). 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the Investigator (or designee) 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 


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subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 5). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the CRU. The Investigator (or designee) may also request that 
the subject return for an additional Follow-up Visit. All withdrawn subjects will be followed 
until resolution of all their adverse events or until the unresolved adverse events are judged 
by the Investigator (or designee) to have stabilised. 
Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of 
adverse events thought to be related to the study drug will generally not be replaced. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• adverse events unknown to date (ie, not previously reported in any similar 
investigational study drug trial with respect to their nature, severity, and/or duration) 
• increased frequency, severity, and/or duration of known, anticipated, or previously 
reported adverse events (this may also apply to adverse events defined at Check-in 
[Day -1] as baseline signs and symptoms) 
• medical or ethical reasons affecting the continued performance of the study 
• difficulties in the recruitment of subjects 
• cancellation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labelling 
The study drugs (200 mg icosabutate capsules in Self-Micro Emulsifying Drug Delivery 
System [SMEDDs] and placebo capsules) will be supplied by the Sponsor (or designee), 
along with the batch/lot number(s) and Certificate(s) of Analysis. A Certificate of Release 
authorised by a Qualified Person in the European Union will also be issued for the study 
drugs. The study drugs will be provided in high-density polyethylene (HDPE) bottles and 
stored according to the instructions on the label. 
All study drugs will be stored at the study site in a location that is locked with restricted 
access. 
The bulk drug container and unit dose containers will be labelled in accordance with national 
laws and regulations. The study drugs will be transferred from bulk supplies into the subject’s 
dose container by qualified clinical staff. 
Moxifloxacin tablets (400 mg) are commercially available in the EU and will be sourced by 
the CRU. The moxifloxacin tablets will be stored in accordance with the requirements 
detailed in the package insert. The moxifloxacin tablets will be subject to accountability 
procedures and unused supplies will be destroyed at the end of the study. 


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5.2. 
Study Treatment Administration 
Subjects will be dosed at the time indicated in the Schedule of Assessments (Appendix 5). 
Each dose of icosabutate, placebo, and moxifloxacin will be administered orally with 
approximately 240 mL of room temperature water. If the capsules cannot be swallowed at the 
same time, drug administration may be divided, but dosing should be completed within 
2 minutes of the scheduled time. Additional water up to a maximum of 50 mL may be 
administered if needed by the subject. All doses will be administered on the mornings of 
Days 1, 6, 11, and 16 following an overnight fast (not including water) of at least 8 hours, and 
will be followed by a fast (not including water) for at least 4 hours postdose. Except as part of 
dose administration, subjects will restrict their consumption of water from 1 hour predose 
until 2 hours postdose; water will be freely available at all other times. 
The number of capsules to be administered on each respective dosing occasion are presented 
in Table 2. 
Table 2: 
Number of Capsules to be Administered on Each Respective Dosing 
Occasion 
 
Number of Capsules 
Icosabutatea 
Placebob 
Moxifloxacin 
600 mg icosabutate (therapeutic dose)c 
3 
7 
NA 
2000 mg icosabutate (supratherapeutic dose)c 
10 
NA 
NA 
400 mg moxifloxacin (positive control)c 
NA 
NA 
1 
Placeboc 
NA 
10 
NA 
Abbreviations: NA = not applicable. 
a. Supplied as 200 mg icosabutate in Self-Micro Emulsifying Drug Delivery System (SMEDDS). 
b. Placebo capsules matched to icosabutate. 
c. Subjects will be randomised to 1 of 12 treatment sequences and will receive a single oral dose of each of the treatments, 
with a minimum 5-day wash-out between doses. To maintain the blind, with the exception of dosing with moxifloxacin, 
the same number of capsules will be given on each dosing occasion. 
Subjects will be administered the study drugs in numerical order while standing and will not 
be permitted to lie supine for 2 hours after dosing, except as necessitated by the occurrence of 
an adverse event(s) and/or study procedures. A hand-and-mouth check will be performed to 
verify that the dose administered was swallowed. 
5.3. 
Randomisation 
The randomisation code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. Subjects will be randomised to 
1 of 12 treatment sequences (Table 1). 
Prior to the start of the study, a copy of the master randomisation code will be supplied in 
sealed envelopes to the Covance CRU pharmacy staff and the biopharmaceutical analyst at 
the bioanalytical laboratory. 


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5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo capsules will be identical in appearance to icosabutate. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomisation code during the assembly procedure. 
• With the exception of dosing with moxifloxacin, the same number of capsules will be 
given on each dosing occasion (Table 2). 
To maintain the blind, the Investigator will be provided with a sealed randomisation code for 
each subject, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject 
safety (in the event of possibly treatment-related serious adverse events or severe adverse 
events), the decision to unblind resides solely with the Investigator. Whenever possible, and 
providing it does not interfere with or delay any decision in the best interest of the subject, 
the Investigator will discuss the intended code-break with the Sponsor. If it becomes 
necessary to break the code during the study, the date, time, and reason will be recorded in 
the subject’s source data and on the individual envelope and will be witnessed by a second 
person. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
• All doses will be administered under the supervision of suitably qualified study site 
staff. 
• Immediately after dose administration, visual inspection of the mouth and hands will 
be performed for each subject. 
• At each dosing occasion, a predose and postdose inventory will be performed on the 
dose containers. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription medications/products (including NSAIDs 
or sucralfate and other medications known to prolong the QT/QTc interval) from 14 days (or 
5 half-lives, whichever is longer) or non-prescription/OTC medications/products including 
vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations or omega-3 fish 
oil from 7 days prior to first dose (ie, Day 1) and during the study until the Follow-up Visit, 
unless the Investigator (or designee) and/or Sponsor have given their prior consent. 
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary in a medical emergency. Any medication taken 
by a subject during the course of the study and the reason for its use will be documented in 
the source data. 
6.2. 
Diet 
While confined at the study site, subjects will receive a standardised diet at scheduled times 
that do not conflict with other study-related activities. Subjects will be fasted overnight (not 
including water; at least 8 hours) before collection of blood samples for clinical laboratory 
evaluations. 
The subjects will be fasted overnight (not including water; at least 8 hours) prior to dosing 
and will refrain from consuming water from 1 hour predose until 2 hours postdose, excluding 
the amount of water consumed at dosing. Food is allowed from 4 hours postdose. Other than 
these fluid restrictions, water will be freely available at all times. 
Foods and beverages containing poppy seeds, Seville oranges, grapefruit, or grapefruit juice 
will not be allowed from 7 days prior to Check-in (Day -1) until the Follow-up Visit. 
Caffeine- or xanthine-containing foods and beverages will not be allowed from 72 hours prior 
to Check-in (Day -1) until discharge from the CRU (Day 18). 
Consumption of alcohol will not be permitted from 72 hours prior to Check-in (Day -1) until 
discharge from the CRU (Day 18). Up to 2 units/day of alcohol are permitted from discharge 
until 36 hours before the Follow-up Visit. 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 30 days 
prior to first dose (ie, Day 1) until the Follow-up Visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 4 days before Check-in (Day -1) 
until after the final Follow-up Visit and will otherwise maintain their normal level of physical 


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activity during this time (ie, will not begin a new exercise program nor participate in any 
unusually strenuous physical exertion). 
6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 3 months prior to Screening, 
plasma from 2 weeks prior to Screening, and platelets from 6 weeks prior to Screening until 
3 months after the Follow-up Visit. 
6.6. 
Contraception 
Female subjects who are of non-childbearing potential will not be required to use 
contraception. Females of non-childbearing potential are defined as permanently sterile (ie, 
due to hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), confirmed by 
history, or post-menopausal (defined as at least 12 months post-cessation of menses without 
an alternative medical cause). Post-menopausal status will be confirmed with a screening 
serum FSH level >40 mIU/mL. 
Female subjects of childbearing potential must be willing to use a highly effective method of 
birth control (ie, contraceptive measure with a failure rate of <1% per year) in conjunction 
with male barrier contraception (ie, male condom with spermicide) from the time of signing 
the ICF until 90 days after the last dose of study drug. Highly effective methods of 
contraception include: 
• established use of oral, implantable, transdermal, or injectable hormonal method of 
contraception associated with inhibition of ovulation 
• hormonal or non-hormonal intrauterine device (IUD; eg, Mirena®). 
• bilateral tubal ligation or occlusion (performed at least 90 days prior to the Screening 
Visit) 
• male sterilisation (performed at least 90 days prior to the Screening Visit), with verbal 
confirmation of surgical success (for female subjects on the study, the vasectomised 
male partner should be the sole partner for that subject) 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
(Day -1) until 90 days after the last dose of study drug. 
Male subjects with partners of childbearing potential must use a male barrier method of 
contraception (ie, male condom with spermicide) in addition to a second method of 
acceptable contraception used by their female partners from Check-in (Day -1) until 90 days 
after the last dose of study drug. In addition to the list of highly effective contraception 
methods above, other acceptable methods of contraception for the female partner include: 
• established use of progesterone only oral contraception, where inhibition of ovulation 
is not the primary mode of action 
• diaphragm, cap, or sponge in conjunction with spermicide. 
For male subjects, sexual intercourse with female partners who are pregnant or breastfeeding 
should be avoided unless condoms are used from the time of the first dose until 90 days after 


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the last dose of study drug. Male subjects are required to refrain from donation of sperm from 
Check-in (Day -1) until 90 days after the last dose of study drug. 
Subjects who practice true abstinence, because of the subject’s lifestyle choice (ie, the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. If a 
subject who is abstinent at the time of signing the ICF becomes sexually active they must 
agree to use contraception as described previously. 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. If a subject who is in a same-sex relationship at the time of signing the ICF becomes 
engaged in a heterosexual relationship, they must agree to use contraception as described 
previously. 
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and the other procedures to be performed at the same timepoint. 
The order of priority for scheduling procedures around a timepoint is (in descending order of 
priority): 
• dosing 
• ECG extraction 
• blood samples 
• any other procedures (safety ECGs will be scheduled before vital sign measurements) 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples (approximately 1 × 2.0 mL) will be collected by venepuncture or cannulation 
at the times indicated in the Schedule of Assessments (Appendix 5). Furthermore, up to 
3 additional blood samples may be taken from each subject per dosing period, with the 
maximum volume of blood withdrawn per subject not exceeding the limit detailed in 
Appendix 3. Any changes to the scheduled times of PK assessments will be agreed with the 
Sponsor and documented in the Trial Master File (TMF). Samples taken from subjects 
following the administration of placebo will not be analysed. 
Procedures for collection, processing, and shipping of PK blood samples will be detailed in a 
separate document. 


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7.1.2. 
Analytical Methodology 
Plasma concentrations of icosabutate and moxifloxacin will be determined using validated 
analytical procedures. Specifics of the analytical methods will be provided in separate 
document(s). 
7.2. 
Cardiodynamic (Continuous) 12-lead Electrocardiogram Recordings 
7.2.1. 
Electrocardiogram Collection 
Electrocardiograms for the assessment of QT/QTc will be recorded continuously, which will 
obtain ECGs prior to, and for approximately 25 hours after, administration of study drug in 
each treatment period. The cardiodynamic assessments will be performed through 12-lead 
ECGs extracted from continuous recordings at pre-specified timepoints, paired with PK 
samples, at the times indicated in the Schedule of Assessments (Appendix 5). 
To ensure quality ECG extractions, subjects will be resting (supine) for at least 10 minutes 
before and 5 minutes after each ECG extraction window. The ECGs will be extracted from 
continuous 24-hour ECG recording during an extraction window of 5 minutes after the 
nominal timepoint. Environmental distraction (eg, television, playing games, radio, 
conversation) should be avoided during the pre-ECG resting period and during ECG 
recording. 
7.2.2. 
QTc Analysis 
Continuous 12-lead ECG recordings will be performed from 1 hour predose to approximately 
25 hours postdose in each dosing period (ie, Days 1, 6, 11, and 16). 
The 12-lead ECGs to be used in the analyses will be selected by pre-determined timepoints as 
defined in the Schedule of Assessments (Appendix 5). At the ECG core laboratory, up to 
10 replicate ECGs will be extracted at each of the following timepoints in each dosing period 
(ie, Days 1, 6, 11, and 16): -45, -30, and -15 minutes predose, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 
8, 10, 12, and 24 hours postdose. 
The following principles will be followed in the ECG core laboratory when data are analysed: 
• The ECG analysts are blinded to the subject, visit, and treatment allocation. 
• Baseline and on-treatment ECGs for a particular subject will be over-read on the same 
lead and will be analysed by the same reader. 
• The primary analysis lead is lead II. If lead II is not analysable, then primary lead of 
analysis will be changed to another lead for the entire subject data set. 
A brief description of the ECG analysis methods utilised by iCardiac’s core laboratory are 
presented in Sections 7.2.3 and 7.2.4. 
7.2.3. 
12-lead Electrocardiogram Extraction Technique 
Ten 14-second digital 12-lead ECG tracings will be extracted from continuous Holter 
recordings using the ‘TQT Plus method’. This method enables extraction of ECGs with the 


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lowest HR variability and noise within the protocol-specified extraction time window (eg, the 
HR and QT changes from beat-to-beat in the range of <10%). At each protocol-specified 
timepoint, 10 ECG replicates will be extracted from a 5-minute ‘ECG window’ (typically, the 
last 5 minutes of the 15 minute period when the subject is maintained in a supine or 
semi-recumbent quiet position). 
7.2.4. 
High-precision QT Analysis 
High-precision QT analysis will be performed on all analysable (non-artefact) beats in the 
10 ECG replicates. Statistical quality control procedures are used to review and assess all 
beats and identify ‘high’ and ‘low’ confidence beats using several criteria, including: 
• QT or QTc values exceeding or below certain thresholds (biologically unlikely) 
• RR values exceeding or below certain thresholds (biologically unlikely) 
• Rapid changes in QT, QTc, or RR from beat-to-beat 
Measurement of all primary ECG parameters (QT, QTc, and RR) in all recorded beats of all 
replicates that are deemed ‘high confidence’ is performed using COMPAS software. All ‘low 
confidence’ beats are reviewed manually and adjudicated using pass-fail criteria. The final 
quality control assessment is performed by a cardiologist. The beats found acceptable by 
manual review will be included in the analysis. The median QT, QTc, and RR value from 
each extracted replicate will be calculated, and the mean of all available medications from a 
nominal timepoint will be used as the subject’s reportable value at that timepoint. 
Categorical T-wave morphology analysis and the measurement of PR and QRS intervals will 
be performed manually in 3 of the 10 ECG replicates at each extraction timepoint. Each 
fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) will 
be electronically marked. The T-wave morphology categories are presented in Table 3. 
Table 3: 
T-wave Morphology Categories 
Category 
Description 
Normal T-wave 
Any T-wave not meeting any criterion below 
Flat T-wave 
T amplitude <1 mm (either positive or negative) including flat isoelectric line 
Notched T-wave 
Presence of notch(es) of at least 0.05 mV amplitude on ascending or 
descending arm of the positive T-wave 
Biphasic T-wave 
T-wave that contains a second component with an opposite phase that is at 
least 0.1 mV deep (both positive and negative/positive polyphasic T-waves 
included) 
Normal T-wave (-) 
T amplitude that is negative, without biphasic T-wave or notch(es) 
Notched T-wave(-) 
Presence of notch(es) of at least 0.05 mV amplitude on descending or 
ascending arm of the negative T-wave 
In addition to the T-wave categorical analysis, the presence of abnormal U-waves will be 
noted. 
The ECG extractions will be time-matched to the PK samples; however, these will be 
obtained prior to the actual PK sampling time in order to avoid changes in autonomic tone 


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associated with the psychological aspects of blood collection, in addition to the reduction in 
blood volume subsequent to blood collection. 
7.3. 
Safety and Tolerability Assessments 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
serious adverse events are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to final 
discharge from the study. Subjects will be observed for any signs or symptoms and asked 
about their condition by open questioning, such as ‘How have you been feeling since you 
were last asked?’, at least once each day while resident at the study site and at each study 
visit. Subjects will also be encouraged to spontaneously report adverse events occurring at 
any other time during the study. 
Any adverse events and remedial action required will be recorded in the subject’s source 
data. The nature, time of onset, duration, and severity will be documented, together with an 
Investigator’s (or designee’s) opinion of the relationship to study drug. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
12-lead Safety Electrocardiogram 
Cardiac safety will be assessed by Investigator evaluation of standard 12-lead ECGs 
measured using ECG recorders at the times indicated in the Schedule of Assessments 
(Appendix 5). Resting 12-lead ECGs will be recorded after the subjects has been supine and 
at rest for at least 5 minutes. Single 12-lead ECGs will be repeated once if either of the 
following criteria apply: 
• QTcF value >450 ms for females or >430 ms for males 
• QTcF change from the baseline (predose) is >60 ms 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG. 
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The median value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, and oral body temperature will be assessed at the 
times indicated in the Schedule of Assessments (Appendix 5), and repeated once if outside 
the relevant clinical reference ranges. Vital signs may also be performed at other times if 


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judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of vital signs is required. 
Subjects must be supine for no less than 5 minutes before blood pressure and pulse rate 
measurements. 
7.3.4. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, haematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments (Appendix 5). Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
(Appendix 5). For all female subjects, a pregnancy test and FSH will be performed at the 
times indicated in the Schedule of Assessments (Appendix 5). 
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory 
data. 
7.3.5. 
Physical Examination 
A full physical examination or abbreviated physical examination will be performed at the 
timepoints specified in the Schedule of Assessments (Appendix 5). 
7.3.6. 
Body Weight and Height 
Body weight (in underclothes) and height (for calculation of BMI) will be recorded at the 
times indicated in the Schedule of Assessments (Appendix 5). 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
A total of 32 subjects will be enrolled in order that a minimum of 28 subjects complete the 
study. Based on experience from the IQ-CSRC study3 simulations to evaluate the power of 
small studies with exposure-response analysis4, and the observations from 25 recent TQT 
studies using exposure-response analysis, a sample size of 28 will provide more than 95% 
power to exclude that icosabutate causes more than a 10-ms QTc effect at clinically relevant 
plasma levels, as shown by the upper bound of the 2-sided 90% confidence interval (CI) of 
the model predicted QTc effect (∆∆QTcF) at the observed geometrical mean Cmax of 
icosabutate in the study. 
In addition to the evaluation through modelling and simulation, the sample size can be 
estimated approximately using a simple paired t-test for equivalence. Under the assumption 
that the QTc effect is 3 ms for icosabutate and 0 ms for placebo with a common standard 
deviation (SD) of change-from-baseline QTcF (∆QTcF) of 8 ms for each treatment, and that 


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‘No Effect’ will be concluded if the 90% CI of ∆∆QTcF is lower than 10 ms, 28 subjects will 
provide >95% power with a one-sided alpha of 5% in paired t-test. This estimation was 
performed using the paired t-test for equivalence of Means in R Version 3.2.5. 
8.2. 
Sample Size Considerations for Assay Sensitivity 
To demonstrate assay sensitivity with exposure-response analysis, it has to be shown that the 
ΔΔQTcF of a single dose of 400 mg moxifloxacin exceeds 5 ms (ie, the lower bound of the 
2-sided 90% CI of the predicted QTc effect [ΔΔQTcF] should exceed 5 ms). In a similarly 
designed recent crossover study with 24 healthy subjects, the standard error (SE) for the 
prediction of the QT effect of moxifloxacin based on the exposure-response analysis was 
1.24 ms. The within-subject SD of ΔQTcF in the referred study was 5.4 ms. If the effect of 
moxifloxacin is assumed to be 10 ms, the SE of 1.24 ms corresponds to an effect size of 
൮(10 −5)
(1.24 × √24)
൘
൲= 0.82, where the effect size is the effect assumed under the 
alternative hypothesis divided by the SD of the test variable. In a one-sample t-test situation 
with a sample size of 24 subjects, this effect size results in a power of 98.8%. This value 
should be compared with the effect size of 0.57 required to guarantee a power of at least 90% 
in a one-sample t-test situation with a sample size of 28 subjects. Based on this calculation, a 
power of at least 90% will be obtained as long as the variability of ΔQTcF, as measured by its 
SD, does not exceed 7.8 ms (ie, 144% of the 5.4 ms observed in the referred study). 
8.3. 
Analysis Populations 
8.3.1. 
Safety Population 
The Safety Population will include all subjects enrolled in the study who receive at least 
1 dose of study drug (icosabutate, moxifloxacin, or placebo). 
8.3.2. 
Pharmacokinetic Population 
The Pharmacokinetic Population will include all subjects who received at least 1 dose of 
icosabutate or moxifloxacin and have evaluable PK data. Subjects will be excluded from the 
PK summary statistics and statistical analysis if a subject has an adverse event of vomiting 
that occurs at or before 2 times median time to maximum concentration. 
8.3.3. 
QT/QTc Population 
The QT/QTc Population will include all subjects in the Safety Population with measurements 
at baseline as well as on-treatment with at least 1 postdose timepoint with a valid 
change-from-baseline QTcF (ΔQTcF) value. The QT/QTc population will be used for the 
analysis of ECG parameters. 
8.3.4. 
Pharmacokinetic/QTc Population 
The Pharmacokinetic/QTc Population will include all subjects who are in both the 
Pharmacokinetic and QT/QTc Populations with at least 1 pair of postdose PK and QTcF data 
from the same timepoint. The Pharmacokinetic/QTc population will be used for the 
exposure-response analysis and will be defined for icosabutate and for moxifloxacin. 


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8.4. 
Statistical Analyses of Cardiodynamic (Continuous) 12-lead Electrocardiogram 
Data 
The primary analysis will be based on exposure-response modelling of the relationship 
between icosabutate and Δ∆QTcF, with the intent to exclude an effect >10 ms at clinically 
relevant icosabutate plasma concentrations. 
In addition, the effect of icosabutate on ∆∆QTcF will be evaluated at each postdose timepoint 
(‘by-timepoint’ analysis) using the Intersection Union Test. An analysis of categorical 
outliers will be performed for changes in HR, PR, QRS, QTcF, T-wave morphology, and 
U-wave presence. 
Assay sensitivity will be evaluated by exposure-response analysis of the effect on Δ∆QTcF of 
moxifloxacin using a similar model as for the primary analysis. If the slope of the 
exposure-response relationship is statistically significant at 10% level of significance in a 
2-sided test and the lower bound of the 2-sided 90% CI of the predicted QT effect at the 
observed geometric mean Cmax following a single dose of 400 mg moxifloxacin is above 
5 ms, it will be concluded that assay sensitivity has been demonstrated. 
8.4.1. 
Baseline 
For all 12-lead ECG parameters from each dosing period, baseline will be the average of the 
derived ECG intervals from the 3 ECG timepoints prior to dosing (ie, -45, -30, 
and -15 minutes) at each dosing period (Days 1, 6, 11, and 16). 
8.4.2. 
Exposure-response Analysis 
The exposure-response analysis will be based on ΔΔQTcF; ie, for the placebo adjustment, the 
individual ΔQTcF for placebo calculated at a specific timepoint is subtracted from ΔQTcF for 
the same subject on icosabutate at the same timepoint to generate ΔΔQTcF. The relationship 
between icosabutate plasma concentration and ΔΔQTcF will be investigated by linear 
mixed-effects modelling. The following 3 linear models will be considered: 
• Model 1; a linear model with an intercept 
• Model 2; a linear model with mean intercept fixed to 0 (with variability) 
• Model 3; a linear model with no intercept 
Time-matched concentration of icosabutate will be included in the model as a covariate and 
subject as a random effect for both intercept and slope, when applicable. The model that fits 
the data best (ie, has the smallest Akaike Information Criterion and model-predicted CI 
similar to the observed CIs) will be used for predicting population average ΔΔQTcF and its 
corresponding 2-sided 90% CI at the observed mean Cmax. If the upper bound of the 2-sided 
90% CI of the predicted effect at this plasma level is below 10 ms, it will be concluded that 
icosabutate does not cause clinically relevant QTc prolongation. 
The plot of the observed median-quantile icosabutate concentrations and associated mean 
ΔΔQTcF interval (90% CI) together with the regression line presenting the predicted 
ΔΔQTcF interval (90% CI)5 will be used to evaluate the adequacy of the model fit of the 
primary model to the assumption of linearity and the impact on quantifying the 


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exposure-response. For evaluation of the HR-QTc interval, scatter plot of QTcF and 
RR intervals by treatment with regression line will be also given. Additional exploratory 
analyses (via graphical displays and/or model fitting) will include accounting for a delayed 
effect (hysteresis) and the justification for the choice of pharmacodynamic model (linear 
versus nonlinear) as follows. 
8.4.2.1. 
Investigation of Hysteresis 
Hysteresis will be assessed based on joint graphical displays of the least squares (LS) mean 
difference between ΔQTcF under icosabutate and under placebo (ΔΔQTcF) for each postdose 
timepoint and the mean concentrations of icosabutate at the same timepoints. In addition, 
hysteresis plots will be given for mean ΔΔQTcF and each of the mean concentrations. If a QT 
effect (∆∆QTcF) >10 ms cannot be excluded from the by-timepoint analysis and if a delay 
between peak ∆∆QTcF and peak plasma concentration in the plot (ΔΔQTcF versus 
icosabutate) of more than 1 hour is observed, other exposure-response models, such as a 
model with an effect compartment, may be explored. With the provision stated above, 
hysteresis will be assumed if the curve shows a counterclockwise loop. 
8.4.2.2. 
Appropriateness of a Linear Model 
To assess the appropriateness of a linear model, normal Q-Q plots for the residuals and plots 
of weighted residuals versus concentration and versus fitted values will be produced. The 
scatter plot of residuals versus concentration by LOESS fitting (ie, locally weighted scatter 
plot smoothing)6 will also be produced with an optimal smoothing parameter selected by the 
Akaike Information Criterion with a correction (AICC).7 In addition, a model with both the 
original term and a quadratic term in concentration will be fitted and the quadratic term will 
be tested on the 2-sided 5% level. If there is an indication that a linear model is inappropriate, 
additional models will be fitted; in particular: 
• a maximum response (Emax) model 
• a log-transformation model where the plasma concentration ‘C’ is replaced by 
ln/(C/C0), where C0 is the limit of quantification of the assay used to determine C, 
and all values below C0 are replaced by C0 (ie, log [C0/C0]=0) 
The exposure-response analysis will be repeated for the model found to best accommodate 
the nonlinearity detected. 
8.4.3. 
Assay Sensitivity 
To determine assay sensitivity, the exposure-response (∆∆QTcF) of 400 mg oral 
moxifloxacin will be utilised. If the slope of the moxifloxacin plasma concentration/∆∆QTcF 
relationship is statistically significant at the 10% level in a 2-sided test and the lower bound 
of the 2-sided 90% CI of the predicted QT effect at the geometric mean Cmax following a 
single dose of 400 mg moxifloxacin is above 5 ms, it will be concluded that assay sensitivity 
has been demonstrated. 


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8.4.4. 
By-timepoint Analysis (Secondary Analysis) 
The ‘by-timepoint analysis’ for QTcF will be based on a linear mixed-effects model with 
ΔQTcF as the dependent variable, period, sequence, time (ie, timepoint will be categorical), 
treatment (icosabutate, moxifloxacin, and placebo), and time-by-treatment interaction as 
fixed effects, and baseline QTcF as a covariate. An unstructured covariance matrix will be 
specified for the repeated measures at postdose timepoints for subject within dosing period. If 
the model with unstructured covariance matrix fails to converge, other covariance matrix 
such as autoregressive and compound symmetry will be considered. If the fixed effects for 
period and/or sequence should prove to be non-significant (ie, if the p-value >0.1), these 
effects may be removed from the model and the analysis will be repeated without those 
covariates. Subjects dosed with placebo will be analysed as a pooled group. From this 
analysis, the LS means and 2-sided 90 % CI will be calculated for the contrast ‘icosabutate 
versus placebo’ at each dose of icosabutate and each postdose timepoint on Days 1, 6, 11, and 
16 in addition to each predose timepoint on Days 6, 11, and 16, separately. 
For HR, PR, and QRS interval, the analysis will be based on the change-from-baseline 
postdose (ΔHR, ΔPR, and ΔQRS, respectively). The same (by-timepoint analysis) model will 
be used as described for QTcF. The LS mean, SE and 2-sided 90% CI from the statistical 
modelling for both change-from-baseline and placebo-corrected change-from-baseline values 
will be listed in the tables and graphically displayed. 
8.4.5. 
Categorical Analysis 
The analysis results for categorical outliers, T-wave morphology, and U-wave presence will 
be summarised in frequency tables with counts percentages for both number of subjects and 
number of timepoints. For categorical outliers, the number (percentage) of subjects in 
addition to timepoints with increases in absolute QTcF interval values >450 ms and ≤480 ms, 
>480 ms and ≤500 ms, and >500 ms, and changes from predose >30 ms and ≤60 ms, and 
>60 ms; increase in PR interval from predose >25% to a PR >200 ms; increase in QRS 
interval from predose >25% to a QRS >120 ms; decrease in HR from predose >25% to a HR 
<50 bpm; and increase in HR from predose >25% to a HR >100 bpm will be determined. 
For T-wave morphology and U-wave presence, the analysis will be focused on change from 
baseline, ie, treatment-emergent changes (across all timepoints). 
8.5. 
Pharmacokinetic Analyses 
Non-compartmental PK analysis will be performed on individual plasma concentration data, 
using commercial software such as Phoenix® WinNonlin®. Plasma concentrations of 
icosabutate and PK parameters will be listed and summarised using descriptive statistics. 
For each subject, the following PK parameters will be calculated for icosabutate, where 
possible: 
• AUC0-t: 
area under the plasma concentration-time curve from time zero to the 
 
 
time of the last observed concentration 
• Cmax:  
maximum observed plasma concentration 
• Tmax:  
time of the maximum observed plasma concentration 


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Additional PK parameters may be determined, if deemed appropriate. Details of the 
parameters, and handling procedures, will be described in the Statistical Analysis Plan (SAP). 
For the purposes of establishing assay sensitivity, moxifloxacin plasma concentrations will be 
measured to allow concentration QTc analysis. 
Plasma concentrations and PK parameters will be summarised by treatment using descriptive 
statistics. No formal statistical analysis of PK parameters will be performed. 
8.6. 
Safety Analysis 
Safety will be evaluated in terms of reported adverse events and other clinical observations, 
clinical laboratory test results (haematology, clinical chemistry, and urinalysis), vital sign 
measurements (blood pressure, pulse rate, and oral body temperature), 12-lead safety ECG 
results, and physical examination findings. 
Safety parameters will be listed and summarised using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each adverse event will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
8.7. 
Interim Analysis 
No interim analyses are planned for this study. 
9. REFERENCES 
1.  Food and Drug Administration. Guidance for Industry: E14 Clinical Evaluation of 
QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic 
Drugs. Food and Drug Administration; 2005.  
2.  NorthSea Therapeutics. NST-4016 - Investigator’s Brochure. Version 7, 24 January 2018.  
3.  Darpo B, Benson C, Dota C, Ferber G, Garnett C, Green CL, et al. Results from the IQ-
CSRC prospective study support replacement of the thorough QT study by QT 
assessment in the early clinical phase. Clin Pharmacol Ther. 2015 Apr;97(4):326–35.  
4.  Ferber G, Zhou M, Darpo B. Detection of QTc effects in small studies--implications for 
replacing the thorough QT study. Ann Noninvasive Electrocardiol Off J Int Soc Holter 
Noninvasive Electrocardiol Inc. 2015 Jul;20(4):368–77.  
5.  Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin Pharmacol. 2011 Jul;51(7):1035–42.  
6.  S. Cleveland W, J. Devlin S. Locally Weighted Regression: An Approach to Regression 
Analysis by Local Fitting. J Am Stat Assoc. 1988 Sep 1;83:569–610.  
7.  Hurvich CM, Simonoff JS, Tsai C-L. Smoothing parameter selection in nonparametric 
regression using an improved Akaike information criterion. J R Stat Soc Ser B Stat 
Methodol. 2002 Jan 6;60(2):271–93.  


Protocol 
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Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 39 of 51 
10. APPENDICES 


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Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 40 of 51 
APPENDIX 1: Adverse Event Reporting 
Definitions 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavourable and/or 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a study drug, whether or not related to the study drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the adverse event 
using the following categories: 
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
• Severe: Interrupts usual activities of daily living, or significant affects clinical status, 
or may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The Investigator will make a determination of the relationship of the adverse event to the 
study drug using a 2-category system according to the following guidelines: 
• Not Related: The adverse event is definitely caused by the subject’s clinical state or 
the study procedure/conditions. 
• Related: The adverse event follows a reasonable temporal sequence from 
administration of the drug, abates upon discontinuation of the drug, follows a known 
or hypothesised cause-effect relationship, and (if appropriate) reappears when the 
drug is reintroduced. 
Follow-up of Adverse Events 
Every reasonable effort will be made to follow-up with subjects who have adverse events. 
Any subject who has an ongoing adverse event that is related to the study drug (icosabutate, 
placebo, or moxifloxacin) or study procedures at the Follow-up Visit will be followed up, 
where possible, until resolution. This will be completed at the Investigator’s (or designee’s) 
discretion. Any subject who has an ongoing adverse event that is not related to the study drug 
or study procedures at the Follow-up Visit can be closed out as ongoing at the Investigator’s 
discretion. 


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Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 41 of 51 
Adverse Drug Reactions 
All noxious and unintended responses to a study drug (ie, where a causal relationship 
between a study drug and an adverse event is at least a reasonable possibility) related to any 
dose should be considered adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended and 
which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of 
diseases or for modification of physiological function is to be considered an adverse drug 
reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (eg, Investigator’s 
Brochure [IB] for an unapproved investigational medicinal product [IMP]). 
Serious Adverse Events 
A serious adverse event is defined as any untoward medical occurrence that at any dose 
either: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered serious adverse events when, based upon appropriate 
medical judgment, they may jeopardise the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
Instances of death or congenital abnormality, if brought to the attention of the Investigator at 
any time after cessation of the study treatment and considered by the Investigator to be 
related to the study treatment, will be reported to the Sponsor. 
Definition of Life-threatening 
An adverse event is life-threatening if the subject was at immediate risk of death from the 
event as it occurred (ie, does not include a reaction that might have caused death if it had 
occurred in a more serious form). For instance, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life-threatening even though 
drug-induced hepatitis can be fatal. 
 
 


Protocol 
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Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 42 of 51 
Definition of Hospitalisation 
Adverse events requiring hospitalisation should be considered serious. In general, 
hospitalisation signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalisation occurred or was necessary, the adverse event should be considered as serious. 
Hospitalisation for elective surgery or routine clinical procedures, which are not the result of 
an adverse event, need not be considered adverse events and should be recorded on a Clinical 
Assessment Form and added to the electronic Case Report Form. If anything untoward is 
reported during the procedure, this must be reported as an adverse event and either ‘serious’ 
or ‘non-serious’ attributed according to the usual criteria. 
Serious Adverse Event Reporting 
The Sponsor, NorthSea Therapeutics BV, DC Naarden, The Netherlands are responsible for 
coordinating the reporting of serious adverse events in accordance with the European 
Directive 2001/20/EC. 
The Investigator will complete a serious adverse event report form and forward it by email or 
fax to Bionical Emas immediately (within 24 hours) upon becoming aware of a serious 
adverse event. 
Email: drug.safety@bionical-emas.com 
Or 
Fax: +44 (0)1462 600456 
The responsibilities of Bionical Emas include the following: 
• Prepare a serious adverse event reporting plan prior to the start of the study. Where 
this plan differs from the applicable CRU standard operating procedure on serious 
adverse event reporting, the adverse event reporting plan will always take precedence. 
• Write serious adverse events case narratives for entry into the PV-works database. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions 
and forward to the Ethics Committee, Medicines and Healthcare Products Regulatory 
Agency, and Principal Investigator within the timeframes stipulated in the Clinical 
Trials Directive Guideline (ENTR/CT 3). 
The responsibility for reporting SAEs will be transferred to the Sponsor 28 days after the end 
of the study. 
Pregnancy 
Female subjects of childbearing potential will be instructed to use adequate contraceptive 
precautions until 90 days after the last dose of study drug. To ensure subjects’ safety, each 
pregnancy in a subject who has received study drug must be reported using the appropriate 


Protocol 
CONFIDENTIAL 
Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 43 of 51 
pregnancy form and forward it by email or fax to Bionical Emas (contact details below) 
within 24 hours of learning of its occurrence (either from the result of a urine pregnancy test 
or the verbal information). The pregnancy outcomes, including spontaneous or voluntary 
termination, details of the birth, and the presence/absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications will be followed. Any serious 
adverse events experienced during pregnancy should also be reported. 
Female subjects who are of non-childbearing potential, subjects who practice true abstinence, 
and subjects who are exclusively in same-sex relationships will not be required to use 
contraception. 
Email: drug.safety@bionical-emas.com 
Or 
Fax: +44 (0)1462 600456 


Protocol 
CONFIDENTIAL 
Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 44 of 51 
APPENDIX 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Haematology: 
Urinalysis: 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase (GGT) 
Glucose 
Inorganic phosphate 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Urea 
Uric acid 
Haematocrit 
Haemoglobin 
Mean cell haemoglobin (MCH) 
Mean cell haemoglobin 
concentration (MCHC) 
Mean cell volume (MCV) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination 
Serology:a 
Drug screen:b 
Hormone panel - females only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency (HIV-1 
and HIV-2) antibodies 
Including but not limited to: 
Amphetamines/methamphetamines
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/cannabinoids
Tricyclic antidepressants 
Alcohol breath test 
Cotinine 
Follicle-stimulating hormone (FSH)c
Serum pregnancy test (human 
chorionic gonadotropin)c 
Urine pregnancy testd,e 
a. Only analysed at Screening. 
b. Only analysed at Screening and Check-in (Day -1). 
c. Performed at Screening for all females. 
d. Performed at Check-in (Day -1) and Follow-up at 7 to 10 days after the final dose administration. 
e. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 


Protocol 
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Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 45 of 51 
APPENDIX 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
 
Volume per Blood 
Sample (mL) 
Maximum Number 
of Blood Samples 
Total Amount of 
Blood (mL) 
Serology 
3.5 
1 
3.5 
Clinical laboratory evaluations 
(clinical chemistry and 
haematology)a 
7.5 
6 
45.0 
Pharmacokinetic samples 
2.0 
64b 
128.0 
Total: 
176.5 
a. Includes pregnancy and follicle-stimulating hormone (FSH) test for all female subjects; a pregnancy test is performed in 
serum at Screening. 
b. Includes an additional 3 blood samples per dosing period (Section 7.1.1). 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 255 mL. 


Protocol 
CONFIDENTIAL 
Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 46 of 51 
APPENDIX 4: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure 
(IB), and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated. 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any non-substantial changes, as defined 
by regulatory requirements. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the EC. 
• Notifying the EC of serious adverse events or other significant safety findings as 
required by EC procedures. 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 


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Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 47 of 51 
Following discussion of the study with Clinical Research Unit (CRU) personnel, subjects will 
sign 2 copies of the ICF in the presence of a suitably trained member of staff to indicate that 
they are freely giving their informed consent. One copy will be given to the subject, and the 
other will be maintained in the subject’s records. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic 
Case Report Forms (eCRFs), study-related forms, study reports, or any related publications. 
Subject and Investigator personal data will be treated in compliance with all applicable laws 
and regulations. In the event the study protocol, study report, or study data are included in a 
public registry, all identifiable information from individual subjects or Investigator will be 
redacted according to applicable laws and regulations. 
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data 
may be examined by Sponsor or Contract Research Organisation (CRO) auditors or other 
authorised personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Covance is responsible for the data management of this study including quality 
checking of the data. Pre-defined, agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on the 
data may be included in a Data Management Plan. 


Protocol 
CONFIDENTIAL 
Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 48 of 51 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorised site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH Good Clinical Practice 
(GCP), and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in the study site archive for at least 5 years after 
the end of the study unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the 
written approval of the Sponsor. No records may be transferred to another location or 
party without written notification to the Sponsor. 
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 Code of Federal 
Regulations (CFR) Part A1-compliant electronic data capture (EDC) system on an eCRF in a 
timely fashion. 
All data generated from external sources (eg, laboratory and bioanalytical data), and 
transmitted to Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedures, according to the eCRF completion instructions. The Sponsor, or CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 
the accuracy of the electronic data. The Investigator will ensure that corrections are made to 
the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognised (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process shall 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator shall submit reports, abstracts, manuscripts, and or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor shall have 60 days to respond with any requested revisions, 
including without limitation, the deletion of confidential information. The Investigator shall 
act in good faith upon requested revisions, except the Investigator shall delete any 
confidential information from such proposed publications. The Investigator shall delay 
submission of such publication or presentation materials for up to an additional 90 days in 
order to have a patent application(s) filed. 


Protocol 
CONFIDENTIAL 
Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 49 of 51 
APPENDIX 5: Schedule of Assessments 


Protocol 
CONFIDENTIAL 
Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 50 of 51 
Table 4: 
Schedule of Assessments for NST-01 
 
Screening
(Day -28 to 
Day -2) 
Check-in
(Day -1) 
Study Day 
Follow-up Visit 
(7 to 10 days 
Post-final Dose)a 
Dosing 
Period 1 
Dosing 
Period 2 
Dosing 
Period 3 
Dosing 
Period 4 
1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 16 17 18
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data (including 
smoking history)b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary drug screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine cotinine test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum follicle-stimulating hormone 
(FSH)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Previous medications 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Residency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
Non-residential visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Randomisation 
 
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administrationf 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling (plasma)g 
 
 
X X
 
 
 
X
X 
 
 
 
X
X
 
 
 
X
X
 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8383557 
Protocol Reference: NST-01 
Final, 11 April 2018 
Page 51 of 51 
 
Screening
(Day -28 to 
Day -2) 
Check-in
(Day -1) 
Study Day 
Follow-up Visit 
(7 to 10 days 
Post-final Dose)a 
Dosing 
Period 1 
Dosing 
Period 2 
Dosing 
Period 3 
Dosing 
Period 4 
1
2
3
4
5
6
7 8 9 10 11 12 13 14 15 16 17 18
Cardiodynamic (Continuous) 
12-lead Electrocardiogram (ECG)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG recordingsh 
 
 
X X
 
 
 
X
X 
 
 
 
X
X
 
 
 
X
X
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
X 
X 
X X X X X X
X X
X
X
X
X
X
X
X
X
X
X
X 
Concomitant therapy 
X 
X 
X X X X X X
X X
X
X
X
X
X
X
X
X
X
X
X 
12-lead safety ECGi 
X 
X 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
X 
Vital signs (blood pressure, pulse 
rate, and oral body temperature)j 
X 
X 
X X X X X X
X X
X
X
X
X
X
X
X
X
X
X
X 
Clinical laboratory evaluations 
X 
X 
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
X 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
X 
Abbreviated physical examination 
 
X 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
 
X
 
 
 
a. If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the withdrawal will be documented in the subject’s electronic Case Report Form (eCRF); efforts 
will be made to perform all follow-up assessments, if possible. Other procedures may be performed at the Investigator’s (or designee’s) and/or Sponsor’s discretion. If the subject is 
in-house, these procedures should be performed before the subject is discharged from the Clinical Research Unit (CRU). The Investigator (or designee) may also request that the 
subject return for an additional Follow-up Visit. 
b. Demographics will also include alcohol and caffeine consumption. 
c. Interim medical history. 
d. Serum FSH will be performed in all female subjects at Screening to confirm menopausal status. 
e. In all female subjects, performed in serum at Screening and in urine at all other times. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
f. Doses will be administered on the morning of Days 1, 6, 11, and 16 following an overnight fast (not including water) of at least 8 hours. 
g. Blood samples for plasma pharmacokinetic (PK) analysis will be taken at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose in each dosing period. 
h. Continuous 12-lead ECG recordings will be performed from 1 hour predose to approximately 25 hours postdose in each dosing period. On Days 1, 6, 11, and 16, 12-lead ECGs will be 
extracted in replicates at 3 timepoints prior to dosing (-45, -30, and -15 minutes) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours postdose. At each extraction timepoint, subjects 
will be supine for at least 10 minutes prior to and 5 minutes after each timepoint. 
i. The 12-lead safety ECGs should be performed after the subject has been in a supine position and at rest for at least 5 minutes. Safety12-lead ECGs will be collected at Screening, 
Check-in (Day -1), and the Follow-up Visit, and on Days 1, 6, 11, and 16 at predose and 1.5 and 6 hours postdose. At predose on Day 1, 12-lead ECGs will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. 
j. On Days 1, 6, 11, and 16, vital sign assessments will be taken at predose and 2 hours postdose. Subjects must be supine for no less than 5 minutes before blood pressure and pulse rate 
measurements. 

SAP_001.pdf: 
Final: 26 July 2018 
 
Page 1 of 16 
 
STATISTICAL ANALYSIS PLAN 
A Randomised, Partially Double-blind, Placebo- and Positive-controlled, 4-way Crossover 
Study to Evaluate the Effect of Icosabutate (NST-4016) on the QT/QTc Interval in Healthy 
Subjects 
Statistical Analysis Plan Status: Final 
Statistical Analysis Plan Date: 26 July 2018 
Study Drug: icosabutate (NST-4016) 
Sponsor Reference Number: NST-01 
Covance Study Number: 8383557 
Clinical Phase 1 
 
 
Sponsor: 
 
NorthSea Therapeutics BV 
Gooimeer 2-35 
1411, DC Naarden 
The Netherlands 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House, Hyde Street 
Leeds, LS2 9LH 
UK 
 
 
Sponsor Signatory: 
Dr. Patrick Round, MBBS FFPM 
Principal Investigator: 
Dr. Ashley Brooks, MBChB 
 
 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8383557 
 
Sponsor Reference: NST-01 
 
Final: 26 July 2018 
 
Page 2 of 16 
 
1  STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES 
By signing this page when the Statistical Analysis Plan (SAP) is considered final, the signatories 
agree to the safety and pharmacokinetic (PK) analyses to be performed for this study, and to the 
basic format of the tables, figures, and listings (TFLs). Once the SAP has been signed, 
programming of the TFLs based upon this document can proceed. Any modifications to the SAP 
and TFLs made after signing may result in a work-scope change. 
 
Covance approval: 
 
 
 
 
 
 
 
Izabela Antys, MSc 
Statistician 
 
Date 
 
 
 
 
 
 
 
Nicola Eraut, PhD 
Pharmacokineticist 
 
Date 
 
 
Sponsor approval: 
 
 
 
 
 
 
 
Dr. Patrick Round, MBBS FFPM  
Chief Medical Officer 
 
Date 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8383557 
 
Sponsor Reference: NST-01 
 
Final: 26 July 2018 
 
Page 3 of 16 
 
2  TABLE OF CONTENTS 
1 
STATISTICAL ANALYSIS PLAN APPROVAL SIGNATURES ................................... 2 
2 
TABLE OF CONTENTS ................................................................................................... 3 
3 
ABBREVIATIONS ............................................................................................................ 4 
4 
INTRODUCTION .............................................................................................................. 5 
5 
STUDY OBJECTIVES ...................................................................................................... 5 
6 
STUDY DESIGN ............................................................................................................... 6 
7 
TREATMENTS .................................................................................................................. 8 
8 
SAMPLE SIZE JUSTIFICATION ..................................................................................... 9 
9 
DEFINITION OF ANALYSIS POPULATIONS ............................................................ 10 
10 STATISTICAL METHODOLOGY ................................................................................. 10 
10.1 General ....................................................................................................................... 10 
10.1.1 Definition of Baseline and Change from Baseline ........................................... 11 
10.1.2 Repeat and Unscheduled Readings .................................................................. 11 
10.2 Demographics and Subject Disposition ..................................................................... 12 
10.3 Pharmacokinetic Assessment ..................................................................................... 12 
10.3.1 Pharmacokinetic Analysis ................................................................................ 12 
10.3.2 Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis ................................................................................ 13 
10.3.2.1 Anomalous Values ........................................................................................... 13 
10.3.3 Presentation of Pharmacokinetic Data ............................................................. 13 
10.3.3.1 Presentation of Pharmacokinetic Plasma Drug Concentration Data ................ 13 
10.3.3.2 Presentation Pharmacokinetic Parameters ........................................................ 14 
10.3.4 Pharmacokinetic Statistical Methodology ........................................................ 14 
10.4 Safety and Tolerability Assessments ......................................................................... 14 
10.4.1 Adverse Events ................................................................................................. 14 
10.4.2 Clinical Laboratory Parameters ........................................................................ 15 
10.4.3 Vital Signs ........................................................................................................ 15 
10.4.4 Electrocardiogram ............................................................................................ 15 
10.4.5 Other Assessments ........................................................................................... 16 
10.4.6 Safety and Tolerability Statistical Methodology .............................................. 16 
11 INTERIM ANALYSES .................................................................................................... 16 
12 CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 16 
13 DATA PRESENTATION ................................................................................................ 16 
13.1 Insufficient Data for Presentation ............................................................................... 16 
14 REFERENCES ................................................................................................................. 16 
 


Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Study: 8383557 
 
Sponsor Reference: NST-01 
 
Final: 26 July 2018 
 
Page 4 of 16 
 
3  ABBREVIATIONS 
Abbreviations pertain to the SAP only (not the TFLs). 
ΔQTcF 
placebo-corrected change-from-baseline QTcF 
ΔQTcF 
change-from-baseline QTcF 
ADaM 
Analysis Data Model 
AE 
adverse event 
AUC0-t 
area under the plasma concentration-time curve from time 0 to the time of 
the last observed concentration 
BLQ 
below the level of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
Cmax 
maximum observed plasma concentration 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
CV 
coefficient of variation 
EC 
Early Clinical 
ECG 
electrocardiogram 
HR 
heart rate 
ICH 
International Conference on Harmonisation 
NC 
not calculated 
NR 
no result 
PK 
pharmacokinetic 
QTc 
QT interval corrected for heart rate 
QTcF 
Fridericia correctedQT interval 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
Tlast 
the time of the last observed plasma concentration 
Tmax 
time of the maximum observed plasma concentration 
 


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4  INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version dated 
11 April 2018). 
This SAP describes the planned analysis of the safety, tolerability and PK data from this study. A 
detailed description of the planned TFLs to be presented in the Clinical Study Report (CSR) is 
provided in the accompanying TFL shell document. 
Separate SAP describing all other planned analysis, including analysis of the ECG data will be 
produced by of iCardiac Technologies, Inc.. 
The intent of this document is to provide guidance for the statistical analyses of PK data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between NorthSea Therapeutics BV and Covance Early Clinical (EC) Biometrics. 
A limited amount of information concerning this study (eg, objectives, study design) is given to 
help the reader’s interpretation. This SAP must be finalised prior to the lock of the clinical 
database for this study. When the SAP and TFL shells are agreed upon and finalised, they will 
serve as the template for this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between NorthSea Therapeutics BV and Covance EC Biometrics and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline entitled, “Guidance for Industry: Statistical 
Principles for Clinical Trials” and the ICH E3 guideline entitled, “Guidance for Industry: 
Structure and Content of Clinical Study Reports.”1,2 
5  STUDY OBJECTIVES 
The primary objective of the study is: 
 To evaluate the effects of therapeutic and supratherapeutic concentrations of icosabutate on 
the Fridericia’s corrected QT interval (QTcF) in healthy subjects (this will be a 
responsibility of iCardiac Technologies, Inc.).  
The secondary objectives of the study are: 
 To evaluate the effect of therapeutic and supratherapeutic doses of icosabutate on other 
electrocardiogram (ECG) parameters (heart rate [HR], PR and QRS intervals, and T-wave 
morphology) in healthy subjects (this will be a responsibility of iCardiac Technologies, 
Inc.). 


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 To evaluate the PK of single doses of 600 mg and 2000 mg icosabutate in healthy subjects 
(this will be a responsibility of Covance EC Biometrics). 
 To assess the safety and tolerability of single doses of 600 mg and 2000 mg icosabutate in 
healthy subjects (this will be a responsibility of Covance EC Biometrics).  
6  STUDY DESIGN 
This will be a Phase 1, single-centre, randomised, double-blind (except for moxifloxacin), 
placebo- and positive-controlled, 4-way crossover study assessing the ECG effects of therapeutic 
and supratherapeutic doses of icosabutate in healthy male and female subjects. 
Thirty-two subjects will be randomised to 1 of 12 treatment sequences (Table 1), with 
approximately 3 subjects randomised into 8 of the 12 sequences, and 2 subjects randomised into 
4 of the 12 sequences, and will receive a single oral dose of each of the following treatments, 
with a minimum 5-day wash-out between doses: 
 therapeutic dose of icosabutate (600 mg) 
 supratherapeutic dose of icosabutate (2000 mg) 
 moxifloxacin (400 mg) 
 placebo 
Moxifloxacin will be used as a positive control to determine the assay sensitivity of this study, 
with an expected peak QT effect (placebo-corrected change-from-baseline QTcF [∆∆QTcF]) of 
10 ms to 15 ms. 


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Table 1: 
Treatment Sequences 
Treatment 
Sequence 
Dosing Period 
1 
(Day 1) 
2 
(Day 6) 
3 
(Day 11) 
4 
(Day 16) 
1 
icosabutate 
(600 mg) 
icosabutate 
(2000 mg) 
placebo 
moxifloxacin 
(400 mg) 
2 
icosabutate 
(2000 mg) 
moxifloxacin 
(400 mg) 
icosabutate 
(600 mg) 
placebo 
3 
placebo 
icosabutate 
(600 mg) 
moxifloxacin 
(400 mg) 
icosabutate 
(2000 mg) 
4 
moxifloxacin 
(400 mg) 
placebo 
icosabutate 
(2000 mg) 
icosabutate 
(600 mg) 
5 
icosabutate 
(2000 mg) 
placebo 
icosabutate 
(600 mg) 
moxifloxacin 
(400 mg) 
6 
placebo 
moxifloxacin 
(400 mg) 
icosabutate 
(2000 mg) 
icosabutate 
(600 mg) 
7 
icosabutate 
(600 mg) 
icosabutate 
(2000 mg) 
moxifloxacin 
(400 mg) 
placebo 
8 
moxifloxacin 
(400 mg) 
icosabutate 
(600 mg) 
placebo 
icosabutate 
(2000 mg) 
9 
placebo 
icosabutate 
(600 mg) 
icosabutate 
(2000 mg) 
moxifloxacin 
(400 mg) 
10 
icosabutate 
(600 mg) 
moxifloxacin 
(400 mg) 
placebo 
icosabutate 
(2000 mg) 
11 
icosabutate 
(2000 mg) 
placebo 
moxifloxacin 
(400 mg) 
icosabutate 
(600 mg) 
12 
moxifloxacin 
(400 mg) 
icosabutate 
(2000 mg) 
icosabutate 
(600 mg) 
placebo 
Subjects will be screened to assess their eligibility from Day -28 to Day -2. Subjects will be 
admitted to the Clinical Research Unit (CRU) on Day -1 and remain in the CRU until Day 18. 
Each subject will participate in 4 dosing periods, with doses administered in the morning of 
Days 1, 6, 11, and 16 after an overnight fast of at least 8 hours (not including water). Dose 
administration in each dosing period will be separated by a wash-out period of at least 5 days. 
There will be a Follow-up Visit 7 to 10 days after the final dose administration. An overview of 
the study design is shown in Figure 1. 


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Figure 1: Study Schematic 
 
The total duration of study participation for each subject (from Screening through Follow-up 
Visit) is anticipated to be approximately 8 weeks. 
7  TREATMENTS 
The following is a list of the study treatment and ordering that will be used in the TFLs. 
Study Treatment 
Order on TFLs 
600 mg icosabutate 
1 
2000 mg icosabutate 
2 
400 mg moxifloxacin 
3 
Placebo 
4 


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The following is a list of the study treatment sequence abbreviations and ordering that will be 
used in the baseline TFLs. 
Study Treatment Sequence 
Abbreviation 
Order on 
TFLs 
600 mg icosabutate/2000 mg icosabutate/Placebo/400 mg moxifloxacin 
A/B/C/D 
1 
2000 mg icosabutate/400 mg moxifloxacin/600 mg icosabutate/Placebo  B/D/A/C  
2 
Placebo/600 mg icosabutate/400 mg moxifloxacin/2000 mg icosabutate 
C/A/D/B 
3 
400 mg moxifloxacin/Placebo/2000 mg icosabutate/600 mg icosabutate 
D/C/B/A 
4 
2000 mg icosabutate/Placebo/600 mg icosabutate/400 mg moxifloxacin 
B/C/A/D 
5 
Placebo/400 mg moxifloxacin/2000 mg icosabutate/600 mg icosabutate 
C/D/B/A 
6 
600 mg icosabutate/2000 mg icosabutate/400 mg moxifloxacin/Placebo 
A/B/D/C 
7 
400 mg moxifloxacin/600 mg icosabutate/Placebo/2000 mg icosabutate 
D/A/C/B 
8 
Placebo/600 mg icosabutate/2000 mg icosabutate/400 mg moxifloxacin 
C/A/B/D 
9 
600 mg icosabutate/400 mg moxifloxacin/Placebo/2000 mg icosabutate 
A/D/C/B 
10 
2000 mg icosabutate/Placebo/400 mg moxifloxacin/600 mg icosabutate 
B/C/D/A 
11 
400 mg moxifloxacin/2000 mg icosabutate/600 mg icosabutate/Placebo 
D/B/A/C 
12 
 
8  SAMPLE SIZE JUSTIFICATION 
A total of 32 subjects will be enrolled in order that a minimum of 28 subjects complete the study. 
Based on experience from the IQ CSRC study3 simulations to evaluate the power of small 
studies with exposure response analysis4, and the observations from 25 recent TQT studies using 
exposure response analysis, a sample size of 28 will provide more than 95% power to exclude 
that icosabutate causes more than a 10 ms QTc effect at clinically relevant plasma levels, as 
shown by the upper bound of the 2 sided 90% confidence interval of the model predicted QTc 
effect (∆∆QTcF) at the observed geometrical mean Cmax of icosabutate in the study. 
In addition to the evaluation through modelling and simulation, the sample size can be estimated 
approximately using a simple paired t-test for equivalence. Under the assumption that the QTc 
effect is 3 ms for icosabutate and 0 ms for placebo with a common standard deviation (SD) of 
change-from-baseline QTcF (∆QTcF) of 8 ms for each treatment, and that ‘No Effect’ will be 
concluded if the 90% confidence interval of ∆∆QTcF is lower than 10 ms, 28 subjects will 
provide >95% power with a one sided alpha of 5% in paired t-test. This estimation was 
performed using the paired t-test for equivalence of Means in R Version 3.2.5. 


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To demonstrate assay sensitivity with exposure-response analysis, it has to be shown that the 
ΔΔQTcF of a single dose of 400 mg moxifloxacin exceeds 5 ms (ie, the lower bound of the 
2-sided 90% CI of the predicted QT interval corrected for heart rate (QTc) effect [ΔΔQTcF] 
should exceed 5 ms). In a similarly designed recent crossover study with 24 healthy subjects, the 
standard error (SE) for the prediction of the QT effect of moxifloxacin based on the 
exposure-response analysis was 1.24 ms. The within-subject SD of change-from-baseline QTcF 
(ΔQTcF) in the referred study was 5.4 ms. If the effect of moxifloxacin is assumed to be 10 ms, 
the SE of 1.24 ms corresponds to an effect size of 
, where the effect 
size is the effect assumed under the alternative hypothesis divided by the SD of the test variable. 
In a one-sample t-test situation with a sample size of 24 subjects, this effect size results in a 
power of 98.8%. This value should be compared with the effect size of 0.57 required to 
guarantee a power of at least 90% in a one-sample t-test situation with a sample size of 
28 subjects. Based on this calculation, a power of at least 90% will be obtained as long as the 
variability of ΔQTcF, as measured by its SD, does not exceed 7.8 ms (ie, 144% of the 5.4 ms 
observed in the referred study). 
9  DEFINITION OF ANALYSIS POPULATIONS 
The Safety Population will consist of all subjects who received at least 1 dose of study drug 
(icosabutate, moxifloxacin, placebo) and have at least 1 postdose safety assessment. 
The PK Population will consist of all subjects who received at least 1 dose of study drug 
(icosabutate, moxifloxacin) and have evaluable PK data. A subject will be excluded from the PK 
summary statistics and statistical analysis if the subject has an adverse event (AE) of vomiting 
that occurs at or before 2 times median time of  the maximum observed plasma concentration 
(Tmax), or important protocol deviations or AE thought to significantly affect the PK of 
icosabutate. 
The All Subjects Population will be consistent with the Safety Population.  
All protocol deviations that occur during the study will be considered prior to database lock for 
their severity/impact and will be taken into consideration when subjects are assigned to analysis 
populations. Details of subject assignment to the analysis populations will be listed. 
10  
STATISTICAL METHODOLOGY 
10.1 General 
Data listings will be provided for the All Subjects Population. Summary statistics will be 
performed for subjects included in the relevant analysis populations (Safety/PK).  
For continuous data, summary statistics will include the arithmetic mean, arithmetic standard 
deviation, median, minimum, maximum, and number. For log-normal data (eg, the PK 


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parameters: areas under the concentration-time curve [AUCs] and maximum observed plasma 
concentration [Cmax]), the geometric mean and geometric coefficient of variation (CV) will also 
be presented. For categorical data, frequency counts and percentages will be presented. Data 
listings will be provided for all subjects up to the point of withdrawal, with any subjects 
excluded from the relevant population highlighted. For the calculation of summary statistics 
unrounded data will be used. 
Missing values will not be imputed. 
Data analysis will be performed using SAS® Version 9.4. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1, and CDISC ADaM Implementation Guide 
Version 1.1. Pinnacle 21 Community Validator Version 2.2.0 will be utilised to ensure 
compliance with CDISC standards. 
Period day (day within the dosing period) will be used throughout all TFLs. It will be derived in 
the ADaM datasets (where applicable) and the mapping from study day to period day will be as 
follows.  
 
Dosing 
Period 1 
Dosing 
Period 2 
Dosing 
Period 3 
Dosing 
Period 4 
Study Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 
Period Day 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
1 
2 
3 
 
10.1.1 Definition of Baseline and Change from Baseline 
Baseline for each parameter is defined as the last value measured prior to last dosing, including 
repeat (vital signs and ECGs) and unscheduled (clinical laboratory parameters) readings (see 
Section 10.1.2 for definitions of repeat and unscheduled readings). For ECGs taken in triplicate, 
baseline will be the median of the last 3 values taken prior to last dosing. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate. 
10.1.2 Repeat and Unscheduled Readings 
Repeat readings occur when the original vital signs or ECG result requires confirmation. Repeat 
readings are labelled as ‘Repeat’ in the listings and replace the original readings in all summaries 
and changes from baseline presentations and calculations. Prior to dosing, all readings taken in 
addition to the original reading are defined as predose repeats. Postdose repeat readings are 
defined as readings collected within 15 minutes of the actual time of the original reading. Where 


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results are taken in triplicate and repeated, the last 3 readings are used in all subsequent 
calculations. 
With the exception of predose results described above, unscheduled readings for vital signs or 
ECGs are defined as readings collected >15 minutes from the actual time of the original reading. 
Where results are taken in triplicate, the original reading is defined as the first reading of the 
triplicate. All results not taken at a scheduled timepoint for other data types (eg, clinical 
laboratory parameters) are unscheduled. Unscheduled readings are labelled as ‘Unscheduled’ in 
the listings. Because unscheduled readings are not associated with any scheduled timepoint, they 
are excluded from all summaries (with the exception that they may be used as baseline, as stated 
in Section 10.1.1). 
10.2 Demographics and Subject Disposition 
The demographic variables age, sex, race, ethnicity, body weight, height, and body mass index 
will be summarised by treatment sequence and listed. Subject disposition will be summarised by 
treatment sequence and listed. 
10.3 Pharmacokinetic Assessment 
10.3.1 Pharmacokinetic Analysis 
The following PK parameters will be determined where possible, from the plasma concentrations 
of icosabutate, using non-compartmental methods in validated software program, Phoenix 
WinNonlin (Certara, Version 6.4 or later): 
Parameter 
Definition 
AUC0-t 
area under the plasma concentration-time curve from time 0 to the time of the last 
observed plasma concentration (Tlast), calculated using the linear trapezoidal rule for 
increasing concentrations and the logarithmic rule for decreasing concentrations 
Cmax 
maximum observed plasma concentration 
Tmax 
time of the maximum observed plasma concentration 
Additional PK parameters may be determined where appropriate. 
The Cmax for moxifloxacin will be calculated by iCardiac Technologies, Inc. 
Pharmacokinetic analysis will, where possible, be carried out using actual postdose times 
recorded in the raw data. If actual times are missing, nominal times may be used with Sponsor’s 
approval.  
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
Both Cmax and Tmax will be obtained directly from the plasma concentration-time profiles.   


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For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest Tmax will be reported. 
10.3.2 Criteria for Handling Concentrations Below the Limit of Quantification in 
Pharmacokinetic Analysis 
 Concentration values that are below the level of quantification (BLQ) will be set to zero, 
with defined exceptions as follows; 
o Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values 
following the last quantifiable concentration in a profile will be set to missing for the 
purposes of PK analysis. 
o If there are late positive concentration values following 2 BLQ concentration values 
in the apparent terminal phase, these values will be evaluated. If these values are 
considered to be anomalous, they will be set to missing. 
o If an entire concentration-time profile is BLQ, the profile will be excluded from the 
PK analysis. 
o If a predose concentration is missing, these values may be set to zero for single dose 
studies and first dose of multiple dose studies with sponsor approval 
10.3.2.1 Anomalous Values 
 If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in the raw data and 
study report. 
 Embedded BLQ values may be considered anomalous depending on the route of 
administration and the characteristics of the drug. 
 PK parameters associated with positive predose value(s) greater than 5% of Cmax may be 
excluded from the summary statistics of PK tables and statistical analysis at the discretion 
of the pharmacokineticist. 
10.3.3 Presentation of Pharmacokinetic Data 
10.3.3.1 Presentation of Pharmacokinetic Plasma Drug Concentration Data 
 The following rules will be applied if there are values that are BLQ or if there are missing 
values (e.g., no result [NR]) in a plasma concentration data series to be summarised. 
 For the calculation of summary statistics, BLQ values will be set to zero. 


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 If an embedded BLQ value is considered anomalous within the concentration-time profile, 
this value will be excluded from the summary statistics. 
 Where there is NR, these will be set to missing. 
 If there are less than three values in the data series, only the min, max, and N will be 
presented. The other summary statistics will be denoted as not calculated (NC). BLQ is 
considered a value. 
 If all the values are BLQ, then the arithmetic mean, arithmetic SD, median, min and max 
will be presented as zero, and the geometric mean and geometric CV% will be denoted as 
NC. 
 If the value of the arithmetic mean or median is below the lower limit of quantification, 
these values will be presented as zero and the geometric mean and geometric CV% will be 
denoted as NC. 
 Concentrations for which actual sampling time deviated > (5 mins + 10% of nominal time) 
will be excluded from summary statistics. 
10.3.3.2 Presentation Pharmacokinetic Parameters 
 For the calculation of summary statistics of PK parameters, all NR and NC values in a data 
series will be set to missing. 
 The AUC0-t values will be set to NC if they have been calculated using fewer than three 
concentrations, and/or three concentrations if the last is Cmax. 
10.3.4 Pharmacokinetic Statistical Methodology 
No inferential statistical analysis will be performed. 
PK parameters and plasma concentrations of icosabutate will be summarised by treatment and 
listed. Plasma concentrations will be graphically represented with an arithmetic mean plot and a 
concentration-time profile by subject (linear scale and semi-logarithmic scale). 
10.4 Safety and Tolerability Assessments 
10.4.1 Adverse Events 
A baseline sign and symptom is defined as an AE that starts after the subject has provided 
written informed consent and that resolves prior to the first dosing occasion, or an AE that starts 
prior to the first dosing occasion and does not increase in severity after dosing. A 
treatment-emergent AE (TEAE) is defined as an AE that occurs postdose or that is present 
predose and becomes more severe postdose.  


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All AEs will be listed. The TEAEs will be summarised by treatment, severity, and relationship to 
the study drug. The frequency (the number of TEAEs, the number of subjects experiencing a 
TEAE, and the percentage of subjects experiencing a TEAE) of TEAEs will be summarised by 
treatment, and by Medical Dictionary for Regulatory Activities system organ class and preferred 
term. The summary and frequency TEAE tables will be presented for all causalities and for those 
TEAEs considered related to the study treatment. Any severe or serious AEs will be tabulated. 
For any AEs that change severity ratings the AE will be included only once under the maximum 
severity rating in the summaries. 
10.4.2 Clinical Laboratory Parameters 
Clinical chemistry and haematology data will be summarised by treatment. In addition, all 
clinical chemistry, haematology, and urinalysis data outside the clinical reference ranges will be 
listed by parameter and treatment. 
Values for any clinical chemistry, haematology, and urinalysis values outside the clinical 
reference ranges will be flagged on the individual subject data listings. 
10.4.3 Vital Signs 
Vital signs values outside the clinical reference ranges will be flagged on the individual subject 
data listings. 
The absolute values and changes from baseline in vital signs data will be listed and summarised 
by treatment. Figures of mean vital signs and mean change from baseline profiles will be 
presented by treatment.  
10.4.4 Electrocardiogram 
The ECG data will be obtained directly from the 12-lead ECG traces. These data include the QT 
interval calculated using the QTcF, the PR and QT intervals, the QRS interval, and HR.  
Where ECGs are measured in triplicate (at approximately 2-minute intervals), the median value 
will be used in all subsequent calculations.  
Values for ECG parameters outside the clinical reference ranges will be flagged on the individual 
subject data listings. 
The ECG data will be listed and summarised by treatment. Figures of mean ECG data and mean 
change from baseline profiles will be presented by treatment.  
An outlier analysis will be performed including all individual postdose measurements (not the 
mean data), including all repeat and unscheduled readings. The frequency of subjects with a 
maximum increase from baseline in QTcF interval will be summarised for each treatment 
according to the following categories: >30, >60, and ≤30 ms. All incidences of >30 and 
>60 ms will be flagged on the listing. In addition, the frequency of subjects with QTcF postdose 


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values will be summarised for each treatment, according to the following categories: >450, >480, 
>500, and ≤450 ms. All incidences of >450, >480, and >500 ms will be flagged on the listing.  
10.4.5 Other Assessments 
All other safety assessments not detailed in this section will be listed but not summarised or 
statistically analysed. 
Medical history data will not be presented. 
10.4.6 Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
11  
INTERIM ANALYSES 
No interim statistical analyses are planned. 
12  
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES 
There were no changes from the protocol-specified statistical analyses. 
13  
DATA PRESENTATION 
13.1 Insufficient Data for Presentation 
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.” 
14  
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.  
3. Darpo B, Benson C, Dota C, Ferber G, Garnett C, Green CL, et al. Results from the IQ-
CSRC prospective study support replacement of the thorough QT study by QT assessment in 
the early clinical phase. Clin Pharmacol Ther. 2015 Apr;97(4):326–35.  
4. Ferber G, Zhou M, Darpo B. Detection of QTc effects in small studies--implications for 
replacing the thorough QT study. Ann Noninvasive Electrocardiol Off J Int Soc Holter 
Noninvasive Electrocardiol Inc. 2015 Jul;20(4):368–77.