Clinical trial NCT05368831
Conditions: Healthy Volunteers
Sponsor: NorthSea Therapeutics B.V.
Start date: 2022-07-19; Completion date: 2022-09-07
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 1, open label study to evaluate the effects of NST-1024 on the pharmacokinetics (PK) of caffeine (and paraxanthine), flurbiprofen, omeprazole, metoprolol, and midazolam (and 1-hydroxymidazolam) in healthy male and female subjects.

Detailed description:
Up to 21 subjects will be enroled to ensure that 18 subjects complete the study. All subjects will receive each of the following treatments:

* Day 1: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 100 mg metoprolol, and 2.5 mg midazolam
* Days 8 to 22: oral doses of 200 mg NST-1024 qd multiple-dose regimen
* Day 8: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 100 mg metoprolol, and 2.5 mg midazolam coadministered with an oral dose of 200 mg NST-1024
* Day 21: single oral dose of 100 mg caffeine and 2.5 mg midazolam coadministered with an oral dose of 200 mg NST-1024.

Arms: arm 1: Day 1: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 100 mg metoprolol, and 2.5 mg midazolam

* Days 8 to 22: oral doses of 200 mg NST-1024 qd multiple-dose regimen
* Day 8: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 100 mg metoprolol, and 2.5 mg midazolam coadministered with an oral dose of 200 mg NST-1024
* Day 21: single oral dose of 100 mg caffeine and 2.5 mg midazolam coadministered with an oral dose of 200 mg NST-1024.
Interventions: intervention 1: NST-1024
Intervention descriptions: intervention 1: Drug Drug interactions between NST-1024 and caffeine (and paraxanthine), flurbiprofen, omeprazole, metoprolol, and midazolam

Protocol documents:
Prot_000.pdf: 
TITLE PAGE 
Protocol 
A Phase 1, Open-label Study to Evaluate the Effects of NST-1024 on the 
Pharmacokinetics of Caffeine, Flurbiprofen, Omeprazole, Metoprolol, and 
Midazolam in Healthy Subjects 
Protocol Status: Final 
Protocol Version: 1 
Protocol Date: 16 May 2022 
Investigational Medicinal Product: NST-1024 
Protocol Reference: NST-1024-02 
Labcorp Drug Development Study: 8489933 
EudraCT Number: ဨဨ 
Sponsor: 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands季
Study Site: 
Labcorp Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom季
Sponsor Signatory: 
Dr Stephen Rossi, PharmD 
Dr Stephen Harrison, MD季
Principal Investigator: 
Dr Firas Almazedi, MBChB, MSc, CPI, 
DipPharmMed 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
Page 2 of 48


Protocol 
CONFIDENTIAL
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 2 of 
SPONSOR APPROVAL
I have read the protocol and approve it: 
Dr Stephen Rossi, PharmD 
Date
Chief Development Officer
NorthSea Therapeutics B.V.
Dr Stephen Harrison, MD 
Date
Chief Medical Officer
NorthSea Therapeutics B.V.
	
	
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Protocol 
CONFIDENTIAL
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 3 of 
INVESTIGATOR AGREEMENT
I have read the protocol and agree to conduct the study as described herein. 
Dr Firas Almazedi, MBChB, MSc, CPI, 
DipPharmMed 
Date
Principal Investigator
	
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Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 4 of  
STUDY IDENTIFICATION 
Sponsor 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Sponsor’s Study Contact 
Kathline Kim 
Senior Clinical Trial Manager 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Tel: +1 510 282 3024 
Email: kathline.kim@northseatherapeutics.com 
Study Director 
Dr Stephen Rossi, PharmD 
Chief Development Officer 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
7HO 
Email: stephen.rossi@northseatherapeutics.com 
Sponsor’s Medical Contact 
Dr Stephen Harrison, MD 
Chief Medical Officer 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Tel: +1 210 288 586844 
Email: VWHSKHQKDUULVRQ#JPDLOFRP 
Study Site 
Labcorp Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator/Project 
Physician 
Dr Firas Almazedi, MBChB, MSc, CPI, 
DipPharmMed 
Labcorp Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
Tel: +44 (0)113 301 3642 
Tel (after hours): +44 (0)113 301 3500 
Page 5 of 48


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 5 of  
Clinical Laboratory 
Labcorp Early Development Laboratories Ltd. 
Otley Road 
Harrogate, HG3 1PY 
United Kingdom 
Bioanalytical Laboratory 
Labcorp Early Development Laboratories Ltd. 
Otley Road 
Harrogate, HG3 1PY 
United Kingdom 
Statistician 
Izabela Antys, BSc (Hons), MSc, GradStat 
Labcorp Drug Development 
Page 6 of 48


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 6 of  
SYNOPSIS 
Study Title 
A Phase 1, Open-label Study to Evaluate the Effects of NST-1024 on the Pharmacokinetics 
of Caffeine, Flurbiprofen, Omeprazole, Metoprolol, and Midazolam in Healthy Subjects 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
 
x to evaluate the effects of NST-1024 on the 
PK of caffeine, flurbiprofen, omeprazole, 
metoprolol, and midazolam in healthy male 
and female subjects 
x primary PK parameters: AUC0-inf, 
AUC0-tlast, and Cmax 
Secondary: 
 
x to assess the safety and tolerability of 
NST-1024 in healthy subjects 
x incidence and severity of AEs 
x incidence of laboratory 
abnormalities, based on 
haematology, clinical chemistry, 
and urinalysis test results 
x 12-lead ECG parameters 
x vital signs measurements 
x physical examinations 
Abbreviations: AE = adverse event; AUC0-inf = area under the concentration-time curve from time 0 extrapolated to infinity; 
AUC0-tlast = area under the concentration-time curve from time 0 to the time of the last quantifiable concentration; 
Cmax = maximum observed concentration; ECG = electrocardiogram; PK = pharmacokinetic(s). 
Study Design 
This will be a Phase 1, open-label study to evaluate the effects of NST-1024 on the 
pharmacokinetics (PK) of caffeine (and paraxanthine), flurbiprofen, omeprazole, metoprolol, 
and midazolam (and 1-hydroxymidazolam) in healthy male and female subjects. Potential 
subjects will be screened to assess their eligibility to enter the study within 28 days prior to 
the first dose administration. Subjects will be admitted into the study site on Day -1 and be 
confined until discharge on Day 3. Subjects will return for check-LQRQ'D\DQGEHFRQILQHG
until discharge on Day 23. Subjects will return to the study site for a follow-XSYLVLWWR
10 days after the last dose. 
Number of Subjects 
Up to 21 subjects will be enroled in order that 18 subjects complete the study. 
Page 7 of 48


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page  of  
Diagnosis and Main Criteria for Inclusion 
Healthy male and female subjects aged between 18 and 65 years (inclusive) with a body mass 
index between 18.0 and 32.0 kg/m2 (inclusive). 
Investigational Medicinal Products, Dose, and Mode of Administration 
All subjects will receive each of the following treatments: 
x Day 1: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 
100 mg metoprolol, and 2.5 mg midazolam 
x Days 8 to 22: oral doses of 200 mg NST-1024 once daily multiple-dose regimen 
x Day 8: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 
100 mg metoprolol, and 2.5 mg midazolam coadministered with an oral dose of 
200 mg NST-1024 
x Day 21: single oral dose of 100 mg caffeine and 2.5 mg midazolam coadministered 
with an oral dose of 200 mg NST-1024. 
All doses of caffeine, flurbiprofen, omeprazole, metoprolol, and midazolam, including dosing 
occasions when coadministered with NST-1024, will be given in a fasted state. 
Duration of Subject Participation in the Study 
Planned screening duration: approximately 4 weeks 
Planned study duration (screening to follow-up): approximately 9 weeks. 
Statistical Methods 
Pharmacokinetics 
Pharmacokinetic parameters will be determined from the plasma concentrations of caffeine 
(and its metabolite paraxanthine), flurbiprofen, omeprazole, metoprolol, and midazolam (and 
its metabolite 1-hydroxymidazolam) using standard noncompartmental methods. 
The primary PK parameters are area under the concentration-time curve (AUC) from time 0 
extrapolated to infinity (AUC0-inf), AUC from time 0 to the time of the last quantifiable 
concentration (AUC0-tlast), and maximum observed concentration (Cmax). Additional PK 
parameters may be calculated. All other PK parameters will be regarded as secondary and 
will not be subject to inferential statistical analysis. 
A linear mixed-model analysis will be applied to analyse the log-transformed primary PK 
parameters. The model will assume a fixed effect for treatment and a random effect for 
subject. Estimates of geometric least squares mean ratios together with the corresponding 
90% confidence intervals will be derived for each of the parameters separately as follows: 
x Probe drugs coadministered with NST-1024 (profile Day 8) (test) versus probe drugs 
alone (profile Day 1) (reference). This comparison will be done for caffeine, 
Page 8 of 48


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 8 of  
paraxanthine, flurbiprofen, omeprazole, metoprolol, midazolam, and 
1-hydroxymidazolam analytes separately 
x Probe drugs coadministered with NST-1024 (profile Day 21) (test) versus probe drugs 
alone (profile Day 1) (reference). This comparison will be done for caffeine, 
paraxanthine, midazolam, and 1-hydroxymidazolam analytes separately. 
Safety 
Safety parameters will be listed and summarised. No formal statistical analysis of safety data 
is planned. 
Page 9 of 48


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 9 of  
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. 
Nonclinical Pharmacokinetic Drug Interactions ....................................................13 
1.3. 
Summary of Clinical Experience ...........................................................................14 
1.3.1. 
Safety ...........................................................................................................14 
1.3.2. 
Pharmacokinetics .........................................................................................14 
1.4. 
Study Rationale ...................................................................................................... 
1.5. 
Benefit-risk Assessment ......................................................................................... 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................. 
3. 
INVESTIGATIONAL PLAN ..........................................................................................18 
3.1. 
Overall Study Design and Plan ..............................................................................18 
3.2. 
Discussion of Study Design ...................................................................................19 
3.3. 
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. 
Generic Screening ..................................................................................................22 
4.4. 
Subject Number and Identification ........................................................................23 
4.5. 
Subject Withdrawal and Replacement ...................................................................23 
4.6. 
Study Termination .................................................................................................23 
5. 
STUDY TREATMENTS .................................................................................................24 
5.1. 
Description, Storage, Packaging, and Labelling ....................................................24 
5.2. 
Study Treatment Administration ............................................................................24 
5.3. 
Randomisation .......................................................................................................25 
5.4. 
Blinding..................................................................................................................25 
5.5. 
Treatment Compliance ...........................................................................................25 
5.6. 
Drug Accountability...............................................................................................25 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................25 
6.1. 
Concomitant Therapies ..........................................................................................25 
6.2. 
Diet .........................................................................................................................26 
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Protocol 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 10 of  
6.3. 
Smoking .................................................................................................................26 
6.4. 
Exercise ..................................................................................................................26 
6.5. 
Blood Donation ......................................................................................................26 
 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 
 
Pharmacokinetic Assessments ............................................................................... 
 
Pharmacokinetic Blood Sample Collection and Processing ........................ 
 
Analytical Methodology .............................................................................. 
 
Safety and Tolerability Assessments ..................................................................... 
 
Adverse Events ............................................................................................ 
 
Clinical Laboratory Evaluations ..................................................................28 
 
Vital Signs ....................................................................................................28 
 
12-Lead Electrocardiogram .........................................................................28 
 
Physical Examination...................................................................................29 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................29 
8.1. 
Determination of Sample Size ...............................................................................29 
8.2. 
Analysis Populations ..............................................................................................29 
8.2.1. 
Pharmacokinetic Population ........................................................................29 
8.2.2. 
Safety Population .........................................................................................29 
8.2.3. 
All Subjects Population................................................................................29 
8.3. 
Pharmacokinetic Analyses .....................................................................................29 
8.4. 
Safety Analysis ......................................................................................................30 
8.5. 
Interim Analysis .....................................................................................................30 
9. 
REFERENCES ................................................................................................................30 
10. APPENDICES .................................................................................................................31 
Appendix 1: Adverse Event Reporting ..............................................................................32 
Appendix 2: Clinical Laboratory Evaluations ...................................................................36 
Appendix 3: Total Blood Volume ...................................................................................... 
Appendix 4: Contraception Guidance ................................................................................38 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................41 
Appendix 6: Schedule of Assessments ..............................................................................45 
 
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Protocol
CONFIDENTIAL
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 11 of  
LIST OF TABLES AND FIGURES 
Table 1: 
Key Pharmacokinetic Parameters of NST-1024 Single Doses
Evaluated to Date in Study NST-1024-01 .......................................................15 
Table 2: 
Key Pharmacokinetic Parameters of NST-1024 Repeat Doses Evaluated to 
Date in Study NST-1024-01 ............................................................................16 
Table 3:     Objectives and Endpoints ................................................................................18 
Figure 1:  Study Schematic ...............................................................................................19 
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Protocol 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 12 of  
LIST OF ABBREVIATIONS 
Abbreviation Definition 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC0-tlast 
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CRO 
contract research organisation 
CRU 
clinical research unit 
CV 
cardiovascular 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EPA 
eicosapentaenoic acid 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HDL-C 
high-density lipoprotein cholesterol 
HTG 
hypertriglyceridemia 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IMP 
investigational medicinal product 
IRB 
institutional review board 
LDL-C 
low-density lipoprotein cholesterol 
PK 
pharmacokinetic(s) 
qd 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
TG 
triglyceride 
Page 13 of 48


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 13 of  
1. INTRODUCTION 
Refer to the investigator’s brochure (IB)1 for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile 
of the investigational medicinal product (IMP). 
1.1. 
Overview 
NorthSea Therapeutics is developing NST-1024, a novel, orally administered, highly potent, 
semi-synthetic fatty acid for the treatment of severe hypertriglyceridemia (HTG), mixed 
dyslipidemia, and hypercholesterolemia. In severe HTG, the primary goal of therapy is to 
prevent development of acute pancreatitis by lowering triglyceride (TG) levels. Mixed 
dyslipidemia is characterised as elevated low-density lipoprotein cholesterol (LDL-C) and 
TG, often accompanied by low high-density lipoprotein cholesterol (HDL-C) levels. 
Elevations of TG signals lead to an increased risk of atherosclerotic cardiovascular (CV) 
events even when the LDL-C is well controlled by statin therapy. NST-1024 is a semi-
synthetic, structurally engineered eicosapentaenoic acid (EPA) derivative. The structural 
modifications are designed to potentiate the pharmacological effects of naturally occurring 
EPA by (a) targeting the intestine and liver by limiting peripheral distribution and (b) 
remaining as a free acid by reducing both the incorporation into complex lipids and 
PHWDEROLVPYLDȕ-oxidation, thereby increasing availability for fatty-acid sensitive signalling 
pathways. The nonclinical experience with NST-1024 thus far indicates large reductions in 
both TG and non-HDL-C in conjunction with a marked increase in HDL-C. In addition to 
beneficial effects on lipid and lipoprotein metabolism, significant improvements in glycaemic 
control are observed in diabetic mice. It has also been demonstrated that NST-1024 depletes 
hepatic cholesterol, which in turn increases hepatic uptake of plasma cholesterol and TG 
without a compensatory increase in hepatic secretion of very-low-density lipoprotein-TG. 
NST-1024 is a liquid, and is dosed orally, with the current dosage form being a red, soft 
gelatin capsule containing the active pharmaceutical ingredient in a self-emulsifying drug 
delivery system. Current formulations contain 10 or 100 mg NST-1024 formulated in 
polysorbate 80 and medium-chain TGs with dosing anticipated to be once daily (qd). 
1.2. 
Nonclinical Pharmacokinetic Drug Interactions 
Pharmacokinetic (PK) drug interactions were assessed in the Covance study which 
was conducted to measure the extent of induction of specific human cytochrome P450 (CYP) 
enzymes (CYP1A2, CYP2B6, and CYP3A4) following exposure of human hepatocytes from 
3 donors to NST-1024, and to compare the effects of the test article with those of prototypical 
inducers. Results indicated that NST-XSWRȝ0ZDVSUHVHQWLQWKHLQFXEDWLRQ
medium for 24 hours, was not cytotoxic, and induced all of the tested CYP enzymes 
(CYP1A2, CYP2B6, and CYP3A4/5) in at least 1 donor as measured by mRNA and CYP 
activity levels. 
A further study (Covance 8424669) was conducted to characterise the in vitro inhibitory 
potential of NST-1024 on the activities of the following human liver CYP enzymes: 
CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. NST-1024 
(0.3 to ȝ0RUȝ0H[KLELWHGGLUHFWLQKLELWLRQRI&<3$&<3%&<3&
&<3&&<3&&<3'&<3$WHVWRVWHURQHȕ-hydroxylase), and CYP3A4/5 
Page 14 of 48


Protocol 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 14 of  
(midazolam 1’-hydroxylase). NST-1024 exhibited no metabolism-dependent inhibition of the 
CYP enzymes tested. Under the same experimental conditions, the known direct and 
metabolism-dependent inhibitors of CYP enzymes exhibited marked inhibition of the 
corresponding CYP enzymes. Overall, the CYP inhibition-based drug-drug interaction (DDI) 
assessment for NST-1024 using a basic model indicated a potential for DDI is likely to occur 
with CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5 
(testosterone), and CYP3A4/5 (midazolam) probe drugs. 
1.3. 
Summary of Clinical Experience 
1.3.1. 
Safety 
As of the date of this final protocol (Version 1), a total of 94 subjects have been exposed to 
either NST-1024 or matched placebo at doses up to 400 mg as a single dose and up to 200 mg 
in repeat dosing for 14 days. The study is ongoing and remains blinded, but an analysis of the 
treatment-emergent AEs (TEAEs) was performed as part of the most recent dose escalation 
review. A total of 61 TEAEs in 38 subjects were reported during the study period, RIZKLFK
were assessed as related and >85% were assessed as mild severity. All reported events 
resolved during the study period. There were no severe or serious TEAEs reported during the 
study period. The most common TEAE (>2 subjects) reported during the study period were 
headache (n=10; 3 related), loose stools (n=3; 2 related), and coronavirus disease 2019 
positive test (n=3; none related). There were  TEAEs assessed as drug-related, all were 
considered mild and included headache (n=3), loose stools (n=2), nausea (n=1) and 
abdominal pain (n=1). There were no clinically significant changes in laboratory parameters 
suggestive of a safety signal. Vital signs and electrocardiogram (ECG) parameters remained 
stable throughout study drug dosing. In summary, NST-1024 appears to be safe and well 
tolerated at single dose up to 400 mg and repeated dose of 200 mg up to 14 days. 
 
1.3.2. 
Pharmacokinetics 
The PK data of NST-1024 were evaluated for all completed dosing cohorts and reviewed as 
part of the dose escalation meetings for both the single and repeated dose cohorts. Single 
doses of 10, 30, 50, 60, 200, and 400 mg were tested under fasted conditions. Single dosing 
was performed with a high-fat meal at the 30 and 100 mg dosing levels. Repeat dosing was 
performed following a standard breakfast at the 10, 30, 60, and 200 mg dosing levels. 
Standard PK parameters, accumulation ratio, and dose proportionality were evaluated as 
available. There was no significant accumulation noted between single and repeated once 
daily dosing under fed conditions. Dose proportionality for both area under the concentration 
time curve (AUC) and maximum observed concentration (Cmax) was generally observed with 
increasing doses over the range of 10 to 60 mg with less than proportional increases in 
exposure observed following 200 mg and 400 mg single doses in the fasted state. Slightly 
more than proportional increases in exposure relative to increasing dose were observed 
following multiple doses in the fed state. The key PK parameters for doses of NST-1024 
evaluated to date are presented in Table 1 and Table 2.  
 
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Protocol 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 15 of  
Table 1: 
Key Pharmacokinetic Parameters of NST-1024 Single Doses Evaluated to Date in Study NST-1024-01 
Parameter 
(Units) 
10 mg 
(Single, Fasted) 
30 mg 
(Single, Fasted) 
30 mg 
(Single, Fed**) 
50 mg 
(Single, Fasted) 
60 mg 
(Single, Fasted) 
100 mg 
(Single, Fed**) 
200 mg 
(Single, Fasted) 
400 mg 
(Single, Fasted) 
Dosing Group 
A2 
A3 
A1 
A4 
A5 
A6 
A7 
 
N=6 
N=6 
N=6 
N=6 
N=6 
1 
1 
N=6 
AUC0-24 
(ng*h/mL) 
1360 (23.5) 
3800 (15.9) 
3530 (19.5) 
8610 (38.3) 
8160 (22.1) 
13 200 (40.5) 
22 100 
(26.0) 
38400 
(29.6) 
Cmax 
(ng/mL) 
374 (23.0) 
1140 (13.7) 
665 (18.7) 
2310 (32.3) 
2530 (26.6) 
3010 (67.3) 
5090 
(35.0) 
8860 
(32.7) 
tmax a 
(h) 
1.00 
(1.00–1.50) 
1.25 
(1.00-2.00) 
3.00 
(2.00–3.00) 
1.50 
(1.00–2.00) 
1.00 
(1.00-1.50) 
1.00 
(0.500-3.00) 
2.00 
(1.00-3.00) 
3.00 
(2.00-4.00) 
t1/2 
(h) 
3.58 (17.2) 
4.32 (13.3) 
7.15 (25.2) 
4.71 (15.7) 
6.15 (23.4) 
6.46  
(24.0) 
5.47 
(38.3) 
5.87 
(23.2) 
**High-fat meal administered at 30 mg or 100 mg for food effect assessment during single ascending dose phase. 
a Median (min-max) presented. 
NA = Not applicable. 
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Protocol 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
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Table 2: 
Key Pharmacokinetic Parameters of NST-1024 Repeat Doses Evaluated to Date in Study NST-1024-01 
Parameter 
(Units) 
10 mg 
(Single, Fed*) 
10 mg 
(Repeat, Fed*) 
30 mg 
(Single, 
Fed*) 
30 mg 
(Repeat, Fed*) 
60 mg (Single, 
Fed*) 
60 mg 
(Repeat, Fed*) 
200 mg 
(Single, Fed*) 
200 mg (Repeat, 
Fed*) 
Dosing Group 
B1 
B2 
B3 
B4 
 
N=8 
N=8 
N=8 
N=8 
N=6 
N=6 
18 
18 
AUC0-24 
(ng*h/mL) 
898 (26.4) 
1050 (19.3) 
3410 (27.1) 
3530 (20.6) 
5930 (26.9) 
6770 (27.3) 
29100 (26.1) 
29500 (21.8) 
Cmax 
(ng/mL) 
181 (22.5) 
190 (25.3) 
665 (23.1) 
599 (27.7) 
1030 (18.2) 
1390 (23.6) 
6510 (44.5) 
6080 (31.9) 
Cmin 
(ng/mL) 
NA 
2.96 (26.4) 
NA 
9.94 (52.9) 
NA 
16.1 (83.2) 
NA 
84.7 (53.4) 
tmax a 
(h) 
2.50 
(1.00-4.00) 
2.00 
(1.50-4.00) 
2.00 
(1.00-4.00) 
2.50 
(1.50-4.00) 
2.00 
(1.50-4.00) 
1.50 
(1.00-1.50) 
4.00 
(1.50-6.00) 
4.00 
(2.00-6.00) 
t1/2 
(h) 
3.52 (35.3) 
5.16 (17.7) 
3.90 (24.5) 
6.76 (22.3) 
3.81 (12.3) 
5.65 (31.1) 
4.06 (17.4) 
5.77 (23.4) 
* Standard breakfast administered for MAD cohort, with repeat dose PK assessed on Day 14.  
a Median (min-max) presented. 
NA = Not applicable. 
 
 
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Protocol 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page  of  
1.4. 
Study Rationale 
The objective of DDI studies is to determine whether potential interactions between an 
investigational drug and other drugs exist. Drug-drug interaction studies have an important 
role in drug development, and this study is being performed as part of the development 
program for NST-1024.Given the potential for NST-1024 to cause induction and/or inhibition 
of CYP enzymes as discussed in Section 1.2, a DDI study is warranted to investigate the 
potential for CYP induction and/or inhibition clinically. NST-1024 may have the potential to 
raise plasma concentrations of drugs that are probe drugs of CYP1A2, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A4 or lower plasma concentrations that are metabolised by CYP1A2 or 
CYP3A4. This study is designed to determine the effect of NST-1024 on the PK of caffeine 
(CYP1A2), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and 
midazolam (CYP3A4). Caffeine and midazolam on Day 8 will assess the inhibition potential 
of CYP1A2 and 3A4 and on Day 21 will assess the induction potential of CYP1A2 and 3A4. 
The effects of NST-1024 on the PK of other CYP450 probe drugs may be explored in 
separate clinical studies. Caffeine, flurbiprofen, omeprazole, metoprolol, and midazolam are 
commonly used as index probe drugs for CYP450 enzymes in DDI studies. 
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 treatments, 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 
AEs associated with NST-1024 may be found in the IB.1 
The side effects of caffeine, flurbiprofen, omeprazole, metoprolol, and midazolam are well 
characterised and generally predictable. The risks of clinically significant side effects related 
to the doses of probe drugs used in this trial are considered minimal. Dosing will only occur 
while subjects are resident at the clinical research unit (CRU), under medical supervision. 
Information about the known and expected risks of the probe drugs may be found in their 
respective prescribing information. 
2. OBJECTIVES AND ENDPOINTS 
Table 3 shows the objectives and endpoints of the study. 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
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Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
 
x to evaluate the effects of NST-1024 on the 
PK of caffeine, flurbiprofen, omeprazole, 
metoprolol, and midazolam in healthy male 
and female subjects 
x primary PK parameters: AUC0-inf, 
AUC0-tlast, and Cmax 
Secondary: 
 
x to assess the safety and tolerability of 
NST-1024 in healthy subjects 
x incidence and severity of AEs 
x incidence of laboratory 
abnormalities, based on 
haematology, clinical chemistry, 
and urinalysis test results 
x 12-lead ECG parameters 
x vital signs measurements 
x physical examinations 
Abbreviations: AE = adverse event; AUC0-inf = area under the concentration-time curve from time 0 extrapolated to infinity; 
AUC0-tlast = area under the concentration-time curve from time 0 to the time of the last quantifiable concentration; 
Cmax = maximum observed concentration; ECG = electrocardiogram; PK = pharmacokinetic(s). 
3. INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This will be a Phase 1, open-label study to evaluate the effects of NST-1024 on the PK of 
caffeine (and paraxanthine), flurbiprofen, omeprazole, metoprolol, and midazolam (and 
1-hydroxymidazolam) in healthy male and female subjects. Up to 21 subjects will be enroled 
to ensure that 18 subjects complete the study. All subjects will receive each of the following 
treatments: 
x Day 1: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 
100 mg metoprolol, and 2.5 mg midazolam 
x Days 8 to 22: oral doses of 200 mg NST-1024 qd multiple-dose regimen 
x Day 8: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 
100 mg metoprolol, and 2.5 mg midazolam coadministered with an oral dose of 
200 mg NST-1024 
x Day 21: single oral dose of 100 mg caffeine and 2.5 mg midazolam coadministered 
with an oral dose of 200 mg NST-1024. 
An overview of the study design is shown in Figure 1. 
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Protocol 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 19 of 
Figure 1: 
Study Schematic
Abbreviations: CAF = caffeine; FLF = flurbiprofen; MDZ = midazolam; MTP = metoprolol; OMZ = omeprazole; 
PK = pharmacokinetic(s); qd = once daily
a Subjects will discharge on Day 3 and return for check-in RQ'D\
b Pharmacokinetic sampling for CAF, FLF, MDZ, MTP, DQG20=RQ'D\VDQGSUHGRVH
8, 12, 16, 24, and 48 hours postdose. Pharmacokinetic VDPSOLQJIRU&$)DQG0'=RQ'D\SUHGRVH
1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Subjects will be admitted into the study site on Day -1 
and be confined until discharge on Day 3. Subjects will return for check-in on 'D\DQGEH
confined until discharge on Day 23. Subjects will return to the study site for a follow-up visit 
 to 10 days after the last dose.
The total duration of study participation for each subject (from screening through follow-up 
visit) is anticipated to be approximately 61 days. 
The start of the study is defined as the date the first 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).
A Schedule of Assessments is presented in Appendix 6. 
3.2.
Discussion of Study Design
The fixed sequence design used in this study is typical for interaction studies where a 
relatively small number of subjects are required, because it allows intrasubject comparisons 
and reduces intersubject variability. This study will be open-label because the study 
endpoints are not considered subjective.
Study day
Follow-up 
-10 days after 
final dose
1
WRa
8
22
-28
screening
NST-1024 (qd)
CAF and MDZ
21
-1
CAF, FLF, 
OMZ, MTP, 
and MDZ
PK Sampling for NST-1024
PK Sampling for CAF, FLF, OMZ, MTP, and MDZb
CAF, FLF, 
OMZ, MTP, 
and MDZ
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Protocol 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 20 of  
This study will investigate the potential effects of NST-1024 on those hepatic enzymes that 
demonstrated inhibition in human liver microsomes in vitro: CYP1A2 (caffeine), CYP2C9 
(flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A4 (midazolam). 
The study will also investigate the induction potential of CPY1A2 and CYP3A4. The probe 
drugs chosen for this study are principally cleared via metabolism by the indicated CYP and 
are regarded as a prototypical probe drugs of that CYP. The probe drugs are frequently used 
as probe drugs for investigation of DDIs mediated through inhibition or induction of the 
relevant CYP. The PK after a single dose of NST-1024 will investigate inhibition potential; 
PK after multiple doses of NST-1024 to investigate induction potential. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
3.3. 
Selection of Doses in the Study 
Single and multiple doses of 200 mg of NST-1024 have been shown to be safe and well 
tolerated in healthy subjects in Study NST-1024-01. A single dose of 200 mg is considered 
sufficient to assess the inhibition potential of the CYP enzymes while 15 days (Days 8 to 22 
inclusive) of repeat dosing with NST-1024 is considered sufficient for full induction potential 
of the CYP enzymes. Although single doses of 400 mg are safe and well tolerated, a lower 
dose of 200 mg was selected for both the inhibition and induction phases of this study. The 
exposure (both AUC and Cmax) of 200 mg multiple dose is significantly lower than the 
no-observed-adverse-effect level from the dog WR[LFRORJ\VWXG\ mg/kg/day), providing an 
adequate safety margin in case of significant increase in NST-1024 concentration is observed. 
The doses of caffeine, flurbiprofen, omeprazole, metoprolol, and midazolam were selected as 
they are the most sensitive probe drugs and there is a large body of information on the 
relative contribution of specific CYP pathways to their overall elimination, their appropriate 
dosing regimens, safety profiles, and anticipated interaction effects when coadministered with 
strong CYP inhibitors or inducers. 
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 65 years of age, inclusive. 
2. Body mass index between 18.0 and 32.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
12-lead ECG, vital signs measurements, and clinical laboratory evaluations 
(congenital nonhaemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome 
based on total and direct bilirubin] is not acceptable) at screening and/or check-in and 
from the physical examination at check-in, as assessed by the investigator (or 
designee). 
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Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
Page 21 of  
4. Females will not be pregnant or lactating, and females of childbearing potential and 
males will agree to use contraception as detailed in Appendix 4. 
5. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 
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: 
Medical conditions 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, haematological, pulmonary, CV, gastrointestinal, neurological, 
respiratory, endocrine, or psychiatric disorder, as determined by the investigator (or 
designee). 
2. History of febrile illness within 1 week prior to the first dose. 
3. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the investigator (or designee). 
4. History of stomach or intestinal surgery or resection that would potentially alter 
absorption and/or excretion of orally administered drugs (uncomplicated 
appendectomy and hernia repair will be allowed). 
5. Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, 
alkaline phosphatase, or total bilirubin >1.2 × the upper limit of normal at Screening 
or (first) Check-in, confirmed by 1 repeat if necessary. 
6. Confirmed (eg, 2 consecutive measurements) systolic blood pressure >160 or 
<80 mmHg, diastolic blood pressure >90 or <45 mmHg, and pulse rate >100 or 
<40 beats per minute. 
 Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
Prior/concomitant therapy 
8. Administration of a coronavirus disease 2019 vaccine in the past 30 days prior to 
dosing. 
9. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including over-the-counter and herbal 
medication, within 30 days prior to dosing, unless deemed acceptable by the 
investigator (or designee). 
10. Use or intend to use any prescription medications/products other than hormone 
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptives within 14 days prior to dosing, unless deemed acceptable by the 
investigator (or designee). 
11. Use or intend to use slow-release medications/products considered to still be active 
within 14 days prior to check-in, unless deemed acceptable by the investigator (or 
designee). 
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Protocol Reference: NST-1024-02 
Protocol Final Version 1, 16 May 2022 
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12. Use or intend to use any nonprescription medications (except paracetamol, up to 2 g 
per day)/products including vitamins, dietary supplements, minerals, and 
phytotherapeutic/plant-derived SUHSDUDWLRQVZLWKLQ days prior to check-in, unless 
deemed acceptable by the investigator (or designee). Herbal supplements must be 
discontinued at least 28 days prior to the first dose of study drug. 
Prior/concurrent clinical study experience 
13. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days prior to dosing. 
Diet and lifestyle 
14. Alcohol consumption of >21 units (males) and >14 units (females) per week. 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. 
15. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at screening or check-in. 
16. History of alcoholism or drug/chemical abuse within 2 years prior to check-in. 
 Use of tobacco- or nicotine-containing products within 3 months prior to check-in, or 
positive cotinine at screening or check-in. 
18. Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages 
withiQGD\VSULRUWRcheck-in. 
Other exclusions 
19. Receipt of blood products within 2 months prior to check-in. 
20. Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to 
screening, or platelets from 6 weeks prior to screening. Subjects must also be willing 
to not donate blood for 3 months after the follow-up visit. 
21. Poor peripheral venous access. 
22. Subjects who, in the opinion of the investigator (or designee), should not participate 
in this study. 
23. Mental incapacity or language barriers which preclude adequate understanding or 
cooperation, or unwillingness to comply with trial requirements. 
24. An employee of the sponsor or investigator or otherwise dependent on them. 
4.3. 
Generic Screening 
Subjects may previously have been screened on a generic basis to determine their eligibility 
for inclusion in Phase 1 clinical studies conducted at the study site. If generic screening was 
performed within the specified study screening window, selected study-specific procedures 
would be repeated either at an additional screening visit or on admission to the study site on 
Day -1. 
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Protocol Final Version 1, 16 May 2022 
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4.4. 
Subject Number and Identification 
Subjects will have a unique identification number used at screening. Subjects will be assigned 
a subject number prior to the first dosing occasion. Assignment of subject numbers will be in 
ascending order and no numbers will be omitted (eg, Subjects 0101, 0102, 0103). 
Replacement subjects (Section 4.5) 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 screening identification number or subject number only on all 
study documentation. A list identifying the subjects by subject number will be kept in the site 
master file. 
Subjects who are initially found to be ineligible may be rescreened at the discretion of the 
investigator. 
4.5. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn from dosing if any of the following criteria are met: 
x change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the investigator (or designee) 
x noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the investigator (or designee) 
x any clinically relevant sign or symptom that, in the opinion of the investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn from dosing, 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. If a 
subject is withdrawn from the study, efforts will be made to perform all follow-up 
assessments, if possible (Appendix 6). Other applicable safety-related 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 
clinic. 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 AEs or 
until the unresolved AEs are judged by the investigator (or designee) to have stabilised. 
Subjects who are withdrawn for reasons not related to study treatment may be replaced 
following discussion between the investigator and the sponsor. Subjects withdrawn as a result 
of AEs thought to be related to the study treatment will generally not be replaced. 
4.6. 
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: 
x AEs unknown to date (ie, not previously reported in any similar investigational study 
drug trial with respect to their nature, severity, and/or duration) 
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Protocol Final Version 1, 16 May 2022 
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x increased frequency, severity, and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at check-in as baseline signs and 
symptoms) 
x medical or ethical reasons affecting the continued performance of the study 
x difficulties in the recruitment of subjects 
x cancelation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labelling 
NST-1024 will be supplied as liquid in soft gelatin capsules, 100 mg by the sponsor (or 
designee), along with the batch/lot numbers and certificates of analysis. A certificate of 
release authorised by a Qualified Person from a listed country or United Kingdom will also 
be issued for the IMP. NST-1024 will be provided in bulk bags and stored according to the 
instructions on the label. 
The investigator will commercially source caffeine (100 mg in 2 × 50-mg tablets), 
flurbiprofen (50-mg tablet), omeprazole (20-mg capsule), metoprolol (100-mg coated tablet), 
and midazolam (2.5-mg solution). The tablets and capsules will be provided in blisters and 
the solution will be provided in syringes. The probe drugs will be stored according to the 
manufacturer’s instructions. 
Investigational medicinal products 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 IMPs will be transferred from bulk supplies into the subject’s dose 
container by qualified clinical staff. 
5.2. 
Study Treatment Administration 
Each dose of NST-1024 and probe drugs will be administered orally with approximately 
240 mL of room temperature water. When NST-1024 and probe drugs are administered 
concurrently, only 240 mL of room temperature water will be administered for all drugs, 
though additional water (up to another approximately 240 mL) is permissible for the Day 1 
dose and Day 8 dose when the total number of coadministered drugs is relatively high. Water 
restrictions around dosing around dosing are provided in Section 6.2. 
All doses will be given in a fasted state. 
Subjects will be dosed 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 AE(s) and/or 
study procedures. 
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5.3. 
Randomisation 
This is a nonrandomised study. The study has a fixed treatment sequence. 
5.4. 
Blinding 
This is an open-label study. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
x All doses will be administered under the supervision of suitably qualified study site 
staff. 
x Immediately after dose administration, visual inspection of the mouth and hands will 
be performed for each subject. 
x At each dosing occasion, a predose and postdose inventory of NST-1024 and caffeine, 
flurbiprofen, omeprazole, metoprolol, and midazolam will be performed. 
5.6. 
Drug Accountability 
The investigator (or designee) will maintain an accurate record of the receipt of NST-1024 
capsules 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 NST-1024 capsules will be returned to the sponsor 
or disposed of by the study site, per the sponsor’s written instructions. 
Caffeine, flurbiprofen, omeprazole, metoprolol, and midazolam will also be subject to 
accountability procedures, and the study site staff will destroy unused supplies of probe drugs 
at the end of the study. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription or nonprescription medications/products 
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 
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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 for treatment of an AE. 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 (at 
least 8 hours) before collection of blood samples for clinical laboratory evaluations. 
On the days with PK assessments (Days 1, 8, and 21), the subjects will be fasted overnight (at 
least 8 hours) prior to dosing and 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. At all other times during the study, subjects may consume water ad libitum. 
All doses will be given in a fasted state. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
DOORZHGIURP days prior to check-in until the follow-up visit. 
Caffeine-containing foods and beverages will not be allowed from 36 hours before check-in 
until discharge. 
Consumption of alcohol will not be permitted from 36 hours prior to check-in until after the 
follow-up visit. 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 
3 months prior to check-in until the follow-up visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from  days before check-in until the 
follow-up visit and will otherwise maintain their normal level of physical 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. 
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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 highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
x dosing 
x blood samples (for NST-1024 assay) 
x pulse oximetry 
x vital signs 
x 12-lead ECGs 
x any other procedures. 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Pharmacokinetic Blood Sample Collection and Processing 
Blood samples (approximately 1 × 1 mL for NST-1024, 1 × 4 mL for caffeine [and 
paraxanthine] and midazolam [and 1-hydroxymidazolam], 1 × 4 mL for flurbiprofen, 
omeprazole, and metoprolol) will be collected by venepuncture or cannulation at the times 
indicated in the Schedule of Assessments in Appendix 6. Procedures for collection, 
processing, and shipping of PK blood samples will be detailed in a separate document. 
7.1.2. 
Analytical Methodology 
Plasma concentrations of NST-1024, caffeine (and paraxanthine), flurbiprofen, omeprazole, 
metoprolol, and midazolam (and 1-hydroxymidazolam) will be determined using a validated 
analytical procedure. Specifics of the analytical method will be provided in a separate 
document. 
7.2. 
Safety and Tolerability Assessments 
7.2.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
serious AEs 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 AEs occurring at any other 
time during the study. 
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Any AEs 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 treatment. 
Adverse events recorded during the course of the study will be followed up, where possible, 
to resolution or until the unresolved AEs are judged by the investigator (or designee) to have 
stabilised. This will be completed at the investigator’s (or designee’s) discretion. 
7.2.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations at the times 
indicated in the Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are 
listed in Appendix 2. 
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 
in Appendix 6. For all female subjects, a pregnancy test will be performed at the times 
indicated in the Schedule of Assessments in Appendix 6. 
An investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
7.2.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, and oral body temperature will be assessed at the 
times indicated in the Schedule of Assessments in Appendix 6. Vital signs may also 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 vital signs is required. 
Blood pressure will be taken in triplicate at approximately 2-minute intervals on Day 1, 
predose, and as single measurements at all other times. All other measurements will be 
performed singly, and repeated once if outside the relevant clinical reference range. 
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 
7.2.4. 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the Schedule of Assessments in Appendix 6. Single 
12-lead ECGs will be repeated once if either of the following criteria apply: 
x QT interval corrected for heart rate using Fridericia’s method (QTcF) >500 ms 
x 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. 
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7.2.5. 
Physical Examination 
A full physical examination or symptom-directed physical examination will be performed at 
the timepoints specified in the Schedule of Assessments in Appendix 6. 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
Up to 21 subjects will be enroled in order that 18 complete the study. 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of active study 
treatment (NST-1024, caffeine, flurbiprofen, omeprazole, metoprolol, or midazolam) and 
have at least 1 valid PK concentration. 
8.2.2. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of study treatment 
(NST-1024, caffeine, flurbiprofen, omeprazole, metoprolol, or midazolam). 
8.2.3. 
All Subjects Population 
The all subjects population will include all subjects who signed the ICF and have any study 
assessment recorded in the database per the protocol. 
8.3. 
Pharmacokinetic Analyses 
Pharmacokinetic parameters will be determined from the plasma concentrations of caffeine 
(and its metabolite paraxanthine), flurbiprofen, omeprazole, metoprolol, and midazolam (and 
its metabolite 1-hydroxymidazolam) using standard noncompartmental methods. 
The primary PK parameters are AUC from time 0 extrapolated to infinity (AUC0-inf), AUC 
from time 0 to the time of the last quantifiable concentration (AUC0-tlast), and Cmax. 
Additional PK parameters may be calculated. All other PK parameters will be regarded as 
secondary and will not be subject to inferential statistical analysis. Full details of PK 
parameters will be presented in the statistical analysis plan for this study. 
A linear mixed-model analysis will be applied to analyse the log-transformed primary PK 
parameters. The model will assume a fixed effect for treatment and a random effect for 
subject. Estimates of geometric least squares mean ratios together with the corresponding 
90% confidence intervals will be derived for each of the parameters separately as follows: 
x Probe drugs coadministered with NST-1024 (profile Day 8) (test) versus probe drugs 
alone (profile Day 1) (reference). This comparison will be done for caffeine, 
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paraxanthine, flurbiprofen, omeprazole, metoprolol, midazolam, and 
1-hydroxymidazolam analytes separately 
x Probe drugs coadministered with NST-1024 (profile Day 21) (test) versus probe drugs 
alone (profile Day 1) (reference). This comparison will be done for caffeine, 
paraxanthine, midazolam, and 1-hydroxymidazolam analytes separately. 
8.4. 
Safety Analysis 
All AEs will be listed and TEAEs will be summarised. Each AE will be coded using the 
Medical Dictionary for Regulatory Activities. Observed values for clinical laboratory test 
data, 12-lead ECGs, and vital signs, and physical examination findings will be listed. 
8.5. 
Interim Analysis 
No interim analyses are planned for this study. 
9. REFERENCES 
1. NST-1024 [Investigator’s Brochure]. Amsterdam, The Netherlands: NorthSea 
Therapeutics B.V.; Version 1.0, 23 June 2020. 
 
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10. APPENDICES 
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Appendix 1: Adverse Event Reporting 
Definitions 
An adverse event (AE) 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 AE can therefore be any unfavourable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study treatment, whether or not related to the 
study treatment. 
Assessment of Severity 
The investigator will be asked to provide an assessment of the severity of the AE using the 
following categories: 
x Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
x 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. 
x Severe: Interrupts usual activities of daily living, or significantly affects clinical 
status, or may require intensive therapeutic intervention. 
Relationship to Study Treatment 
The investigator (or designee) will make a determination of the relationship of the AE to the 
study treatment using a 4-category system according to the following guidelines: 
x Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
x Unlikely Related: The temporal association between the AE and the drug is such that 
the drug is not likely to have any reasonable association with the AE. 
x Possibly Related: The AE follows a reasonable temporal sequence from the time of 
drug administration but could have been produced by the subject’s clinical state or the 
study procedures/conditions. 
x Related: The AE 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 AEs. Any subject 
who has an ongoing AE that is possibly related or related to the investigational medicinal 
product (IMP) or study procedures at the follow-up visit will be followed up, where possible, 
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until resolution or until the unresolved AE is judged by the investigator (or designee) to have 
stabilised. This will be completed at the investigator’s (or designee’s) discretion. Any subject 
who has an ongoing AE that is not related or unlikely related to the IMP or study procedures 
at the follow-up visit can be closed out as ongoing at the investigator’s discretion. 
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (ie, where a causal relationship between an 
IMP and an AE 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 man 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 for an unapproved IMP). 
Serious Adverse Events 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose either: 
x results in death 
x is life-threatening 
x requires inpatient hospitalisation or prolongation of existing hospitalisation 
x results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
x results in a congenital anomaly/birth defect 
x 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 SAEs when, based upon appropriate medical judgement, 
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 
possibly related to the study treatment, will be reported to the sponsor. 
Definition of Life-threatening 
An AE 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 
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hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 
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 study site. When in doubt as to whether hospitalisation occurred or 
was necessary, the AE should be considered as serious. 
Hospitalisation for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs 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 AE and either ‘serious’ or ‘nonserious’ attributed 
according to the usual criteria. 
Serious Adverse Event Reporting 
Emas Pharma Limited, Trading as Bionical Emas, Hertfordshire, United Kingdom is 
responsible for coordinating the reporting of SAEs in accordance with the European Directive 
2001/20/EC. 
The investigator will complete an SAE report form and forward it by email 
(drug.safety@bionical-emas.com) to Emas Pharma Limited and the sponsor immediately 
(within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Emas Pharma Limited include the following: 
x Prepare an SAE Management Plan prior to the start of the study. Where this plan 
differs from the applicable CRU standard operating procedure on SAE reporting, the 
SAE Management Plan will always take precedence. 
x Receive and review SAE report forms from the CRU and inform the sponsor of the 
SAE within 1 working day of the initial notification to Emas Pharma Limited. Emas 
Pharma Limited will delete any information from the SAE report forms that may 
identify the subject. 
x Write case narratives and enter the case into the safety database as defined in the SAE 
Management Plan. 
x Produce appropriate reports of all suspected unexpected serious adverse reactions and 
forward to the institutional review board/ethics committee, Medicines and Healthcare 
products Regulatory Agency, investigator, and the sponsor 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. 
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Pregnancy 
Pregnancy (maternal or paternal exposure to study treatment) does not meet the definition of 
an AE. However, to fulfil regulatory requirements any pregnancy should be reported by the 
investigator to Emas Pharma Limited and the sponsor immediately (within 24 hours) upon 
becoming aware of the pregnancy, by completing a pregnancy report form and forwarding by 
email to drug.safety@bionical-emas.com. The pregnancy will be followed up to collect data 
on the outcome for both mother and foetus. 
 
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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Haematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bilirubin (total and direct) 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Gamma glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium 
Sodium 
Total protein 
Uric acid 
Haematocrit 
Haemoglobin 
Mean cell haemoglobin 
Mean cell haemoglobin 
concentration 
Mean cell volume 
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: 
Drug screen: 
Hormone panel - females only a: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency virus 
(HIV-1 and HIV-2) antibodies and 
p24 antigen 
Including but not limited to: 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Cotinine test 
Alcohol breath test 
Follicle-stimulating hormone 
Serum pregnancy test (human 
chorionic gonadotropin)b 
a Performed at screening only 
b For 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. 
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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) 
Clinical laboratory evaluationsa 
 
6 
45 
Serology 
3.5 
1 
3.5 
NST-1024 PK 
1 
15 
15 
Caffeine (and paraxanthine) and midazolam 
(and 1-hydroxymidazolam) PK 
4 
42 
168 
Flurbiprofen, omeprazole, and metoprolol 
PK 
4 
28 
112 
Total: 
343.5 
Abbreviations: PK = pharmacokinetic(s) 
a Includes pregnancy and follicle-stimulating hormone tests. 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 550 mL. 
 
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Appendix 4: Contraception Guidance 
Definitions 
Female of Childbearing Potential: premenopausal female who is anatomically and 
physiologically capable of becoming pregnant following menarche. 
Female of Nonchildbearing Potential: 
1. Surgically sterile: female who is permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history and/or 
medical records. Surgical sterilisation to have occurred a minimum of 6 weeks, or 
at the investigator’s discretion, prior to screening. 
2. Postmenopausal: female at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) OHYHORI40 mIU/mL. The amenorrhea should not be induced by 
a medical condition such as anorexia nervosa, hypothyroid disease or polycystic 
ovarian disease, or by extreme exercise. It should not be due to concomitant 
medications that may have induced the amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormones, anti-oestrogens, selective oestrogen 
receptor modulators, or chemotherapy. Females on hormone replacement therapy 
with FSH levels <40 mIU/mL may be included at the discretion of the 
investigator. Women aged >60 years ROGZKRVH)6+YDOXHVDUHQRW40 mIU/mL 
may be included at the discretion of the investigator and in consultation with the 
sponsor. 
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Subjects 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception. For female subjects of childbearing potential, 2 methods (1 primary acceptable 
and 1 secondary method) of birth control are required from the time of signing the informed 
consent form (ICF) until 90 days after the follow-up visit. Primary (non-barrier) methods of 
contraception include: 
x hormonal injection (as prescribed) 
x combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
x combined hormonal patch (as prescribed) 
x combined hormonal vaginal ring (as prescribed) 
x surgical method performed at least 3 months prior to the screening visit: 
o 
bilateral tubal ligation 
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o 
Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes 
x hormonal implant 
x hormonal or non-hormonal intrauterine device 
x vasectomised male partner (sterilisation performed at least 90 days prior to the 
screening visit, with verbal confirmation of surgical success, and the sole partner 
for the female subject). 
A secondary (barrier) method of contraception would include: 
x condom with spermicide. 
Female subjects of childbearing potential should refrain from donation of ova from check-in 
(Day -1) until 90 days after the follow-up visit. 
Male Subjects 
Male subjects in conjunction with partners of childbearing potential use the following 
contraceptive measure: 
x condom and spermicide (even if subject has a history of vasectomy). 
In addition, use a second method of acceptable contraception from check-in until 90 days 
after discharge. Acceptable methods of contraception for female partners include: 
x hormonal injection 
x combined oral contraceptive pill or progestin/progestogen-only pill 
x combined hormonal patch 
x combined hormonal vaginal ring 
x surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion]) 
x hormonal implant 
x hormonal or non-hormonal intrauterine device. 
An acceptable second method of contraception for male subjects is vasectomy that has been 
performed at least 90 days prior to the screening visit, with verbal confirmation of surgical 
success. 
For male subjects (even with a history of vasectomy), 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 the follow-up visit. Male subjects are required to refrain 
from donation of sperm from check-in until 90 days after the follow-up visit. 
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Sexual Abstinence and Same-sex Relationships 
A subject who practices total abstinence is required to identify contraceptive methods he/she 
will use in the event of sexual activity. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
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. 
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Appendix 5: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
x Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
x Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
x Applicable laws and regulations. 
The protocol, protocol amendments, informed consent form (ICF), investigator’s brochure, 
and other relevant documents must be submitted to an institutional review board (IRB)/ethics 
committee (EC) by the investigator and reviewed and approved by the IRB/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 IRB/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 nonsubstantial changes, as defined by 
regulatory requirements. 
The investigator will be responsible for the following: 
x Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC. 
x Notifying the IRB/EC of serious adverse events or other significant safety findings as 
required by IRB/EC procedures. 
x 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 IRB/EC, 
European Directive 2001/20/EC 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 treatments, 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 
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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. 
Following discussion of the study with study site personnel, subjects will sign the ICF in the 
presence of a suitably trained member of staff to indicate that they are freely giving their 
informed consent. A copy of the ICF will be given to the subject. 
Subjects must be reconsented 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 IRB/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: 
x All relevant 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. 
x The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
x The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. 
x Labcorp Drug Development is responsible for the data management of this study 
including quality checking of the data. Predefined agreed risks, monitoring thresholds, 
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quality tolerance thresholds, controls, and mitigation plans will be documented in a 
project management plan. Additional details of quality checking to be performed on 
the data may be included in a data management plan. 
x 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 GCP, and all applicable 
regulatory requirements. 
x 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 CFR 
Part 11-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 Labcorp Drug Development electronically will be integrated with the subject’s 
eCRF data in accordance with the data management plan. 
An eCRF must be completed for each enroled subject who 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 
Publications will be addressed in a separate agreement. 
x The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments. 
x The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicentre studies only in their entirety and not as 
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individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
x Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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Appendix 6: Schedule of Assessments 
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Schedule of Assessments 
Study Procedures 
Screening 
Day -1 
Days 1 to 23 
Follow-up 
(7 to 10 days 
post final dose) 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
Day 1: predose 
 
Demographic data 
X 
 
 
 
Medical history 
X 
Xa 
 
 
Urinary drug screen 
X 
X 
'D\ 
 
Urine cotinine test 
X 
X 
'D\ 
 
Alcohol breath test 
X  
X 
'D\ 
 
Serology 
X 
 
 
 
Pregnancy testb 
X 
X 
'D\ 
 
FSHc 
X 
 
 
 
Height and body weight 
X 
 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X 
'D\ 
 
Check-out 
 
 
Days 3 and 23 (24 hours post final dose) 
 
Nonresidential visit 
X 
 
 
X 
Study treatment administration: 
 
 
 
 
NST-1024 
 
 
Days 8 to 22 (inclusive) 
 
Omeprazole, flurbiprofen, metoprolol 
 
 
Days 1 and 8 
 
Caffeine and midazolam 
 
 
Days 1, 8, and 21 
 
Pharmacokineticsd: 
 
 
 
 
NST-1024 blood sampling (15 samples/subject) 
 
 
Days 8 to 22: predose 
 
Flurbiprofen, omeprazole, metoprolol blood 
sampling 
(28 samples/subject) 
 
 
'D\VDQGSUHGRVH, and 48 
hours postdose 
 
Caffeine (and paraxanthine) and midazolam (and 
1-hydroxymidazolam) blood sampling (42 
samples/subject) 
 
 
Days 1, 8, DQGSUHGRVH, 
and 48 hours postdose 
 
Safety and tolerability: 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
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Schedule of Assessments 
Study Procedures 
Screening 
Day -1 
Days 1 to 23 
Follow-up 
(7 to 10 days 
post final dose) 
Prior/concomitant medication monitoring 
X 
X 
Ongoing 
X 
Clinical laboratory evaluations 
X 
X 
Days 8, 14, and 21 
X 
Blood pressure, pulse ratee 
X 
 
Days 1, 8, and 21: predose, 0.5, 1, 2, 3, 4, 8, 12, 24, and 48 hours 
postdose 
Days 15 and 18: predose 
X 
Oral body temperature 
X 
 
Days 1, 8, and 21: predose, 0.5, 1, 2, 3, 4, 8, 12, 24, and 48 hours 
postdose 
Days 15 and 18: predose 
X 
Pulse oximetry 
 
 
Days 1, 8, and 21: -1 to 6 h postdose with source data collected at 
predose, 1, 2, 3, 4, 5, and 6 hours postdose 
 
12-lead ECGf 
X 
 
Days 1, 8, and 21: predose, 1, 4, and 24 hours postdose 
Days 15, and 18: predose 
X 
Physical examinationg 
 
X 
Symptom-directed physical examination when required 
X 
Abbreviations: ECG = electrocardiogram; FSH = follicle-stimulating hormone 
a Interim medical history 
b Performed for all female subjects in serum at screening and in urine at all other times. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
c Performed for all female subjects 
d Predose pharmacokinetic blood samples should be taken within 30 minutes prior to dosing. 
e Blood pressure will be taken in triplicate at approximately 2-minute intervals on Day 1, predose, and as single measurements at all other times. On Day 1 predose assessments should be 
performed within 2 hours prior to dosing. On all other days of dose administration, predose assessment should be performed within 30 minutes prior to dosing. 
f 12-lead ECGs will be taken in triplicate at screening at approximately 2-minute intervals and as single measurements at all other times. On Day 1 predose assessments should be performed 
within 2 hours prior to dosing. On all other days of dose administration, predose assessment should be performed within 30 minutes of dosing. 
g A full physical examination will be conducted at check-in. Symptom-directed physical examinations will be conducted thereafter. 
Page 48 of 48

SAP_001.pdf: 
 
 
TITLE PAGE 
Statistical Analysis Plan 
A Phase 1, Open-label Study to Evaluate the Effects of NST-1024 on the 
Pharmacokinetics of Caffeine, Flurbiprofen, Omeprazole, Metoprolol, and 
Midazolam in Healthy Subjects 
SAP Status: Final 
SAP Version: 1.0 
SAP Date: 05OCT2022 
Investigational Medicinal Product: NST-1024 
Protocol Reference: NST-1024-02 
Labcorp Drug Development Study: 8489933 
 
 
Sponsor: 
NorthSea Therapeutics B.V. 
Paasheuvelweg 25-C6 
1105 BP, Amsterdam 
The Netherlands 
Study Site: 
Labcorp Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
 
 
Principal Investigator: 
Dr Firas Almazedi, MBChB, MSc, CPI, 
DipPharmMed 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 
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SAP 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
Page 2 of 22 
 
 
ST-AD-031 Version 02 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF IN-TEXT TABLES AND FIGURES ......................................................................... 3 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES AND ENDPOINTS ......................................................................... 6 
3. STUDY DESIGN................................................................................................................... 7 
4. SAMPLE SIZE JUSTIFICATION ........................................................................................ 8 
5. STUDY TREATMENTS ....................................................................................................... 8 
6. DEFINITIONS OF POPULATIONS .................................................................................... 9 
6.1. All Subjects Population ................................................................................................... 9 
6.2. Safety Population ............................................................................................................ 9 
6.3. Pharmacokinetic Population ......................................................................................... 10 
7. STATISTICAL METHODOLOGY .................................................................................... 10 
7.1. General .......................................................................................................................... 10 
7.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions ....................................................................................................................... 10 
7.1.2. Calculation of the Summary Statistics ................................................................... 11 
7.1.3. Triplicate Readings................................................................................................. 12 
7.1.4. Repeat and Unscheduled Readings ........................................................................ 12 
7.1.5. Definitions of Baseline and Change from Baseline ............................................... 12 
7.2. Subject Disposition and Population Assignment .......................................................... 13 
7.3. Screening Demographics .............................................................................................. 13 
7.4. Prior and Concomitant Medication ............................................................................... 13 
7.5. Pharmacokinetic Assessments ...................................................................................... 13 
7.5.1. Pharmacokinetic Analysis ...................................................................................... 13 
7.5.2. Presentation of Pharmacokinetic Data ................................................................... 16 
7.5.3. Pharmacokinetic Statistical Methodology (Drug-drug Interaction) ....................... 17 
7.6. Safety and Tolerability Assessments ............................................................................ 18 
7.6.1. Adverse Events ....................................................................................................... 18 
7.6.2. Clinical Laboratory Parameters .............................................................................. 20 
7.6.3. Vital Signs Parameters ........................................................................................... 20 
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Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
Page 3 of 22 
 
 
ST-AD-031 Version 02 
7.6.4. 12-lead Electrocardiogram Parameters .................................................................. 20 
7.6.5. Other Assessments ................................................................................................. 20 
7.6.6. Safety and Tolerability Statistical Methodology .................................................... 20 
8. INTERIM ANALYSES ....................................................................................................... 20 
9. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES .......... 20 
10. REFERENCES .................................................................................................................. 21 
11. APPENDICES ................................................................................................................... 22 
Appendix 1: 
Document History ................................................................................ 22 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1: 
Objectives and Endpoints........................................................................................ 7 
Table 2: 
Presentation of Study Treatments in TFLs ............................................................. 9 
Table 3: 
Presentation of Study Treatment Sequence in TFLs ............................................... 9 
 
Figure 1: 
Study Schematic ...................................................................................................... 8 
 
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Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
Page 4 of 22 
 
 
ST-AD-031 Version 02 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]). 
%AUCextrap 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
ADaM 
Analysis Data Model 
AE 
adverse event 
AUC0-∞ 
area under the concentration-time curve from time 0 extrapolated to 
infinity 
AUC0-tlast 
area under the concentration-time curve from time 0 to the time of the 
last quantifiable concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent total clearance 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019 
CSR 
clinical study report 
CV 
coefficient of variation 
DMP 
data management plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GLSM 
geometric least squares mean 
ICF 
informed consent form  
ICH 
International Council for/Conference on Harmonisation 
LLOQ 
lower limit of quantification 
ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRAUC 
metabolite:parent ratio based on AUC0-∞ 
PK 
pharmacokinetic(s) 
QD 
once daily 
R2-adj 
adjusted coefficient for determination of exponential fit 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDV 
source document verification 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
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Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
Page 5 of 22 
 
 
ST-AD-031 Version 02 
TFL 
table, figure, and listing 
tlast 
time of the last quantifiable concentration 
tmax 
time of the maximum observed concentration 
Vz/F 
apparent volume of distribution during the terminal phase 
WHODrug 
World Health Organization Drug Dictionary  
λz 
apparent terminal elimination rate constant 
λz Lower 
start of exponential fit 
λz N 
number of data points included in the log-linear regression 
λz Span Ratio 
time period over which λz was determined as a ratio of t1/2 
λz Upper 
end of exponential fit 
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SAP 
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Labcorp Drug Development Study: 8489933 
Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
Page 6 of 22 
 
 
ST-AD-031 Version 02 
1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 1 
dated 16 May 2022) and electronic case report form (eCRF).  
This SAP describes the planned analysis of the pharmacokinetic (PK), safety, and tolerability 
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 shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with NorthSea Therapeutics B.V. A limited amount of information 
about this study (eg, objectives, study design) is given to help the reader’s interpretation.  
This SAP must be finalized prior to the lock of the clinical database. Additionally, the SAP 
and TFL shells should be finalized prior to any programming activities commencing. 
This SAP supersedes any 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 accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with NorthSea Therapeutics B.V. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E3 guideline Structure and Content of Clinical Study 
Reports, ICH E8 guideline General Considerations for Clinical Trials, and ICH E9 guideline 
Statistical Principles for Clinical Trials.1,2,3 
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES AND ENDPOINTS  
Table 1 shows the objectives and endpoints of the study. 
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Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
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ST-AD-031 Version 02 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary: 
 
 to evaluate the effects of NST-1024 on the 
PK of caffeine, flurbiprofen, omeprazole, 
metoprolol, and midazolam in healthy male 
and female subjects 
 primary PK parameters: AUC0-inf, 
AUC0-tlast, and Cmax 
Secondary: 
 
 to assess the safety and tolerability of 
NST-1024 in healthy subjects 
 incidence and severity of AEs 
 incidence of laboratory 
abnormalities, based on 
haematology, clinical chemistry, 
and urinalysis test results 
 12-lead ECG parameters 
 vital signs measurements 
 physical examinations 
Abbreviations: AE = adverse event; AUC0-inf = area under the concentration-time curve from time 0 extrapolated to infinity; 
AUC0-tlast = area under the concentration-time curve from time 0 to the time of the last quantifiable concentration; 
Cmax = maximum observed concentration; ECG = electrocardiogram; PK = pharmacokinetic(s). 
3. STUDY DESIGN  
This will be a Phase 1, open-label study to evaluate the effects of NST-1024 on the PK of 
caffeine (and paraxanthine), flurbiprofen, omeprazole, metoprolol, and midazolam (and 
1-hydroxymidazolam) in healthy male and female subjects. Up to 21 subjects will be enrolled 
to ensure that 18 subjects complete the study. All subjects will receive each of the following 
treatments: 
● Day 1: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 
100 mg metoprolol, and 2.5 mg midazolam 
● Days 8 to 22: oral doses of 200 mg NST-1024 once daily (QD) multiple-dose regimen 
● Day 8: single oral dose of 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 
100 mg metoprolol, and 2.5 mg midazolam coadministered with an oral dose of 200 mg 
NST-1024 
● Day 21: single oral dose of 100 mg caffeine and 2.5 mg midazolam coadministered 
with an oral dose of 200 mg NST-1024. 
An overview of the study design in Figure 1. 
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Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
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ST-AD-031 Version 02 
Figure 1: Study Schematic 
 
 
 
 
Abbreviations: CAF = caffeine; FLF = flurbiprofen; MDZ = midazolam; MTP = metoprolol; OMZ = omeprazole; 
PK = pharmacokinetic(s); QD = once daily 
a Subjects will discharge on Day 3 and return for check-in on Day 7. 
b Pharmacokinetic sampling for CAF, FLF, MDZ, MTP, and OMZ on Days 1 and 8: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 
8, 12, 16, 24, and 48 hours postdose. Pharmacokinetic sampling for CAF and MDZ on Day 21: predose, 0.25, 0.5, 0.75, 1, 
1.5, 2, 4, 6, 8, 12, 16, 24, and 48 hours postdose. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Subjects will be admitted into the study site on Day -1 
and be confined until discharge on Day 3. Subjects will return for check-in on Day 7 and be 
confined until discharge on Day 23. Subjects will return to the study site for a follow-up visit 
7 to 10 days after the last dose. 
The total duration of study participation for each subject (from screening through follow-up 
visit) is anticipated to be approximately 61 days. 
The start of the study is defined as the date the first 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). 
4. SAMPLE SIZE JUSTIFICATION  
Up to 21 subjects will be enrolled in order that 18 complete the study. 
5. STUDY TREATMENTS  
The study treatment names and ordering to be used in the TFLs are presented in Table 2.  
Study day 
Follow-up 
7-10 days after 
final dose 
 
Follow-up 
1 
2 to 7a 
 
8 
22 
 
-28 
screening 
NST-1024 (QD) 
 
 
CAF and MDZ 
21 
-1 
CAF, FLF, 
OMZ, MTP, 
and MDZ 
PK Sampling for NST-1024 
CAF, FLF, 
OMZ, MTP, 
and MDZ 
PK Sampling for CAF, FLF, OMZ, MTP, and MDZb 
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Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
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Table 2: 
Presentation of Study Treatments in TFLs 
Study Treatment 
Order in TFLs 
Probe Drugs Cocktail#1 
1 
200 mg NST-1024 + Probe Drugs Cocktail#1  
2 
200 mg NST-1024 (QD) 
3 
200 mg NST-1024 (QD) + Probe Drugs Cocktail#2 
4 
QD = once daily 
Probe drugs cocktail#1 = 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 100 mg metoprolol, and 2.5 mg 
midazolam; probe drugs cocktail#2 = 100 mg caffeine and 2.5 mg midazolam 
The study treatment sequence names, abbreviations, and ordering to be used in the TFLs are 
presented in Table 3. 
Table 3: 
Presentation of Study Treatment Sequence in TFLs 
Study Treatment Sequence 
Order in TFLs 
Probe Drugs Cocktail#1 on Day 1; 200 mg NST-1024 + Probe Drugs Cocktail#1 
on Day 8; 200 mg NST-1024 (QD) on Days 9 to 20; 200 mg NST-1024 (QD) 
+ Probe Drugs Cocktail#2 on Day 21; 200 mg NST-1024 (QD) on Day 22 
1 
QD = once daily 
Probe drugs cocktail#1 = 100 mg caffeine, 50 mg flurbiprofen, 20 mg omeprazole, 100 mg metoprolol, and 2.5 mg 
midazolam; probe drugs cocktail#2 = 100 mg caffeine and 2.5 mg midazolam 
The ‘(Days X to Y)’ part of the treatment and treatment sequence labels will be kept 
unchanged even if a subject misses a dose on 1 or more days. Exact dosing regimen details 
including duration and days on which dose was received will be presented in the treatment 
administration listing only.  
6. DEFINITIONS OF POPULATIONS  
Any protocol deviations, including those due to coronavirus disease 2019 (COVID-19) and 
related restrictions (see Section 7.1.1), will be considered prior to database lock for their 
importance and taken into consideration when assigning subjects to populations. 
6.1. All Subjects Population  
The all subjects population will include all subjects who signed the ICF and had any study 
assessment recorded in the database per the protocol.  
6.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(NST-1024, caffeine, flurbiprofen, omeprazole, metoprolol, or midazolam). 
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Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
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ST-AD-031 Version 02 
6.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of active study 
treatment (NST-1024, caffeine, flurbiprofen, omeprazole, metoprolol, or midazolam) and 
have at least 1 valid PK concentration.  
7. STATISTICAL METHODOLOGY  
7.1. General  
Listings will be provided for all data captured in the database, with the exception of medical 
history. Listings will include all subjects assigned to the all subjects population and include 
data up to the point of study completion or discontinuation. Subjects are generally considered 
to have completed the study if they complete the scheduled follow-up visit (rather than early 
termination visit). Any subject who discontinues the study will be identified accordingly in 
the listings. Summaries and statistical analyses will include the subjects assigned to the 
relevant population based on data type. 
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if a new version is issued during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if a new version is issued 
during the study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if a new 
version is issued during the study). Pinnacle 21 Community Validator Version 4.0.1 (or 
higher if a new version is issued during the study) will be utilized to ensure compliance with 
CDISC standards. 
For all statistical analyses, the hypothesis testing will be 2-sided and carried out on 0.05 
significance level, unless specifically stated otherwise. 
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations. 
Where reference is made to ‘valid’ data, this refers to non-missing data which meet the 
predetermined criteria (eg, are not flagged for exclusion).  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, and changes from baseline. 
All figures will be produced on linear-linear or discrete-linear scales, as applicable, unless 
specifically stated otherwise. 
7.1.1. Handling of Data Quality Issues Due to Coronavirus Disease 2019 and Related 
Restrictions 
Due to COVID-19 and related restrictions, there is a high risk for impact to data integrity, 
with the recognized potential for: 
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● Missed visits, caused by, for example: 
o Subject unable to travel to site due to restrictions, the need to quarantine, or 
COVID-19 infection 
o Subject unwilling to go to site due to fear of COVID-19 infection 
o Site postponing subject’s visit due to investigator not being available (eg, if they 
have been dispatched to hospital handling COVID-19 infections) 
● Site unable to replenish supply of investigational product 
● Incomplete data entry by sites due to limited resources to support study or no access to 
source documents or to eCRF 
● Outstanding source document verification (SDV) due to sponsor or country restrictions 
on remote SDV, or no or limited access to site(s) for on-site visits 
● Unanswered queries 
At the time of the reporting of the study results, all protocol deviations due to COVID-19 or 
related restriction will be assessed for their severity and impact on the analyses. If needed, 
appropriate statistical methods will be applied as a mitigating action (eg, data might be 
categorized into 2 analysis groups, with and without COVID-19 and related restrictions 
impact); however, this will exclude any imputations of the missing values. Any mitigating 
actions will be agreed with NorthSea Therapeutics B.V. in advance and identified in the CSR.  
7.1.2. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum. 
● In general, as early termination data are not associated with any scheduled timepoint, 
they will be excluded from all calculations of summary statistics. Exceptions may be 
made where justified. 
For categorical data the following rules will be applied:  
● For ordered categorical data (eg, adverse event [AE] severity), all categories between 
the possible minimum and maximum categories will be included, even if n = 0 for a 
given category.  
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● For non-ordered categorical data (eg, race), only those categories for which there is at 
least 1 subject represented will be included; unless specifically stated otherwise.  
● Missing values will not be imputed, unless specifically stated otherwise. A ‘missing’ 
category will be included for any parameter for which information is missing. This will 
ensure that the population size totals are consistent across different parameters.  
7.1.3. Triplicate Readings  
For vital signs data only, where triplicate readings are taken, the median of triplicate readings 
will replace the separate individual triplicate readings in all calculations.  
For 12-lead electrocardiogram (ECG) data only, where triplicate readings are taken, the mean 
of triplicate readings will replace the separate individual triplicate readings in all calculations.  
In case of incomplete triplicate readings (eg, only 2 out of 3 readings were recorded), the 
mean and/or medians will be calculated, as appropriate, based on the number of readings 
available.  
7.1.4. Repeat and Unscheduled Readings  
For vital signs and 12-lead ECG data only, any predose value recorded in addition to the 
original value or a postdose value recorded within 15 minutes of the original value will be 
defined as a repeat value; any postdose value recorded more than 15 minutes after the 
original value will be defined as an unscheduled value. For all other data types (eg, laboratory 
parameters), any value recorded in addition to the original value will be defined as an 
unscheduled value.  
The original value will be replaced by the last associated repeat value in all calculations. 
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 7.1.5).  
7.1.5. Definitions of Baseline and Change from Baseline  
The baseline will be defined as the last value recorded prior to the first dose. If the date/time 
of the value is incomplete or missing, it will be excluded from the baseline calculation, unless 
the incomplete date/time indicates the value was recorded prior to the first dose. 
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the postdose timepoint. 
The summary statistics for change from baseline will be derived from individual subjects’ 
values (eg, mean change from baseline will be the mean of the individual changes from 
baseline for all subjects, rather than difference between the mean value at the postdose 
timepoint and mean value at baseline). 
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See Section 7.1.4 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 7.1.3 for more detail on handling of triplicate readings in the 
calculations.  
7.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by overall will be provided, based on the safety population. 
7.3. Screening Demographics 
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed.  
A summary table by overall will be provided, based on the safety population. 
7.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts during or after the first dose or starts but 
does not end prior to the first dose. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version March 2022 (or later if a new version is 
issued during the study; see the data management plan [DMP] for more details). Prior and 
concomitant medications will be listed. 
7.5. Pharmacokinetic Assessments 
7.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma 
concentrations of flurbiprofen, omeprazole, and metoprolol on profile days 1 and 8, and for 
caffeine (and metabolite paraxanthine) and midazolam (and metabolite 1-hydroxymidazolam) 
on profile days 1, 8, and 21 using noncompartmental methods in validated software program 
Phoenix WinNonlin (Certara, Version 8.1 or higher): 
Parameter 
Unitsa 
Definition 
AUC0-tlast 
h*ng/mL 
area under the concentration-time curve from time 0 to the time 
of the last quantifiable concentration (tlast)b 
AUC0-∞ 
h*ng/mL 
area under the concentration-time curve from time 0 extrapolated 
to infinityc 
%AUCextrap 
% 
percentage of area under the concentration-time curve due to 
extrapolation from the last quantifiable concentration to infinity 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time of the maximum observed concentration 
tlast 
h 
time of the last quantifiable concentration 
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t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total clearance (parent analyte only) 
Vz/F 
L 
apparent volume of distribution during the terminal phase 
(parent analyte only) 
MRAUC 
 
metabolite:parent ratio based on AUC0-∞ (metabolites only) 
a Units are based on concentration units (provided by the bioanalytical lab or preferred units for presentation of PK 
parameters) and dose units used in the study. 
b The AUC will be calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (linear up/log down rule).  
c Based on the last observed quantifiable concentration 
Additional PK parameters may be determined where appropriate. 
Pharmacokinetic analysis will be carried out where possible using actual dose administered 
(mg) and actual postdose blood sampling times. If an actual time is missing, the sample 
concentration result will be treated as missing unless there is scientific justification to include 
the result using the nominal time. 
The parameters Cmax, tlast, and tmax will be obtained directly from the concentration-time 
profiles. If Cmax occurs at more than 1 timepoint, tmax will be assigned to the first occurrence 
of Cmax. 
The metabolite:parent ratio (MRAUC) will be calculated as follows: 
MRAUC = (AUC0-∞ metabolite / MW metabolite) / (AUC0-∞ parent drug / MW parent drug), 
where MW is the molecular weight of each analyte. 
The molecular weights of parent analyte and metabolites to be used in the adjustment are as 
follows:  
caffeine = 194.19 g/mol 
paraxanthine = 180.16 g/mol 
midazolam = 325.78 g/mol 
1-hydroxymidazolam = 341.8 g/mol 
The parameter AUC0-tlast or other common partial area may be used to determine MRAUC if 
AUC0-∞ cannot be reliably calculated for the majority of subjects. 
7.5.1.1. Criteria for the Calculation of Apparent Terminal Elimination Rate Constant 
and Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations. 
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Protocol Reference: NST-1024-02 
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ST-AD-031 Version 02 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz for their calculation (eg, AUC0-∞, t1/2, CL/F, Vz/F, and Vss/F) will 
only be calculated if the R2-adj value of the regression line is ≥0.7. 
The following regression-related diagnostic PK parameters will be determined, when 
possible: 
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 
Where possible, the span of time used in the determination of λz (ie, the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the clinical study report (CSR). 
7.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 
3 consecutive concentrations above the lower limit of quantification. If there are only 
3 consecutive concentrations, at least 1 should follow Cmax. An exception may be made for 
metabolites, where Cmax may be the last timepoint. 
If the extrapolated area is >30%, AUC0-∞ (and derived parameters) may be excluded from the 
summary statistics and statistical analysis at the discretion of the sponsor or 
pharmacokineticist and any such occurrences will be identified in the report.  
If AUC0-∞ cannot be determined reliably for all subjects and/or treatments, an alternative 
AUC measure, such as AUC to a fixed timepoint or AUC0-tlast, may be used in the statistical 
analyses. 
7.5.1.3. Criteria for Handling Concentration Below the Limit of Quantification or 
Missing Concentrations for Pharmacokinetic Analysis 
Plasma concentrations below the limit of quantification (BLQ) will be assigned a value of 0 
before the first measurable concentration and thereafter BLQ concentrations will be treated as 
missing. The following rules apply to the specific situations defined below: 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
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● Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters, unless they are considered to be 
a true characteristic of the profile of the drug. 
● If a predose plasma concentration is missing, it will be set to 0 by default within 
Phoenix WinNonlin. 
7.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude the value from the PK analysis. However, the 
exclusion of any data must have strong justification and will be documented in the CSR. 
Any quantifiable predose concentration value in the first treatment period will be considered 
anomalous and set to missing for the PK analysis. This will be set to 0 by default in Phoenix 
WinNonlin. 
If the predose concentration is >5% of Cmax in the second or any subsequent treatment period, 
all PK concentration and parameter data will be excluded from the summary statistics and 
statistical analysis for that period. 
7.5.2. Presentation of Pharmacokinetic Data 
All PK concentrations and parameters will be listed.  
Summary tables, arithmetic mean (+ standard deviation [SD]) figures, overlaying individual 
figures, and individual figures by treatment and time postdose will be provided for plasma 
PK concentrations. All figures will be produced on both linear-linear and linear-logarithmic 
scales, with the exception of figures across all days, which will be produced on the 
linear-linear scale only. The +SD bars will only be displayed on the linear-linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. 
A subject may be excluded from the PK summary statistics and statistical analysis if the 
subject has an AE of vomiting that occurs at or before 2 times the median tmax. 
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the concentration will be flagged in the listings.  
Individual concentrations deemed to be anomalous will be flagged in the listings and 
excluded from the summary statistics. 
For plasma concentration data the following rules will apply: 
● Values that are BLQ will be set to 0 for the calculation of summary statistics. 
● Arithmetic mean or median values that are BLQ will be presented as 0. 
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For PK parameters the following rule will apply: 
● Geometric mean and coefficient of variation will not be calculated for tlast or tmax. 
7.5.3. Pharmacokinetic Statistical Methodology (Drug-drug Interaction) 
A statistical analysis will be conducted to investigate the drug-drug interaction of NST-1024 
on the PK of the probe drugs by comparing: 
 200 mg NST-1024 + Probe Drugs Cocktail#1 (test treatment) to Probe Drugs 
Cocktail#1 (reference treatment). This comparison will be done for caffeine, 
paraxanthine, flurbiprofen, omeprazole, metoprolol, midazolam, and 
1-hydroxymidazolam analytes separately. 
 200 mg NST-1024 (QD) + Probe Drugs Cocktail#2 (test treatment) to Probe Drugs 
Cocktail#1 (reference treatment). This comparison will be done for caffeine, 
paraxanthine, midazolam, and 1-hydroxymidazolam analytes separately. 
The natural log (ln)-transformed5 AUC0-tlast, AUC0-∞, and Cmax will be analyzed using a 
mixed model.6 The model will include actual treatment as fixed effect and subject as a 
random effect.  
For each PK parameter separately, the least squares mean (LSM) for each treatment, 
difference in LSMs between the test and reference treatments, and corresponding 90% 
confidence interval (CI) will be calculated; these values will then be back-transformed to give 
the geometric least square mean (GLSM), ratio of GLSMs, and corresponding 90% CI. 
Additionally, the pooled estimate (across treatments) of the within-subject coefficient of 
variation (CV) will be calculated, and residual plots will be produced to assess the adequacy 
of the model(s) fitted.  
Examples of the SAS code that will be used are as follows: 
Mixed Model Analysis 
proc mixed data = <data in>; 
  by parcat1n parcat1 pkday paramn param; 
  class trtan usubjid; 
  model lpk = trtan / cl residual ddfm = kr2; 
  lsmeans trtan / cl pdiff = control('1') alpha = 0.1; 
  random intercept / subject = usubjid;  
  ods output lsmeans = <data out>;   
  ods output diffs = <data out>; 
  ods output covparms = <data out>; 
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run;  
7.6. Safety and Tolerability Assessments  
7.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 25.0 (or higher if a new version is issued during the study; see the DMP for more 
details).  
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after the first dose, or starts prior to the first dose and increases in severity after the first dose. 
A treatment-related TEAE will be defined as a TEAE with a relationship of possibly related 
or related to the study treatment, as determined by the investigator. 
The assignment of TEAEs to treatments will be as follows: 
● A TEAE occurring during or after Day 1 dosing and prior to Day 8 dosing will be 
assigned to ‘Probe Drugs Cocktail#1’. 
● A TEAE occurring during or after Day 8 dosing and prior to Day 10 dosing will be 
assigned to ‘200 mg NST-1024 + Probe Drugs Cocktail#1’. 
● A TEAE occurring during or after Day 10 dosing and prior to Day 21 dosing will be 
assigned to ‘200 mg NST-1024 (QD)’. 
● A TEAE occurring during or after Day 21 dosing will be assigned to ‘200 mg 
NST-1024 (QD) + Probe Drugs Cocktail#2’. 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of the 
last associated dose for TEAEs only. Where the last associated dose is referring to the last 
dose received prior to the start of a TEAE. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment  
● Treatment-related TEAEs by severity and treatment  
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The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  
For the AE data the following rules will apply:  
● For the derivation of treatment-emergent status (applicable to all AEs): If the start 
date/time of an AE is incomplete or missing, an AE will be assumed to not be a TEAE, 
unless the incomplete start date/time or the end date/time indicates an AE started after 
the first dose. 
● For the derivation of treatment-related status (applicable to TEAEs only): If the study 
treatment relationship for a TEAE is missing, a TEAE will be assumed to not be a 
treatment-related TEAE.  
● For the derivation of onset time (applicable to TEAEs only): If the start date/time of a 
TEAE is missing, onset time will not be calculated. If the start date/time of a TEAE is 
incomplete, where possible, the minimum possible onset time will be calculated and 
presented in ‘≥DD:HH:MM’ format (eg, if the date/time of the last associated dose is 
01MAY2019/08:00 and recorded start date/time of a TEAE is 03MAY2019, then the 
minimum possible onset time will be calculated by assuming a TEAE started at the first 
hour and minute of 03MAY2019 [03MAY2019/00:00], thus will be presented as onset 
time ≥01:16:00 in the listing). If the start date of a TEAE is the same as the date of the 
last associated dose but the start time of a TEAE is missing, an onset time will be 
presented as ‘≥00:00:01’. Any clock changes will be accounted for in the derivation. 
● For the derivation of duration (applicable to all AEs): If the end date/time of an AE is 
missing, duration will not be calculated. If the start or end date/time of an AE is 
incomplete, where possible, the maximum possible duration will be calculated and 
presented in ‘≤DD:HH:MM’ format (eg, if the start of an AE date/time is 
01MAY2019/08:00 and its recorded end date/time is 03MAY2019, then the maximum 
possible duration will be calculated by assuming an AE ended at the last hour and 
minute of 03MAY2019 [03MAY2019/23:59], thus will be presented as 
duration ≤02:15:59 in the listing). Any clock changes will be accounted for in the 
derivation.  
● For the calculation of TEAE summary statistics: If the severity of a TEAE is missing, 
that TEAE will be counted under the ‘missing’ category. 
● For the calculation of TEAE summary statistics: If a subject experienced multiple 
TEAEs with the same preferred term for the same treatment, this will be counted as 1 
TEAE for that treatment under the maximum severity recorded.  
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7.6.2. Clinical Laboratory Parameters  
All clinical laboratory parameters will be listed; any value outside the clinical reference range 
will be flagged. Separate listings will be provided for any parameter for which there is any 
individual subject value outside the respective clinical reference range. 
Summary tables and boxplots by timepoint will be provided for clinical chemistry and 
hematology parameters. 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, all calculations, and presentation in the figures, <x and ≤x values 
will be set to half of x, whereas >x and ≥x values will be set to x. 
7.6.3. Vital Signs Parameters  
All vital signs parameters and their changes from baseline will be listed, as applicable; any 
value outside the clinical reference range will be flagged.  
Summary tables and boxplots by timepoint will be provided for all vital signs parameters and 
their changes from baseline. 
7.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters and their changes from baseline will be listed; any value outside 
the clinical reference range will be flagged. 
Summary tables and boxplots by timepoint will be provided for all 12-lead ECG parameters 
and their changes from baseline. 
7.6.5. Other Assessments  
Medical history will not be listed. 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
7.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned. 
8. INTERIM ANALYSES  
No interim analyses are planned for this study. 
9. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  
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Protocol Reference: NST-1024-02 
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ST-AD-031 Version 02 
10. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
2. ICH. ICH Harmonised Tripartite Guideline: General considerations for clinical trials (E8). 
17 July 1997.  
3. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
5. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
6. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
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Protocol Reference: NST-1024-02 
Final Version 1.0, 05OCT2022 
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ST-AD-031 Version 02 
11. APPENDICES 
Appendix 1: 
Document History 
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
NA = not applicable 
 
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Statistical Analysis Plan (SAP)/Initiation of 
Programming Approval Form
Type of Approval (select one) :   
SAP    
Initiation of Programming
Sponsor Name:
NorthSea Therapeutics B.V.
Sponsor Protocol ID:
NST-1024-02
Labcorp Study ID:
8489933
SAP text filename:
NST-1024-02_SAP_Final_V1.0.pdf
TFL shells filename:
NST-1024-02_TFL_Shells_Final_V1.0.pdf
Version:
1.0
Date:
05OCT2022
Labcorp Approval(s):
Lead Statistician
Approval Signature
Print Name
Date
Sponsor Approval(s):
By signing below when the statistical analysis plan (SAP) is considered final, the 
signatories agree to the analyses to be performed for this study and to the format of 
the associated tables, figures, and listings (TFLs). Once the SAP has been signed, 
programming of the Analysis Dataset Model (ADaM) datasets and TFLs based on these
documents can proceed. Any modifications to the SAP text and TFL shells made after 
signing may result in a work-scope change.
Approval Signature
Print Name
Date
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Clinical Study Report 
CONFIDENTIAL 
Labcorp Drug Development Study: 8489933  
Protocol Reference: NST-1024-02 
 
16.1.9.2. 
Quality Tolerance Limit Definitions 
Parameter 
Justification for Parameter 
Unit Tolerance 
Minimum number of 
evaluable subjects needed. 
A shortfall in the overall number of 
subjects could have had a significant 
impact on interpretation of the primary 
endpoint because of limited/insufficient 
exposure. 
N: 21 
 
Final
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