Conditions: Pain
Keywords: Pain Pain Injection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 116
Healthy volunteers: yes

Brief summary:
The primary objective of the study is to assess the safety and tolerability of single and multiple subcutaneous doses of OLP-1002 in healthy subjects.

Detailed description:
The exploratory objectives of the study are to evaluate the pharmacodynamic effect of OLP-1002 following single subcutaneous doses in healthy volunteers using a capsaicin pain model, and to monitor the effects of a single subcutaneous doses of OLP-1002 on cardiac QT interval. Where possible, single and/or multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy subjects will be determined.

Arms:
arm 1: Subcutaneous Injection: 30 ng, 120 ng, 400 ng, 1.2 μg, 3 μg, 6 μg, 12 μg, 20 μg, 40 μg, 80 μg, 160 μg arm 2: Subcutaneous Injection: 5 x 2 μg, 5 x 5 μg, 5 x 10 μg, 5 x 20 μg, 5 x 40 μg, 5 x 80 μg arm 3: Subcutaneous Injection: Placebo arm 4: Subcutaneous Injection: Placebo x 5

Interventions: intervention 1: OLP-1002 (Test): Part A, Single Ascending Dose intervention 2: OLP-1002 (Test): Part B, Multiple Ascending Dose intervention 3: Placebo: Placebo Part A, Single Ascending Dose intervention 4: Placebo: Placebo Part B, Multiple Ascending Dose
Intervention descriptions: intervention 1: Subcutaneous Injection: 30 ng, 120 ng, 400 ng, 1.2 µg, 3 µg, 6 µg, 12 µg, 20 µg, 40 μg, 80 μg, 160 μg intervention 2: Subcutaneous Injection: 5 x 2 μg, 5 x 5 μg, 5 x 10 μg, 5 x 20 μg, 5 x 40 μg, 5 x 80 μg intervention 3: Subcutaneous Injection: Placebo intervention 4: Subcutaneous Injection: Placebo x 5

Protocol document:
Prot_000.pdf: 
Document Type: Final Protocol 
Document Date:  
Version 5: 27 September 2019 
 
 
 
Version 4: 26 March 2019 
 
 
 
Version 3: 29 January 2019 
 
 
 
Version 2.2: 12 December 2018 
 
 
 
Version 2.1: 29 November 2018 
 
 
 
Version 2: 02 October 2018 
 
 
 
Version 1: 31 August 2018 
Study Title: OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single and 
Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic 
Study in Healthy Male and Female Subjects 
Protocol Reference Number: OLP-1002-001 
NCT Number: NCT03760913 
 
 
 


TITLE PAGE 
Protocol 
OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single 
and Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, 
and Pharmacodynamic Study in Healthy Male and Female Subjects 
Protocol Status: Final 
Protocol Date: 27 September 2019 
Protocol Version: 5 
Investigational Product: OLP-1002 
 
Protocol Reference Number: OLP-1002-001 
Covance Study Number: 8379789 
EudraCT Number: 2018-003085-13 
 
 
Sponsor: 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung-gu, Yongin, Gyeonggi 17015 
Republic of Korea 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street  
Leeds, LS2 9LH 
United Kingdom 
 
 
Sponsor Signatory: 
 
 
Principal Investigator: 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
Covance Study: 83 79789 
CONFIDENTIAL 
Protocol Reference: OLP-1002-001 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
 
Protocol Version 5, 27 September 2019 
?-ef \-e "' 
7; 0 , 'VO I 
Date 
Page 2 of89 


Protocol 
Covance Study. 8379789 
CONFIDENTIAL 
Protocol Reference OLP-1002-001 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
 
Principal Investigator 
Protocol Vers10n 5, 27 September 2019 
Date 
Page 3 of89 


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STUDY IDENTIFICATION 
Sponsor 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Study Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Medical Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Medical Monitor 
(24-hour emergency 
medical contact) 
 
 
 
 
 
 
 
Study Site 
Covance Clinical Research Unit Ltd. 
Springfield House, 
Hyde Street, 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
Project Physician 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 


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United Kingdom 
 
Clinical Laboratory 
 
 
 
Statistician 
 
Covance 


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SYNOPSIS 
Title of study: OLP-1002 – A first-in-human, double-blind, placebo-controlled, single and multiple 
subcutaneous dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy 
male and female subjects 
Objectives:  
The primary objective of the study is to assess the safety and tolerability of single and multiple 
subcutaneous doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the pharmacodynamic effect of OLP-1002 
following single subcutaneous doses in healthy volunteers using a capsaicin pain model, and to 
monitor the effects of a single subcutaneous doses of OLP-1002 on cardiac QT interval. Where 
possible, single and/or multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy 
subjects will be determined. 
Study design: 
This will be a double-blind, randomized, placebo-controlled, single and multiple subcutaneous dose 
study conducted in 2 parts, including healthy male and female subjects. 
Number of subjects: 
Part A: 68 subjects will be studied in 11 groups (5 groups of 4 and 6 groups of 8). 
Part B: 32 subjects will be studied in 4 groups (Groups B1 to B4). 
 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged between 18 and 60 years (inclusive) with a body mass index 
between 18.0 and 28.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test product: OLP-1002 
Proposed dose levels for Part A: 30 ng, 120 ng, 400 ng, 1.2 µg, 3 µg, 6 µg, 12 µg, 20 µg, 40 µg, 
80 µg, and 160 µg. 
Proposed dose levels for Part B: the doses for Part B will be decided in consultation with the 
Sponsor and on the basis of data from Part A of the study.  The highest daily dose in Part B will be 
up to 50% of the highest dose in Part A. 
Administration route: subcutaneous 
Reference product and mode of administration: 
Reference product: placebo 
Administration route: subcutaneous 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 8 weeks for Part A and 
approximately 12 weeks for Part B. 


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Endpoints: 
Pharmacodynamics: 
In Part A, the analgesic effect of OLP-1002 will be investigated in 6 groups consisting of 8 subjects 
(6 active: 2 placebo) using experimental capsaicin-evoked pain methods. Measurement of 
capsaicin-evoked pain will be performed at pre-screening, baseline and on Day 2, and secondary 
hyperalgesia at 5 and 30 minutes post-capsaicin injection. Continuous electrocardiogram (ECG) 
recording will be conducted to investigate the effect of OLP-1002 on cardiac function. 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 12-lead 
ECGs, vital signs measurements, injection site assessment, heat pain threshold and tolerance, and 
physical examinations. 
Pharmacokinetics: 
In Part A, the following PK parameters will be determined where possible: area under the plasma 
concentration-time curve (AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the 
time of the last quantifiable concentration (AUC0-tlast), maximum observed plasma concentration 
(Cmax), time of the maximum observed plasma concentration (tmax), and apparent plasma terminal 
elimination half-life (t1/2). PK analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups 
occurring in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by 
bioanalytical stability data. 
In Part B, the following PK parameters will be determined where possible: AUC over a dosing 
interval (AUC0-τ), AUC0-∞, Cmax, minimum observed plasma concentration (Cmin), tmax, t1/2, observed 
accumulation ratio based on AUC0-τ (RAAUC0-τ), observed accumulation ratio based on Cmax 
(RACmax), and Temporal change parameter (TCP). PK samples from all groups in Part B will be 
analyzed. 
Statistical methods: 
Pharmacodynamics: 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of pharmacodynamic data is planned. 
Safety: 
Safety parameters will be listed and summarized using descriptive statistics. No formal statistical 
analysis of safety data is planned. 
Pharmacokinetics: 
Individual plasma concentrations and PK parameters of OLP-1002 will be listed and summarized 
using descriptive statistics. Individual and mean OLP-1002 concentration-time profiles will be 
presented graphically. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................12 
1.1. 
Overview ................................................................................................................12 
1.2. 
Summary of Nonclinical Pharmacology ................................................................12 
1.2.1. 
In Vitro Pharmacology Studies ....................................................................12 
1.2.2. 
In Vivo Pharmacology Studies ....................................................................13 
1.2.3. 
Ex Vivo Pharmacology Studies ...................................................................15 
1.3. 
Summary of Safety Pharmacology ........................................................................15 
1.4. 
Summary of Toxicology ........................................................................................15 
1.5. 
Summary of Nonclinical Pharmacokinetics ...........................................................16 
1.6. 
Study Rationale ......................................................................................................17 
1.7. 
Benefit-risk Assessment .........................................................................................17 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................17 
2.1. 
Objectives ..............................................................................................................17 
2.2. 
Endpoints ...............................................................................................................18 
2.2.1. 
Primary Endpoints .......................................................................................18 
2.2.2. 
Exploratory Endpoints .................................................................................18 
3. 
INVESTIGATIONAL PLAN ..........................................................................................19 
3.1. 
Overall Study Design and Plan ..............................................................................19 
3.1.1. 
Part A ...........................................................................................................19 
3.1.2. 
Part B ...........................................................................................................22 
3.2. 
Start of Study and End of Study Definitions .........................................................23 
3.3. 
Additional Groups ..................................................................................................23 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................23 
3.4.1. 
Dose Interval ................................................................................................25 
3.4.2. 
Pharmacodynamic Assessment ....................................................................25 
3.5. 
Selection of Doses in the Study .............................................................................26 
3.5.1. 
Starting Dose ................................................................................................26 
3.5.2. 
Exposure ......................................................................................................27 
3.5.3. 
Proposed Doses ............................................................................................28 
3.6. 
Dose Escalation ......................................................................................................30 


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3.7. 
Dose Escalation Stopping Criteria .........................................................................30 
4. 
SELECTION OF STUDY POPULATION .....................................................................31 
4.1. 
Inclusion Criteria ...................................................................................................31 
4.2. 
Exclusion Criteria ..................................................................................................32 
4.3. 
Subject Number and Identification ........................................................................33 
4.4. 
Subject Withdrawal and Replacement ...................................................................33 
4.5. 
Study Termination .................................................................................................34 
5. 
STUDY TREATMENTS .................................................................................................35 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................35 
5.2. 
Study Treatment Administration ............................................................................35 
5.3. 
Randomization .......................................................................................................35 
5.4. 
Blinding..................................................................................................................35 
5.5. 
Treatment Compliance ...........................................................................................36 
5.6. 
Drug Accountability...............................................................................................36 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................36 
6.1. 
Concomitant Therapies ..........................................................................................36 
6.2. 
Diet .........................................................................................................................37 
6.3. 
Smoking .................................................................................................................37 
6.4. 
Exercise ..................................................................................................................37 
6.5. 
Blood Donation ......................................................................................................37 
6.6. 
Other Restrictions ..................................................................................................37 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................38 
7.1. 
Pharmacokinetic Assessments ...............................................................................38 
7.1.1. 
Sample Collection and Processing ...............................................................38 
7.1.2. 
Analytical Methodology ..............................................................................38 
7.2. 
Pharmacodynamic Assessments ............................................................................39 
7.2.1. 
Capsaicin-evoked Pain Model .....................................................................39 
7.2.2. 
Secondary Hyperalgesia ...............................................................................39 
7.3. 
Safety and Tolerability Assessments .....................................................................39 
7.3.1. 
Adverse Events ............................................................................................39 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................40 
7.3.3. 
Vital Signs ....................................................................................................40 
7.3.4. 
Electrocardiogram ........................................................................................40 
7.3.5. 
Heat Pain Threshold Test .............................................................................41 
7.3.6. 
Physical Examination...................................................................................42 
7.3.7. 
Body Weight and Height .............................................................................42 
7.3.8. 
Injection Site Assessments ...........................................................................42 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................44 
8.1. 
Determination of Sample Size ...............................................................................44 


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8.2. 
Analysis Populations ..............................................................................................44 
8.2.1. 
Pharmacokinetic Population ........................................................................44 
8.2.2. 
Pharmacodynamic Population .....................................................................44 
8.2.3. 
Safety Population .........................................................................................44 
8.3. 
Pharmacokinetic Analyses .....................................................................................44 
8.4. 
Pharmacodynamic Analyses ..................................................................................44 
8.5. 
Safety Analysis ......................................................................................................44 
9. 
REFERENCES ................................................................................................................45 
10. APPENDICES .................................................................................................................46 
Appendix 1: Adverse Event Reporting ..............................................................................47 
Appendix 2: Clinical Laboratory Evaluations ...................................................................51 
Appendix 3: Total Blood Volume ......................................................................................52 
Appendix 4: Contraception Guidance ................................................................................53 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................56 
Appendix 6: Schedule of Assessments ..............................................................................59 
Appendix 7: Protocol Amendment Summary of Changes .................................................67 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 ........................27 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 ....................28 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B ..........................................................................................................29 
Figure 1: 
Study Schematic (Part A)...........................................................................21 
Figure 2: 
Study Schematic (Part B) ...........................................................................23 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve extrapolated to infinity 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
postdose 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
DN 
Dose normalized 
DRG 
dorsal root ganglion 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Emax 
maximum pain intensity 
FCA 
Freund's Complete Adjuvant 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SNL 
spinal nerve ligation 
t1/2 
elimination half-life 
tEmax 
time of maximum pain intensity 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
VAS 
Visual Analogic Scale 
VGSC 
voltage-gated sodium channel 


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1. INTRODUCTION 
1.1. 
Overview 
OLP-1002 is a novel peptide nucleic acid (PNA) derivative which acts as a specific 
voltage-gated sodium channel (VGSC) protein (Nav1.7) inhibitor, and is being developed by 
OliPass for the treatment of pain. 
The Nav1.7 protein is a subtype of VGSCs. Nav1.7 is particularly important in nociception 
and pain signaling, with congenital loss-of-function mutations in Nav1.7 resulting in the 
inability to experience pain. Selective Nav1.7 inhibitors are believed to have the potential to 
treat severe pain safely1. The active sites of VGSC subtypes are virtually indistinguishable by 
their 3-dimensional structure and thus the discovery of selective Nav1.7 small molecule 
inhibitors has been extremely challenging. Since inhibition of Nav1.5 subtype elicits long QT 
cardiotoxicity, inhibition of Nav1.5 subtype should be avoided at therapeutic doses. 
To date, there are several Nav1.7 inhibitors claimed to be selective that have been evaluated 
in human subjects: 
• Vixotrigine (formerly known as raxatrigine) inhibits Nav1.7 as well as other VGSC 
subtypes. Vixotrigine is in phase III clinical development for trigeminal neuralgia. 
Due to the limited Nav1.7 selectivity over Nav1.5, vixotrigine was evaluated primarily 
in patients with a low heart risk. 
• Funapide is a Nav1.7 inhibitor with limited Nav1.7 selectivity, and was in phase IIb 
clinical trials as of July 2014. Although funapide showed analgesic activity in a small 
number of erythromelalgia patients, dose-limiting adverse events (AEs), including 
dizziness and somnolence, were observed2. The central nervous system (CNS) AEs 
were due to its poor Nav1.7 selectivity. 
• PF-05089771 is a Nav1.7 selective inhibitor with a claimed Nav1.7 selectivity of 
> 2000-fold versus other subtypes of sodium channel and was evaluated in patients of 
erythromelalgia or dental pain. It is thought low drug concentrations achieved in the 
target tissue could be a possible explanation for its poor analgesic activity in human 
patients3. 
OLP-1002 is fully complementary to a 14-mer RNA sequence spanning the junction of 
intron 4 and exon 5 in the human SCN9A pre-mRNA which codes for the Nav1.7 channel. 
OLP-1002 yields SCN9A mRNA splice variant(s) encoding variant Nav1.7 protein(s) lacking 
the sodium channel activity (ie, a non-functional channel), thereby inhibiting Nav1.7 channel 
function. 
1.2. 
Summary of Nonclinical Pharmacology 
1.2.1. 
In Vitro Pharmacology Studies 
Overall, results from the in vitro pharmacology studies showed OLP-1002 elicits responses 
consistent with its designed function4. It inhibits SCN9A mRNA expression and yields the 


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Nav1.7 variant protein or proteins lacking sodium channel activity. Its effects are highly 
selective, which may provide for an improved margin of safety compared to other Nav1.7 
inhibitors. 
OLP-1002 at 1 to 100 zM in PC3 prostate carcinoma cells induced exon skipping and yielded 
SCN9A mRNA splice variant(s) encoding a Nav1.7 variant protein or proteins lacking 
sodium channel activity.  
In rat dorsal root ganglion (DRG) neuronal cells, OLP-1002 at 1000 zM inhibited Nav1.7 
protein expression by > 50%, while OLP-1002R at 100 and 1000 zM inhibited Nav1.7 
expression almost completely. As OLP-1002R is fully complementary to rat SCN9A pre-
mRNA, OLP-1002R would be predicted to be more potent than OLP-1002 in this cell type. 
SCN9A mRNA expression level was evaluated by quantitative polymerase chain reaction 
(qPCR). OLP-1002 inhibited the expression of the SCN9A mRNA in PC3 cells with sub-
attomolar potency.  
In SH-SY5Y human neuroblastoma cells stimulated with tumor necrosis factor (TNF)-1α to 
upregulate the expression of SCN9A mRNA, OLP-1002 decreased expression by 46% to 
49% at 1 fM to 10 pM. In rat DRG neuronal cells, OLP-1002 at 1 fM significantly decreased 
SCN9A mRNA expression by 54%. 
In rat DRG neuronal cells, OLP-1002 markedly and significantly inhibited the sodium current 
by 77% at 0.1 aM and 73% at 1 aM, while for OLP-1002R, the inhibition was 66% at 0.1 aM 
and 70% at 1 aM. Given that rat DRG neuronal cells express various subtypes of sodium 
channel, the observed inhibitions of 66% to 77% correspond to the complete knockout of the 
Nav1.7 sodium channel subtype with OLP-1002 or OLP-1002R. 
The Nav1.7 selectivity over Nav1.5 was evaluated in H9C2 rat cardiomyocytes which are 
known to abundantly express the rat Nav1.5 sodium channel subtype. Following incubation 
with OLP-1002 or OLP-1002R at 1 aM or 1 pM, there were no notable decreases in the 
sodium current. Considering that OLP-1002 and OLP-1002R inhibit the expression of Nav1.7 
protein at 1 aM or lower in rat DRG neuronal cells, the Nav1.7 selectivity of OLP-1002 and 
OLP-1002R over Nav1.5 is estimated to be in excess of one million-fold. Such a large Nav1.7 
selectivity over Nav1.5 has not been realized with small molecule Nav1.7 inhibitors, 
suggesting that OLP-1002 potentially offers pain management with much greater 
cardiovascular safety. 
1.2.2. 
In Vivo Pharmacology Studies 
Spinal nerve ligation (SNL) has been widely applied as a rat model for neuropathic pain. 
OLP-1002 and OLP-1002R were found to be very potent, but highly variable in potency, in 
reversing neuropathic allodynia in this model. Analyses of the therapeutic potency strongly 
suggested that a marked proportion of subcutaneously (SC) administered OLP-1002 or 
OLP-1002R may have been topically delivered directly to the spinal nerves exposed in the 
dorsal cavity created during the SNL modelling. In addition, the variability of the therapeutic 
potency may be due to a variable degree of healing of the SNL surgery wound. If an animal 


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recovers slowly, the animal tends to be left with a dorsal cavity. Therefore, estimations of 
potency in these studies with this model should be treated with caution. 
In one study using the SNL model, allodynia in rats was slowly and gradually reversed by 
OLP-1002 SC administered at nominal doses of 1, 3, and 6 pmol/kg once every 2 days (due 
to adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). As the onset time for pain reduction was 4 days, 
the doses used were not sufficient for fast onset of activity. In this study, the animals should 
have reasonably recovered from the dorsal wound, and therefore less susceptible to topical 
delivery directly to the exposed spinal nerves. However, in another study in this model, when 
OLP-1002 was intraperitoneally (IP) administered once every 3 days to avoid the likelihood 
of local delivery to the spinal nerves, OLP-1002 surprisingly reversed the allodynia at 
5 fmol/kg, and was superior or comparable to pregabalin 30 mg/kg, a gold standard for 
neuropathic pain studies. The high potency shown at 5 fmol/kg IP strongly suggests the 
possibility that OLP-1002 is efficiently absorbed by the enteric nervous system, travels to the 
spinal cord, and then redistributes to the spinal nerves of the SNL ligation. This opens the 
possibility of efficient oral delivery of OLP-1002 to the spinal cord.  
When evaluated for their ability to reverse the inflammatory pain in rats inflicted with 
Freund's Complete Adjuvant (FCA)-induced severe paw inflammation, OLP-1002 at 
300 pmol/kg and OLP-1002R at 100 pmol/kg significantly reversed the thermal hyperalgesia, 
and both were more effective than pregabalin 30 mg/kg. Two further studies investigating 
OLP-1002R at concentrations up to 10,000 pmol/kg using the FCA model showed a reversal 
of inflammatory allodynia in rats. Both studies demonstrated that maintenance of a steady 
state of efficacy over time was dose dependent, with the dose of 100 pmol/kg being sufficient 
over 1 day/30 hours postdose, and the higher doses of 1000 pmol/kg and 10,000 pmol/kg 
being the most suitable up to 3 days/96 hours postdose. Assuming that thermal withdrawal 
latency time of the normal control group was equivalent to 100% allodynia inhibition and that 
of the negative control group was equivalent to 100% allodynia induction, allodynia 
inhibition efficacy by OLP-1002R was estimated to be 20.65% ~ 45.48% and 34.21% ~ 
58.72 % in the 2 studies. During both studies, no abnormalities or clinical finding were 
observed. 
Paw burn injury induces hyperalgesia in rats and is known to upregulate Nav1.7 expression in 
the L5 and L6 DRGs of the affected side. Burn injury induces a far weaker degree of paw 
inflammation than FCA-induced paw inflammation. OLP-1002 SC administered inhibited the 
thermal hyperalgesia in paw burn injury in a dose-dependent manner. At 25 fmol/kg, 
OLP-1002 did not inhibit thermal hyperalgesia. Although OLP-1002 at 625 fmol/kg 
significantly inhibited the thermal hyperalgesia, the efficacy was moderate and weaker than 
pregabalin 30 mg/kg. This suggests that SC dosing does not offer the local topical delivery to 
spinal nerves in this model as seen in rats without a dorsal cavity wound. In this study, the 
Nav1.7 expression in the DRG of the burn injury side significantly decreased by 58% with 
625 fmol/kg OLP-1002, validating the target engagement for analgesic activity. 
An intraplantar injection of formalin induces severe acute pain. The contributors to acute pain 
are known to be complex and require further elucidation. However, acute peripheral 
inflammation is known to contribute much to Phase II Pain (pain from 10 to 40 min after the 
formalin injection). In this model, OLP-1002 significantly inhibited Phase II Pain at 


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comparable or saturated efficacy when SC administered at 10 to 100 pmol/kg (due to 
adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). Thus peripheral acute inflammatory pain could be 
treated with 10 pmol/kg or less. 
1.2.3. 
Ex Vivo Pharmacology Studies 
One day post-SC injection, OLP-1002 and OLP-1002R at 100 pmol/kg significantly inhibited 
the expression of Nav1.7 protein by 39% and 57%, respectively, in the spinal cord of rats 
subjected to SNL.  
In other rats subjected to SNL, OLP-1002R slowly and gradually reversed the allodynia in a 
dose-dependent manner. OLP-1002R at 30 fmol/kg (the highest dose administered) had the 
greatest effect, but the dose was not high enough to elicit full therapeutic efficacy. 
OLP-1002R inhibited expression of Nav1.7 protein in these animals, most notably at 
1 fmol/kg, and decreased SCN9A mRNA expression by approximately 40% at 1 to 
30 fmol/kg. The observed inhibitions were largely consistent with the in vivo therapeutic 
activity findings. 
Taking all the in vivo and ex vivo findings together, OLP-1002R was concluded to inhibit 
neuropathic allodynia by inhibiting the expression of the SCN9A mRNA and the Nav1.7 
protein. 
1.3. 
Summary of Safety Pharmacology 
In vitro, OLP-1002 did not inhibit the human ether-à-go-go-related gene (hERG) channel 
current expressed in human embryonic kidney (HEK) cells at the highest concentration tested 
2 μM (the limit of the validated analytical method for OLP-1002). 
In the in vivo safety pharmacology studies, OLP-1002 SC administered at dose levels up to 
100 nmol/kg had no effect on body temperature, neurological function, or respiratory 
function in rats, and had no significant toxic effect on cardiovascular function in cynomolgus 
monkeys. 
1.4. 
Summary of Toxicology 
In rats, following twice-weekly SC dosing for 13 weeks, OLP-1002-related microscopic 
findings included pigment accumulation in the kidney of males administered 
100 nmol/kg/dose and females administered ≥ 10 nmol/kg/dose, foreign material and 
vacuolated macrophage infiltrates in males and/or females administered ≥ 1 nmol/kg/dose, 
and an increased incidence and/or severity of mononuclear cell infiltrates at the injection sites 
in males and/or females administered ≥ 10 nmol/kg/dose. These findings persisted through 
the recovery phase in animals administered 100 nmol/kg/dose. However, the effects were 
considered non-adverse due to their mild severity and lack of impact on animal health and 
wellbeing. The no-observed-adverse-effect level (NOAEL) was 100 nmol/kg/dose. This dose 
level corresponded to maximum observed plasma concentration (Cmax) and area under the 
plasma concentration-time curve (AUC) from 0 to 24 hours postdose (AUC0-24) values of 
27.6 ng/mL and 174 ng.h/mL, respectively, in males and 24.9 ng/mL and 128 ng.h/mL, 
respectively, in females on Day 88 of the dosing phase. 


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In cynomolgus monkeys, following twice-weekly SC dosing for 13 weeks, OLP-1002-related 
microscopic findings included mononuclear cell infiltrates at the SC injection sites of animals 
administered ≥ 10 nmol/kg/dose. This finding was not resolved with the completion of the 
recovery phase. However, the effects of 100 nmol/kg/dose were considered non-adverse due 
to the mild severity of findings and the lack of impact on animal health and wellbeing. The 
NOAEL was 100 nmol/kg/dose (equivalent to 462.29 µg/kg/dose), which corresponded to 
Cmax and AUC from 0 to 72 hours postdose (AUC0-72) values of 121 ng/mL and 
2840 ng.h/mL in males, respectively, and 216 ng/mL and 4840 ng.h/mL in females, 
respectively, on Day 88 of the dosing phase. 
The genotoxic and mutagenic potential of OLP-1002 was evaluated with standard Good 
Laboratory Practice (GLP) via in vitro bacterial mutagenicity and chromosomal aberration 
studies, and was found to be negative. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
In rats, following a single SC dose of 14C-OLP-1002, the time of maximum observed 
concentration (Tmax) was 0.5 to 1 hour for both radioactivity and parent compound. Plasma 
concentrations of total radioactivity were quantifiable through the last sampling time of 
72 hours postdose, but was variable for the parent compound. The elimination half-life (t1/2) 
of total radioactivity from plasma was 23 hours. Total radioactivity distributed into tissues, 
including those of the CNS protected by the blood-brain barrier. 14C-OLP-1002-derived total 
radioactivity was not rapidly excreted from rats, with minimal amounts present in urine and 
feces. The bulk of the total radioactivity remained in carcasses, primarily in kidneys (cortex 
and medulla) and liver. Parent 14C-OLP-1002 was present in plasma and tissues, but 
concentrations declined over time and were substantially lower than total radioactivity 
concentrations at the later sampling times.  
After a single SC administration of 14C-OLP-1002 to rats, the highest concentrations of total 
radioactivity were retained predominantly in the liver (10.4% to 13.3% of the dose), kidney 
cortex (3.47% to 4.96%), and kidney medulla (1.10% to 1.59% of the dose) through 168 
hours postdose. For all other tissues, the total amounts of total radioactivity were 
substantially less, ranging from 0.0000203% in the 5th DRG to 0.327% in the spleen. 
Radioactivity was excreted slowly via both the renal and fecal routes of elimination. Total 
average recoveries of radioactivity in urine and feces through 336 hours postdose accounted 
for 2.31% and 1.75% of the administered radioactivity, respectively. The bulk of the 
administered total radioactivity was retained in the rat carcasses through 168, 336, 504, and 
840 hours postdose. The kidney cortex, kidney medulla, and liver were the 3 tissues that 
retained the greatest amounts of the administered radioactivity. 
Following a 16.1 µg/kg dose in rats, the plasma concentrations were still quantifiable at 
72 hours postdose and the rate of elimination was slow, with t1/2 17.5 hours. It was not 
possible to accurately define the elimination phase for the 2.67 and 5.28 µg/kg dose levels. 
In cynomolgus monkeys, following a single SC dose of 14C-OLP-1002, Tmax ranged from 
0.25 to 1 hour for both total radioactivity and parent compound. Concentrations of total 
radioactivity were sustained in blood and plasma through the last sampling time of 144 hours 
postdose. Concentrations of parent compound were sustained in plasma through the last 


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sampling time of 144 hours postdose in 2 of 3 monkeys, and were similar to plasma total 
radioactivity concentrations at 8 hours postdose. From 24 to 144 hours postdose, plasma 
concentrations of total radioactivity were substantially higher than for parent 14C-OLP-1002 
plasma concentrations. 
The mean Cmax of parent 14C-OLP-1002 in plasma was 1.96 ng/mL. The mean plasma Tmax 
was 0.833 hours. Plasma exposure of parent 14C-OLP-1002 based on AUC extrapolated to 
infinity (AUC0-∞), was 12.7 ng.h/mL. After reaching Cmax, plasma concentrations of parent 
14C-OLP-1002 declined with a mean t1/2 of 84 hours. 
1.6. 
Study Rationale 
This is the first time OLP-1002 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when OLP-1002 is administered SC as single 
and multiple doses to healthy subjects. This information, together with the pharmacodynamic 
(PD) and pharmacokinetic (PK) data, will help establish the doses and dosing regimen 
suitable for future studies in patients. The analgesic effects of OLP-1002 on a capsaicin-
induced pain model will also be investigated. 
1.7. 
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 investigational medicinal product 
(IMP), although there may also be some discomfort from collection of blood samples and 
other study procedures. For subjects in the PD assessment groups in Part A there will be 
some additional discomfort from the capsaicin test. More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with OLP-1002 may be 
found in the Investigator’s Brochure4. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is to assess the safety and tolerability of single and 
multiple SC doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the PD effect of OLP-1002 following 
single SC doses in healthy volunteers using a capsaicin pain model, and to monitor the effects 
of single SC doses of OLP-1002 on cardiac QT interval. Where possible, single and/or 
multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy subjects will be 
determined. 


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2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of AEs 
• vital signs measurements (blood pressure, pulse rate, respiratory rate) 
• 12-lead electrocardiogram (ECG) parameters 
• incidence of clinical laboratory abnormalities, based on clinical chemistry, 
hematology, and urinalysis test results 
• physical examinations 
• injection site assessment. 
• demonstrate that exposure to OLP-1002 does not exceed pre-defined exposure limits 
from non-clinical studies. 
2.2.2. 
Exploratory Endpoints 
The following exploratory objectives will be assessed:  
• pain intensity and duration will be assessed by AUC, maximum pain intensity (Emax), 
and time of maximum pain intensity (tEmax), calculated using a capsaicin-evoked pain 
model. The exploratory endpoint of secondary hyperalgesia will be assessed by the 
area of secondary area of hyperalgesia (Part A only). 
• continuous (24-hour) ECG monitoring will be recorded in this study and archived for 
potential future analysis of OLP-1002 effects on the QT interval (Part A). 
• heat pain threshold measurements and heat pain tolerance measurements. 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from time zero to 
infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable concentration 
(AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-1002 are as 
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Primary PK: 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 
Other PK parameters may also be added if deemed necessary. 
3. INVESTIGATIONAL PLAN 
This will be a double-blind, randomized, placebo-controlled, single and multiple SC dose 
study conducted in 2 parts. 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a single-dose, sequential-group design. Overall, 68 healthy subjects will 
be studied in 11 groups. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Potential subjects for Groups A2, A4, A6, A9, A10, and 
A11 will attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will return 
for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 2 days), and for a 
poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential visits 
may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 10 (216 hours postdose) from the lower dose levels. For doses 
≥ 12 µg, PK data will also be reviewed up to Day 7 prior to dose escalation. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 3 subjects will receive 
OLP-1002 and 1 subject will receive placebo. To assess PD parameters, Groups A2, A4, A6, 


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A9, A10, and A11 will consist of 8 subjects; 6 subjects will receive OLP-1002 and 2 subjects 
will receive placebo.  
Sentinel dosing will be employed for all groups in Part A. To maintain the blind in a 
4-subject group, the first subject will be dosed 48 hours before the second subject, and the 
second subject will be dosed 48 hours prior to the third and fourth subjects. In PD assessment 
groups, 2 subjects (1 active: 1 placebo) will be dosed 48 hours before the remaining 
6 subjects (5 active: 1 placebo). 
An overview of the study design is shown in Figure 1.


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Figure 1: 
Study Schematic (Part A) 
Group A1 
(30 ng SC)
3 active:
1 placebo
Group A2
(120 ng SC)
6 active:
2 placebo
Group A3
(400 ng SC)
3 active:
1 placebo
Group A4
(1.2 µg SC)
6 active:
2 placebo
Group A5
(3 µg SC)
3 active:
1 placebo
Group A6
(6 µg SC)
6 active:
2 placebo
Group A7
(12 µg SC)
3 active:
1 placebo
Group A8
(20 µg SC)
3 active:
1 placebo
Group A9
(40 µg SC)
6 active:
2 placebo
Group A10
(80 µg SC)
6 active:
2 placebo
Group A11
(160 µg SC)
6 active:
2 placebo
Active = OLP-1002; SC = subcutaneous. 
Six groups consist of 8 subjects (6 active: 2 placebo); all other groups will consist of 4 subjects (3 active: 1 placebo).


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The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 8 weeks. 
3.1.2. 
Part B 
Part B will comprise a multiple-dose, sequential-group study. Overall, 32 subjects will be 
studied in 4 groups (Groups B1 to B4), with each group consisting of 8 subjects. Up to 
2 additional groups (16 subjects in total) may be included for further assessment of safety and 
tolerability (Section 3.3).  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (± 2 days), 22 (± 2 days), 25 
(± 2 days), and 29 (± 2 days), and for a poststudy visit on Day 57 (± 2 days). 
In each of Groups B1 to B4, 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo. For all subjects, a single subcutaneous dose will be administered on Days 1, 4, 7, 10, 
and 13. Prior to each dosing occasion a physician will review the available safety and 
tolerability data from each subject to confirm it is acceptable to continue dosing. The dosing 
frequency in Part B may be changed following review of data from groups in Part A 
(Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to OLP-1002 at 
steady state is predicted to exceed exposures that have been shown to be safe and well 
tolerated in earlier groups in Parts A or B. In the event of sentinel dosing, 2 subjects (1 active, 
1 placebo) will be dosed at least 4 days prior to the remaining 6 subjects (5 active: 1 placebo). 
Safety data for the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 1 and 2 will be 
reviewed prior to the remaining subjects receiving dose 1). In addition, safety data from each 
subject will be reviewed by a physician prior to each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of safety, 
tolerability, and PK data up to Day 22 (216 hours post-final dose) from the lower dose levels. 
Part B may start after a review of the safety, tolerability, and available PK for Groups A1 to 
A6. The total daily dose administered will not exceed the highest single dose given in Part A. 
An overview of the study design is shown in Figure 2. 


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Figure 2: 
Study Schematic (Part B) 
Group B1
(TBC SC)
6 active:
2 placebo
Group B2 
(TBC SC)
6 active:
2 placebo
Group B3
(TBC SC)
6 active:
2 placebo
Group B4
(TBC SC)
6 active:
2 placebo
Group B5 
(TBC SC)
6 active:
2 placebo
Group B6
(TBC SC)
6 active:
2 placebo
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
All doses will be confirmed based on results of Part A and previous groups in Part B. 
Groups B5 and B6 will be included if required. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 12 weeks. 
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
 Start of Study and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, PK, and PD data (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]), 
additional dose groups may be added to the study.  
Up to 2 additional groups of 8 subjects (6 active: 2 placebo) may be included in Part B. The 
requirement for additional groups will be agreed with the Sponsor and documented in the 
Trial Master File (TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For both parts of the study, a sequential-group, ascending-dose design has been chosen for 
safety reasons as OLP-1002 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Subcutaneous doses have been 
chosen for both parts of the study, as this is the intended clinical route of administration. 
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, and PK data up 
to Day 7 will be reviewed for all groups receiving ≥ 12 µg OLP-1002. In Part B, safety, 
tolerability and PK data up to Day 22 will be reviewed for all dose groups. As the t1/2 of 
OLP-1002 is predicted to be approximately 180 hours (based on non-clinical data) review of 


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safety data up to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma exposures are 
anticipated to be low, it is expected that it will only be possible to perform an assessment of 
peak concentrations (Cmax) and therefore PK data to Day 7 (Part A) and Day 22 (Part B) will 
be sufficient. Additionally, a cumulative safety review will occur such that additional 
emerging safety data from earlier groups will be considered when making a dose escalation 
decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of females 
of childbearing potential is in accordance with International Council for Harmonisation (ICH) 
M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be sufficient in 
order to determine safety and tolerability. In order to assess the PD effects of OLP-1002, 
6 groups in Part A will include 8 subjects (6 active; 2 placebo). A full review of the safety 
and tolerability data from Part A will be performed to determine the dose regimen for Part B. 
Part B may start after a full review of all safety and tolerability data from Group A1 to A6. A 
review of PD data may also be performed, at the discretion of the Investigator. Details of the 
dosing regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 57-day 
follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups receiving 
≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring 
in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. Dose escalation decisions for doses < 12 µg in Part A will not require PK data. 
The rationale for this is that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical species has a 
lower limit of quantification (LLOQ) of 5 ng/mL. The increased sample volume possible 
from humans (compared to small animals) may afford an approximate 10-fold increase in 
sensitivity with possibly an additional 5-fold increase from the use of a more sensitive mass 
spectrometer. Additional optimization of the PK analysis has delivered an LLOQ of around 
1 ng/mL with the limit of detection being 0.2 ng/mL. Therefore, even with the increased 
assay sensitivity plasma levels from doses at or below 12 µg are not expected to be 
quantifiable. It is apparent from the predicted plasma concentrations (see Section 3.5.2) that 
only a small number of samples around Cmax at the highest dose would be quantifiable and 
that a conventional approach to pharmacokinetic will not achieve a full definition of the 
plasma concentration vs time profile or enable an estimation of the terminal phase. In 
addition the planned dose levels have a high safety margin when comparing the predicted 
exposures to the exposures at the NOAEL (see Section 3.5.2), with the 12 µg dose level 
having an expected 312-fold and 255-fold safety margin based on Cmax and AUC0-∞, 
respectively. Therefore, if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 


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assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
Continuous ECG monitoring will be recorded in this study and archived for potential future 
analysis of OLP-1002 effects on the QT interval, with a view of supporting a potential 
thorough QT study waiver. 
3.4.1. 
Dose Interval 
Following thorough review of all available nonclinical data (pharmacological and 
toxicological), dosing in Part A for groups consisting of 4 subjects will be such that there will 
be 48 hours between the first and second subjects, and 48 hours between the second and 
remaining 2 subjects in each group. For groups in Part A consisting of 8 subjects, 2 subjects 
(1 active: 1 placebo) will be dosed 48 hours prior to the remaining 6 subjects.  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 at steady state 
is predicted to exceed exposures that have been shown to be safe and well tolerated in earlier 
groups in Parts A or B. When used, two subjects (1 active; 1 placebo), will be dosed 4 days 
prior to the remaining 6 subjects (5 active; 2 placebo). The 2 sentinel subjects will always be 
2 doses ahead of the remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not predicted to 
exceed that tested in Part A will be dosed on the same day. Accumulation of OLP-1002 is 
expected following multiple doses, based on the preclinical data, and will be taken into 
account when determining the doses for Part B (see Section 3.5.3). If it is not possible to 
quantify exposure it will be assumed that multiple dosing results in a 4-fold accumulation 
based on the predicted t1/2 of 180h.  
In Parts A and B, there will be a minimum interval of a 10-minute gap between dosing 
subjects (when dosed on the same day). Continuation to dose the remaining subjects in a 
group will be at the Investigator’s discretion. 
3.4.2. 
Pharmacodynamic Assessment 
Pharmacodynamic assessments will be conducted for subjects in Groups A2, A4, A6, A9, 
A10, and A11. 
Human experimental pain models using healthy volunteers can be used to assess the effect of 
a drug or treatment under controlled clinical conditions. Capsaicin is a vanilloid responsible 
for the pungent taste of hot peppers. In mammalian species, capsaicin-induced pain is 
mediated through Group C nerve fibers following activation of vanilloid 1 transient receptor 
potential (TRPV1) channels5. Nav1.7 has been implicated in controlling neuropeptide release 
from C-fibers, and suppression of capsaicin-induced neurogenic flair has been demonstrated 
by an NAv1.7 inhibitor6. 
Several studies have used intradermal capsaicin for human experimental pain studies7,8. It has 
been possible to demonstrate dose-dependent responses, with intradermal injections of 


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100 μg generally agreed to be the ideal dosage for these studies. Intradermal injection of 
capsaicin causes a brief stinging/burning pain at the injection site (spontaneous pain) 
followed by development of secondary hyperalgesia, which can be assessed using equipment 
such as Von Frey hairs. A study by Gazerani et al.5 found that the response was site-specific 
and while peak pain intensity and duration were greatest in the forehead it was found that 
areas of visible flare and secondary hyperalgesia were significantly larger in the forearm, 
making the forearm the most suitable site for experimentation. 
Covance CRU, Leeds, UK in 2009 performed a validation study using intradermal capsaicin 
(Covance CRU Study: 9999-004) with between-subject and within-subject variability 
demonstrating that the assessments can be reliably conducted to assess pharmacological 
response. 
For these reasons, it has been decided to: 
• Measure both capsaicin-evoked pain and secondary hyperalgesia. 
• Limit the number of capsaicin tests to 3 for each subject (pre-screening, baseline, and 
48 hours postdose) 
• Exclude subjects who have pain <3 or >9 (using a Visual Analogic Scale [VAS]) at 
the pre-screening visit from PD assessment groups. 
3.5. 
Selection of Doses in the Study 
3.5.1. 
Starting Dose 
The rat has been identified as the most sensitive species in a 13-week SC toxicity study with 
a 4-week recovery phase (Covance study no. 8355564). The NOAEL was the 
100 nmol/kg/dose (462.29 µg/kg/dose). This dose level resulted in Cmax of 27.6 ng/mL and 
24.9 ng/mL in males and females, respectively, and AUC0-24 of 174 ng.h/mL and 
128 ng.h/mL in males and females, respectively4. As the exposure was lower in the female 
rats these data have been used to calculate the safety margins. 
The dose of 462.29 µg/kg/dose corresponds to human equivalent doses (HEDs) of 
74.8 µg/kg/dose, which gives a maximum recommended starting dose (MRSD) of 444 µg for 
a 60-kg human and thus a 15000-fold safety margin to the proposed starting dose of 30 ng 
and 2.8-fold margin to the proposed maximum daily dose of 160 µg. Additionally the 
NOAEL dose in the cynomolgus monkey was identified as 100 nmol/kg/dose 
(462.29 µg/kg/dose), which gives a higher HED of 150 µg/kg/dose. 
In vivo, doses of 10 pmol/kg/dose (0.0462µg/kg/dose) or less were found to inhibit peripheral 
acute inflammatory pain. The equivalent human dose for a 60-kg human is 44 ng, thus a dose 
at which minimal biological effect is anticipated has been selected as the starting dose of 
30 ng. 
Based on further in vivo studies in the rat (see Section 1.2.2), single doses of 10,000 pmol/kg 
(10 nmol/kg/dose; 46.2 ug/kg/dose) or less were found to inhibit FCA-induced inflammatory 
pain and there were no clinically adverse findings. The equivalent dose for a 60-kg human is 
44 µg, and this is therefore a dose at which biological effect is anticipated. 


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3.5.2. 
Exposure 
Human exposures have been estimated from the pharmacokinetics in the cynomolgus 
monkey since a non-human primate represents the most closely related species. 
Approximately dose-proportional exposure was seen in the 13-week toxicity study (Covance 
study no. 8355565) and 14C pharmacokinetic study (Covance study no. 8355568) over a dose 
range of approximately 1.1 to 100 nmol/kg (5.06 to 462.29 µg/kg)4. However, the lowest 
dose (5.06 µg/kg) from the 14C study has been used to estimate the human exposures as it is 
closest to the proposed human dose range and has the sufficient quantifiable data. 
The assumptions made in the human exposure estimation were that human exposure would 
be similar to the cynomolgus monkey and that exposure would be linear with dose. Following 
a dose of 5.06 µg/kg in the cynomolgus monkey, the Cmax was 1.96 ng/mL and AUC0-∞ was 
12.7 ng.h/mL. The extrapolated exposures at the planned human doses are shown in Table 1 
with margins calculated to the exposures at the NOAEL in the female rat. 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 
Human dose 
Single dose to human 
Safety margins for single dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax 
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin  
to Cmax 
Margin  
to AUC0-∞ 
0.03 
0.000500 
0.000194 
0.00125 
129000 
102000 
0.12 
0.00200 
0.000775 
0.00502 
32100 
25500 
0.4 
0.00667 
0.00258 
0.0167 
9640 
7650 
1.2 
0.0200 
0.0077 
0.0502 
3210 
2550 
3 
0.0500 
0.0194 
0.125 
1290 
1020 
6 
0.100 
0.0387 
0.251 
643 
510 
12 
0.200 
0.0775 
0.502 
321 
255 
20 
0.333 
0.129 
0.837 
193 
153 
40 
0.667 
0.258 
1.673 
96 
76 
80 
1.333 
0.516 
3.347 
48 
38 
160 
2.667 
1.033 
6.693 
24 
19 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
The dosing interval currently anticipated for the multiple-ascending-dose part of this study is 
72 hours or 96 hours. Thus the average dosing interval (82 hours) is similar to the half-life 
determined in the monkey 14C study of 84 hours. Dosing at approximately once per half-life 
would be anticipated to result in accumulation of around 2-fold. However, higher levels of 
accumulation were observed (2.28-fold for Cmax and 3.76-fold for AUC0-24) on Day 88 at the 
top dose group (100 nmol/kg, 462.28 µg/kg) in the 13-week cynomologus monkey toxicity 
study following twice-weekly dosing (every 72 or 96 hours). Calculations were performed to 
estimate the likely human half-life using a standard 1-point allometric approach from the 14C 
cynomolgus monkey pharmacokinetic study data. The exponents used were 0.75 for apparent 
total plasma clearance (CL/F) and 1 for apparent volume of distribution (Vz/F) values 
combined with the average body weight of the animal (3.1 kg) and scaling to a 60 kg human 
9–11. This resulted in a human half-life estimate of 180 h which in turn gave an accumulation 


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estimate of 3.7-fold based upon a dosing interval of 82 h. This further supports the use of the 
greater than 2-fold accumulation from the 13-week cynomolgus study to estimate exposure 
following multiple dosing. Multiplication of the exposure estimates for the single ascending 
dose by 2.28 for Cmax and 3.76 for AUC resulted in exposure estimates for multiple dosing 
presented in Table 2. 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 
Human dose 
Multiple dose to human 
Safety margins for multiple dose 
(µg) 
(µg/kg) 
Predicted 
Cmax 
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin 
to Cmax 
Margin 
to AUC0-τ,ss 
0.03 
0.000500 
0.000442 
0.00472 
56000 
27000 
0.12 
0.00200 
0.00177 
0.0189 
14100 
6800 
0.4 
0.00667 
0.00589 
0.0629 
4230 
2030 
1.2 
0.0200 
0.017663 
0.189 
1410 
680 
3 
0.0500 
0.0442 
0.472 
560 
270 
6 
0.100 
0.0883 
0.944 
282 
136 
12 
0.200 
0.177 
1.89 
141 
68 
20 
0.333 
0.294 
3.15 
85 
41 
30 
0.500 
0.442 
4.72 
56 
27 
40 
0.667 
0.589 
6.29 
42 
20 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
3.5.3. 
Proposed Doses 
The proposed IMP dose levels for Parts A and B are shown in Table 3. 


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Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
Study Part 
Group 
Dose (OLP-1002) 
Part A 
A1 
30 ng or placebo 
A2 
120 ng or placebo 
A3 
400 ng or placebo 
A4 
1.2 µg or placebo 
A5 
3 µg or placebo 
A6 
6 µg or placebo 
A7 
12 µg or placebo 
A8 
20 µg or placebo 
A9 
40 µg or placebo 
A10 
80 µg or placebo 
A11 
160 µg or placebo 
Part B 
B1 
TBC or placebo 
B2 
TBC or placebo 
B3 
TBC or placebo 
B4 
TBC or placebo 
B5* 
TBC or placebo 
B6* 
TBC or placebo 
Abbreviations: TBC = to be confirmed 
* groups to be included if required.
In Parts A and B, there should not be an increase of > 3-fold between dose levels above 
120 ng. 
Since predictions of human exposure of OLP-1002 suggest that OLP-1002 concentrations 
may be not be quantifiable and human data have been estimated from a single species, it is 
proposed that the highest dose in the multiple-ascending-dose part will be up to 50% of the 
highest dose in the single-ascending-dose part (ie, if the highest dose in the single-ascending-
dose part is 160 µg, the highest dose in the multiple-ascending-dose part will be 80 µg). 
Therefore, if the predicted accumulation of 3.7-fold occurs, the highest exposure in Part B 
will not exceed ~2-fold the maximum exposure in the single-ascending-dose part. 
Group B4 may be dosed concurrently with Group A10 (80 µg), following the dose escalation 
meeting for Group A9 (40 µg). The predicted Cmax and AUC0-∞ for a single dose of 40 µg are 
0.258 ng/mL and 1.673 ng.h/mL, respectively (Table 1). Assuming 3.7-fold accumulation, 
the predicted Cmax and AUC0-∞ at the 20 µg dose level in Group B4 are 0.294 ng/mL and 
3.15 ng.h/mL, respectively (Table 2). Exposure in Group B4, therefore, is not predicted to 
exceed ~2-fold the maximum exposure in Group A9. 
If additional groups (B5 and B6) are required, the predicted systemic exposure will not 
exceed that stated in the dose escalation stopping criteria [Section 3.7]) based on available 
PK data. 
Details of all doses administered in Parts A and B of the study will be documented in the 
TMF. 


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3.6. 
Dose Escalation 
In Part A, doses will be administered in an escalating manner following satisfactory review 
by the Sponsor and Investigator of the safety, and tolerability data up to Day 10 (216 hours 
postdose) from groups that received lower doses of OLP-1002. For escalation to doses 
≥ 12 µg, PK data up to Day 7 (144 hours postdose) will also be reviewed. All available 
safety, tolerability, and PK data from previous groups will be reviewed prior to dose 
escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and may be lower than the starting 
dose. Available safety, tolerability, and PK data from all previous groups will be reviewed 
prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups A1, 
A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, A6, A9, A10, and A11) have been 
reviewed from the previous lower dose group, such that data from a minimum of 3 or 
4 subjects, respectively, who have received OLP-1002 will be used to make the dose-
escalation decision. Dose escalation in Part B will only occur if data from a minimum of 
6 subjects have been reviewed from the previous lower dose group, such that data from a 
minimum of 4 subjects who have received OLP-1002 will be used to make the dose-
escalation decision. 
The justification for this is as follows: 
• The study drug is of a known pharmacological class for which the on-target effects in 
humans are well characterized. Based upon nonclinical data, no clinically important 
off-target effects are expected within the proposed dose range. 
• A minimum of 3 subjects receiving the active drug is considered sufficient to 
characterize the safety profile for OLP-1002. 
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarizing 
results from all available safety assessments, will be sent to the Sponsor and a dose-escalation 
meeting will occur prior to the start of each successive group. Any clinically significant 
results will be discussed with the Sponsor before dose escalation continues. Interim PD data 
may also be reviewed on an ongoing basis. In the event of a disagreement between Sponsor 
and Investigator on the dose-escalation decision, the decision of the Investigator will be 
upheld. 
3.7. 
Dose Escalation Stopping Criteria 
In Parts A and B, following consultation with the Sponsor, dose escalation will be stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in 
a group that, in the opinion of the Investigator, warrant stopping of dose escalation. 
• One or more subjects experience an SAE that is considered to be related to OLP-1002. 


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• Two or more subjects in the same group experience severe non-serious AEs (ie. 
severe non-serious AEs considered as, at least, possibly related to OLP-1002 
administration), independent of whether the AEs are within or not within the same 
system organ class.  
• There is evidence of clinically significant increases in aspartate aminotransferase, 
alanine aminotransferase or alkaline phosphatase (defined as 3 times the upper limit 
of normal), or total bilirubin (defined as 2 times the upper limit of normal) that are 
considered to be related to OLP-1002 in 2 or more subjects in a group. Results will be 
confirmed with repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose for 
Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat measurement) 
in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥ 1 subject in a 
group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 110 mmHg) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• Systemic exposure for any individual subject is predicted to exceed a Cmax of 
24.9 ng/mL (plasma) and/or an AUC0-24 of 128 ng.h/mL; i.e., systemic exposure will 
be no greater than the NOAEL in the most sensitive species (100,000 pmol/kg in rat 
[462 µg/kg]). 
If the sponsor deems it appropriate to resume dosing after the internal safety review, it 
can be done after the approval of a substantial protocol amendment. 
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. Healthy male or females of any race, between 18 and 60 years of age, inclusive. 
2. Body mass index (BMI) between 18.0 and 28.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, single 12-lead ECG (resting heart rate > 45 bpm and 
< 90 bpm), vital signs measurements, and clinical laboratory evaluations (congenital 
nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome based on total 
and direct bilirubin] is not acceptable) at Screening as assessed by the Investigator (or 
designee).  
4. Willing to abide by the contraception requirements as detailed in Appendix 4. 


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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: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. Any of the following: 
• QTcF > 450 ms confirmed by repeat measurement. 
• QRS duration > 110 ms confirmed by repeat measurement. 
• PR interval > 220 ms confirmed by repeat measurement. 
• findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
• history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalemia, family history of long QT syndrome). 
4. Female subjects who are pregnant or breastfeeding. 
5. History of alcoholism or drug/chemical abuse within 1 year prior to Screening. 
6. Alcohol consumption of > 21 units per week for males and >14 units per week for 
females. 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. 
7. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
8. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
9. Active skin conditions such as dermatitis, allergy, eczema, psoriasis, or abnormal 
healing. 
10. Tattoos, scars, or moles that in the opinion of the Investigator are likely to interfere 
with dosing or study assessments at any of the potential injection sites. 
11. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days or 5 half-lives of the investigational product, 
whichever is longer, prior to Check-in. 
12. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 


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13. Use or intend to use any prescription medications/products other than hormone-
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptive concomitant medications within 14 days prior to Check-in, unless 
deemed acceptable by the Investigator (or designee). 
14. 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). 
15. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee) and/or 
Sponsor have given their prior consent. 
16. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in. 
17. Receipt of blood products within 60 days prior to Check-in. 
18. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening. 
19. Poor peripheral venous access. 
20. Have previously completed or withdrawn from this study or any other study 
investigating OLP-1002, and have previously received the investigational product. 
21. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
22. Part A – PD assessment groups only 
• Subjects considered non-acceptable responders to the intradermal capsaicin 
test at screening, defined as maximum VAS score of < 3.0 or > 9.0. 
4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomization. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, in Part A, Subjects 101, 102, 
etc., in Part B Subjects 201, 202, etc.). Replacement subjects (Section 4.4) will be assigned a 
subject number corresponding to the number of the subject he/she is replacing plus 1000 
(eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 


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• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least possibly related to 
OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE considered to 
at least possibly related to OLP-1002 administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements). 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the 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 stabilized. 
Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• 
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) 
• 
medical or ethical reasons affecting the continued performance of the study 
• 
difficulties in the recruitment of subjects 
• 
cancelation of drug development. 


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5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Vials of OLP-1002 Injection Solution 100 µg/mL (1.5 mL in 5-mL vials) and the Diluent for 
OLP-1002 Injection Solution (5 mL in 10-mL vials) will be supplied by the Sponsor, along 
with the batch/lot number and Certificate of Analysis. The Diluent for OLP-1002 Injection 
Solution will also be used as the Placebo formulation. A certificate of batch certification and 
release, authorized by a Qualified Person in the European Union (EU) will also be issued, by 
a Covance CRU Qualified Person, for each batch of IMP imported into the EU. 
The IMPs will be stored according to the instructions on the label at the CRU in a location 
that is locked with restricted access. 
Dose solutions (OLP-1002 Injection Solution diluted with the Diluent for OLP-1002 
Injection Solution) will be prepared by Covance CRU Pharmacy staff in accordance with 
instructions provided in the Pharmacy Manual. The Placebo formulation will be the Diluent 
for OLP-1002 Injection Solution without further manipulation. 
5.2. 
Study Treatment Administration 
Subjects will be administered the IMP in numerical order. OLP-1002 will be administered by 
SC injection in the upper arm. If subcutaneous dosing of OLP-1002 in the upper arm is not 
possible, the subject may be dosed in the abdomen at the Investigator’s discretion. For 
subjects in Groups A2, A4, A6, A9, A10, and A11, dosing will be on the opposite arm to the 
intradermal capsaicin test. At dose levels of ≥40 µg (Groups A9, A10, and A11), doses may 
be administered as multiple SC injections in the same location (ie, 2 SC injections in the 
upper arm).  
5.3. 
Randomization 
The randomization code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. In Part A, 1 subject in groups 
consisting of 4 subjects, and 2 subjects in groups consisting of 8 subjects, will be randomly 
assigned to receive placebo. In Part B, 2 subjects per group will be randomly assigned to 
receive placebo. All other subjects in a group will be randomized to receive OLP-1002. 
Prior to the start of the study, a copy of the master randomization code will be supplied into 
the Covance CRU pharmacy staff (in sealed envelopes). 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo solution will be identical in appearance to the OLP-1002. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 


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To maintain the blind, the Investigator will be provided with sealed randomization 
code-break envelopes for each subject, containing details of their treatment. These individual 
sealed envelopes will be kept in a limited access area that is accessible 24 hours a day. In 
order to manage subject safety or to support dose-escalation decisions (in the event of 
possibly treatment-related SAEs or severe AEs), the decision to unblind resides solely with 
the Investigator. Whenever possible, and providing it does not interfere with or delay any 
decision in the best interest of the subject, the Investigator will discuss the intended code-
break with the Sponsor. If it becomes necessary to break the code during the study, the date, 
time, and reason will be recorded in the subject’s source data and on the individual envelope 
and will be witnessed by a second person. 
5.5. 
Treatment Compliance 
All doses of IMP will be administered by suitably qualified study site staff. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription medications/products from 14 days prior to 
dosing until the Follow-up visit, and non-prescription medications/products from 7 days prior 
to dosing until the Follow-up visit, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone-replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary 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. 


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6.2. 
Diet 
While confined at the study site, subjects will receive a standardized 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 safety laboratory tests. On dosing days, 
subjects will receive a light breakfast approximately 2 hours prior to dosing. Meals will be 
provided as appropriate at other times and water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Check-in until the Follow-up visit. 
Xanthine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until Discharge from the site. Xanthine-containing foods and beverages will also not be 
allowed form 36 hours before non-residential site visits. 
Chilli pepper/hot sauce will not be allowed for 48 hours prior to Check-in for all subjects. 
Subjects in Groups A2, A4, A6, A9, A10, and A11 will not be allowed chilli pepper/hot 
sauce for 48 hours prior to their pre-screening visit. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until 
Discharge. Following discharge, up to 2 units/day of alcohol are permitted until 36 hours 
before each non-residential visit and 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 3 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. Subjects should not be in receipt of blood products for 
60 days prior to check-in. 
6.6. 
Other Restrictions 
Subjects in Groups A2, A4, A6, A9, A10, and A11 will not be allowed to shower within 
1 hour prior to the capsaicin-evoked pain tests at prescreening, predose, and postdose. 


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Subjects will not be allowed to apply moisturizing creams or oils to the dosing site within 
1 hour prior to dosing, or to the assessment site within 1 hour prior to the capsaicin-evoked 
pain test.  
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): 
•
dosing
•
vital signs
•
blood samples
•
cardiac monitoring/ECG extractions
•
any other procedures.
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments (Appendix 6). Furthermore, additional blood samples may be taken 
from each subject per treatment period, with the maximum volume of blood withdrawn per 
subject not exceeding the limit detailed in Appendix 3. Any changes to the scheduled times of 
PK assessments will be agreed with the Sponsor and documented in the TMF. Samples taken 
from subjects who received placebo will not be analyzed. 
In Part A, PK analysis will initially only be conducted for groups receiving ≥ 12 µg 
OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the 
event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 


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7.2. 
Pharmacodynamic Assessments 
Capsaicin intradermal test will be performed for subjects in Groups A2, A4, A6, A9, A10, 
and A11. Each subject will be tested at a pre-screening visit before being tested twice during 
the study (1 predose and 1 postdose). 
7.2.1. 
Capsaicin-evoked Pain Model 
The capsaicin model will be conducted by intradermal injection of capsaicin (100 μg in 
100 μL of sterile saline containing 8% [w/w] Tween 80) into the skin of the anterior aspect of 
the forearm, midway between the elbow and the wrist. The bleb area (wheal) will be a sign of 
local plasma extravasation. An assessment of the pain intensity related to capsaicin injection 
will be estimated by repeated use of a VAS from injection to 5 minutes post-injection or until 
the pain intensity returned to zero. The AUC, Emax, and tEmax will be calculated and reported 
using dedicated software. 
7.2.2. 
Secondary Hyperalgesia 
The area of secondary hyperalgesia will be quantified with a 60-g weighted von Frey hair, by 
stimulating along 8 linear paths (4 vectors crossing at the location of the injection site) 
arranged vertically and horizontally around the stimulation site in 5-mm steps (starting 
approximately 6 cm away from the injection site). The area of secondary hyperalgesia will be 
evaluated at 5 and 30 minutes post-capsaicin injection. 
7.3. 
Safety and Tolerability Assessments 
Safety and tolerability assessments will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). Timepoints may be adjusted based on an ongoing review of the 
data, and additional assessments may be conducted if deemed necessary by the Investigator 
or designee. 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs 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. 
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 drug. 


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Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a follicle-stimulating hormone (FSH) test and 
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. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and 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. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. 
Subjects must be supine for at least 5 minutes before blood pressure, pulse rate, and 
respiratory rate measurements. 
7.3.4. 
Electrocardiogram 
7.3.4.1. 
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: 
•
QTcF value > 500 msec
•
QTcF change from the mean baseline (Day 1 predose) is > 60 msec.


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Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.3.4.2. 
Continuous (24-hour) Electrocardiogram 
At the times indicated in the Schedule of Assessments (Appendix 6), continuous (24-hour) 
ECGs will be performed.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint. Each extraction will last for 5 minutes. 
Environmental distractions (eg, television, playing games, radio, conversation) should be 
avoided during the pre-ECG time window.  
Continuous 24-hour ECGs are not planned for Part B of the study but may be implemented if 
any clinically significant findings are identified in the data from Part A. 
7.3.5. 
Heat Pain Threshold Test 
Heat pain threshold tests will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). 
A computer-controlled thermal sensory analyzer device will be used to measure the heat pain 
threshold and tolerance level of the subjects. The heat pain assessments will be conducted on 
the subject’s thigh. 
Heat Pain Threshold: 
For heat pain threshold measurements, the thermode will be placed directly on the skin of the 
right thigh, within an area selected before the start of the experiment and defined by surgical 
marking. The thermode will have a baseline temperature of 32°C, and will be programmed to 
gradually increase at a rate of 1.0°C per second. The subject will be given a controller in their 
dominant hand, to indicate when the heat pain threshold (first sensation of heat pain) is 
reached by pushing a button. At that time, the test will be stopped and the temperature 
returned to baseline within 1 second. This process will be repeated a further 2 times, with an 
interval of at least 1 minute between measurements (from start to start). The computer will 
record the average value of 3 experiments. 
Heat Pain Tolerance: 
For heat pain tolerance measurements, the thermode will be placed within the same surgically 
marked skin area of the anterior side of the right thigh, which was used to assess heat pain 
threshold. The thermode will have a baseline temperature of 32°C, and will be programmed 


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to gradually increase at a rate of 1.0°C per second. The subject will be given a controller in 
their dominant hand, to indicate when the heat-evoked pain has reached an intensity that is no 
longer tolerable, by pushing a button. At that time, the test will be stopped and the 
temperature returned to baseline within 1 second. This process will be repeated a further 
2 times, with an interval of at least 1 minute between measurements (from start to start). The 
computer will record the average value of 3 experiments. 
Safety Precautions 
As there is a risk that OLP-1002 may affect the heat pain threshold, Covance CRU will put 
appropriate safety measures in place to ensure that subjects are not exposed to extremes of 
temperature when taking a shower or consuming hot drinks. During the heat pain safety 
assessments, the cut-off temperature for either test is 53°C in order to prevent skin injury. 
7.3.6. 
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.  
7.3.7. 
Body Weight and Height 
Body weight (in underclothes) and height will be recorded at the times indicated in the 
Schedule of Assessments in Appendix 6. BMI will be calculated using the following formula: 
BMI = body weight (kg)      (kg/m2) 
 (height [m])2
7.3.8. 
Injection Site Assessments 
Injection site assessments will be made at the times indicated in the Study Plan (Appendix 6). 
Assessments will involve evaluation of the dosing site for the following criteria:  
• Pain will be evaluated according to the following scale:
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Does not 
interfere with 
activity 
Interferes with 
activity or 
repeated use of 
non-narcotic 
pain reliever 
Prevents daily 
activity or 
repeated use of 
narcotic pain 
reliever 
Requires 
medical 
intervention 
greater than 
analgesia 
• Redness will be assessed by estimating the size of the red patch at the injection site across
its widest point, and will be evaluated according to the following scale: 


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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm 
51-100 mm 
More than 100 
mm 
Requires 
medical 
intervention 
greater than 
analgesia  
• Swelling will be assessed by estimating the size of the raised area around the injection site 
across its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm and 
does not 
interfere with 
activity 
51-100 mm or 
interferes with 
activity 
More than 100 
mm and 
prevents daily 
activity 
Requires 
medical 
intervention 
greater than 
analgesia 
In addition, how the swelling affects the subject in their daily routing activities will be 
considered. 
• Tenderness will be evaluated using the following scale: 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Mild pain to 
touch 
Moderate Pain 
to touch 
Severe pain to 
touch 
Requires 
medical 
intervention 
greater than 
analgesia 
• Bruising and ulceration will be evaluated as being present or absent. 
Local tolerability ratings of ≥Grade 3 and the presence of ulceration will be recorded as an 
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8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time OLP-1002 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. As part of Protocol Version 5, 
3 additional groups will be included in Part A (Groups A9, A10, and A11) and 1 additional 
group will be included in Part B (Group B4). Up to 2 additional groups of 8 subjects may be 
added to Part B (6 active; 2 placebo). 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of OLP-1002 that 
have evaluable PK data and have had no AEs or protocol deviations considered to impact PK. 
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo and for whom PD can be evaluated. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo. 
8.3. 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma concentration data, 
using commercial software such as Phoenix® WinNonlin®. Plasma concentrations of 
OLP-1002 and PK parameters will be listed and summarized using descriptive statistics. 
Individual and arithmetic mean OLP-1002 concentration-time profiles will also be presented 
graphically. 
8.4. 
Pharmacodynamic Analyses 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No 
formal statistical analysis of PD data is planned. 
8.5. 
Safety Analysis 
Safety parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 


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9. REFERENCES 
1.  Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A 
channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 
14;444(7121):894–8.  
2.  Goldberg YP, Price N, Namdari R, Cohen CJ, Lamers MH, Winters C, et al. Treatment of 
Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel 
blocker. Pain. 2012 Jan;153(1):80–5.  
3.  Jones HM, Butt RP, Webster RW, Gurrell I, Dzygiel P, Flanagan N, et al. Clinical Micro-
Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of 
Human Nav1.7 Voltage-Dependent Sodium Channels. Clin Pharmacokinet. 
2016;55(7):875–87.  
4.  Investigator Brochure - OLP-1002, 2018. 
5.  Gazerani P, Andersen OK, Arendt-Nielsen L. Site-specific, dose-dependent, and sex-
related responses to the experimental pain model induced by intradermal injection of 
capsaicin to the foreheads and forearms of healthy humans. J Orofac Pain. 
2007;21(4):289–302.  
6.  Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, et al. 
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in 
Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE 
[Internet]. 2016 Apr 6 [cited 2018 Jun 15];11(4). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822888/ 
7.  Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-
dependent pain, allodynia, and hyperalgesia in humans. J Investig Med Off Publ Am Fed 
Clin Res. 2006 Jul;54(5):238–44.  
8.  Anderson WS, Sheth RN, Bencherif B, Frost JJ, Campbell JN. Naloxone increases pain 
induced by topical capsaicin in healthy human volunteers. Pain. 2002 Sep;99(1–2):207–
16.  
9.  Pharmacokinetics and Metabolism in Drug Design, 3rd Edition [Internet]. Wiley.com. 
[cited 2018 Aug 21]. Available from: https://www.wiley.com/en-
us/Pharmacokinetics+and+Metabolism+in+Drug+Design%2C+3rd+Edition-p-
9783527329540 
10.  Mahmood I. Pharmacokinetic allometric scaling of antibodies: application to the first-in-
human dose estimation. J Pharm Sci. 2009 Oct;98(10):3850–61.  
11.  Offman E, Edginton AN. Pharmacokinetic Time Course Scaling of a Subcutaneously 
Administered Pegylated Peptide Conjugate for a First-in-Human Investigation. Eur J 
Drug Metab Pharmacokinet. 2017 Feb;42(1):69–78.  
 
 


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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 unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but posing no 
significant or permanent risk of harm to the subject. 
• 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 drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
• 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. 
• 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. 
• Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized 
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 
stabilized. 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: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize 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 Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization 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 
Covance Drug Safety Services (DSS) Europe, Maidenhead, UK are 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 facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the Safety 
Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of the 
SAE within 2 working days of the initial notification to DSS. Drug Safety Services 
will delete any information from the SAE report forms that may identify the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined in 
the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions 
and forward to the Ethics Committee, Medicines and Healthcare Products Regulatory 
Agency, Principal 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. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfill regulatory requirements any pregnancy reported by female subjects or 


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the female partners of male subjects should be reported following the SAE process to collect 
data on the outcome for both mother and fetus. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Urea 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
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  
Serologya: 
Drug screenb: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
MDMA 
Alcohol breath test 
Follicle-stimulating hormonea  
Serum pregnancy test (human 
chorionic gonadotropin)a 
Urine pregnancy testc 
a Only analyzed at Screening. 
b Only analyzed at Screening and Check-in. 
c 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. 
Part A 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
6 
45 
Serology 
3.5 
1 
3.5 
Total: 
124.5  
Part B 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
194.5  
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
during the study will not exceed that donated during a standard blood donation 
(approximately 500 mL). 


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Appendix 4: Contraception Guidance 
Definitions 
Females of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Females of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 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-estrogens, or selective estrogen 
receptor modulators.  
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. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary and 1 secondary method) of birth control from the time of signing the informed 
consent form until 90 days after the Follow-up visit. Primary (non-barrier) methods of 
contraception include:  
• hormone injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  


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• hormonal or non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject). 
Secondary (barrier) methods of contraception include:  
• male condom with spermicide 
• female condom with spermicide  
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects can only choose a cervical cap or diaphragm if they have already had a 
prescription and fitting by their healthcare provider to ensure protocol requirements are met. 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in until 90 days after the Follow-up 
visit. Acceptable methods of contraception include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide 
• vasectomised male subject (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success). 


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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. 
Sexual Abstinence and Same-sex Relationships 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 


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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: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with Clinical Research Unit personnel, subjects will sign 
2 copies of the ICF in the presence of a suitably trained member of staff to indicate that they 
are freely giving their informed consent. One copy will be given to the subject, and the other 
will be maintained in the subject’s records. 
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 


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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 Organization (CRO) auditors or other 
authorized personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All 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.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality tolerance 
thresholds, controls, and mitigation plans will be documented in a risk management 
register. Additional details of quality checking to be performed on the data may be 
included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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. 
• 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.  


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Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 Code of Federal 
Regulations 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 the Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled and randomized subject, according to the 
eCRF completion instructions. The Sponsor, or CRO, will review the supporting source 
documentation against the data entered into the eCRFs to verify the accuracy of the electronic 
data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 
information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


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Appendix 6: Schedule of Assessments 


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Study Plan – Part A (Single Dose) 
 
Pre- 
screening
d 
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
 
X 
X 
 
 
 
 
 
 
 
Alcohol breath test 
 
X 
X 
 
 
 
 
 
 
 
Cotinine test 
 
X 
X 
 
 
 
 
 
 
 
Serology 
 
X 
 
 
 
 
 
 
 
 
FSH and serum pregnancy 
testa 
 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
 
X 
 
 
 
 
 
 
X 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
Day 3 
(48 hours 
postdose) 
 
 
 
 
 
Non-residential visit 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
 
 
Day 1 
(0 hours)  
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 


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Pre- 
screening
d 
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Supine blood pressure, pulse 
rate, respiratory rate, and 
body temperature 
 
X 
 
 
Predose, 1, 2, 
4, 8, 24 (± 
1 hour), and 
48 hours 
postdose 
X 
X 
X 
X 
X 
Supine 12-lead ECG 
 
X 
 
 
Predose, 4, 24 
(± 1 hour) 
and 48 hours 
postdose 
 
X 
 
X 
X 
Continuous ECG 
extractionb,c 
 
 
 
-24,  
-23.5,  
-23,   
-22.5,  
-22,  
-21.5,  
-21,  
-20, 
-18,  
-16,   
-12 
hours 
Day 1: 
Predose, 0.5, 
1, 1.5, 2, 2.5, 
3, 4, 6, 8, 12 
and 24 hours 
 
 
 
 
 
 
Heat pain threshold test 
(heat pain threshold and heat 
pain tolerance) 
 
 
 
 
Day 1: 
predose, 2, 4, 
12, and 24 
hours 
postdose (± 
1 hour) 
 
 
 
 
 
Clinical chemistry, 
haematology, and urinalysis 
 
X 
X 
 
48 hours 
postdose 
 
X 
 
X 
X 


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Pre- 
screening
d 
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Height and BMI 
 
X 
 
 
 
 
 
 
 
 
Body weight  
 
X 
X 
 
 
 
 
 
 
X 
Physical examination 
 
X 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
 
 
Prior to 
discharge 
 
X 
 
X 
X 
Injection site assessment  
 
 
 
 
Predose, 1, 2, 
4, 8, 24, 48 
hours 
postdose 
 
X 
 
X 
X 
Pharmacokineticse 
 
 
 
 
 
 
 
 
 
 
Blood sampling 
 
 
 
 
Predose, 0.5, 
1, 1.5, 2, 3, 4, 
6, 8, 12, 16, 
24, 36 and 
48 hours 
postdose 
X 
X 
X 
X 
X 
Pharmacodynamicsd: 
 
 
 
 
 
 
 
 
 
 
Intradermal capsaicin test 
(capsaicin-evoked pain and 
secondary hyperalgesia 
measurement) 
X 
 
X 
 
Day 2 (The 
area of 
secondary 
area of 
hyperalgesia 
will be 
evaluated at 5 
and 30 
minutes post-
capsaicin 
injection) 
 
 
 
 
 


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Abbreviations: BMI = body mass index; ECG = electrocardiogram; FSH = follicle-stimulating hormone. 
a Female subjects only; a positive urine pregnancy test result will be confirmed with a serum pregnancy test. 
b All times are relative to dosing with OLP-1002. 
c Continuous ECG recording may begin at approximately 25 hours before dosing to allow for checks to be completed prior to the first extraction timepoint and will continue for 24 hours 
postdose, ie, until after the last timepoint for ECG extraction (24 hours postdose). At timepoints for ECG extractions, subjects will be supinely resting for a total of 15 minutes (10-minute supine 
rest period, 5-minute extraction). Data will be archived for potential future analysis and will not be available for review during the study. 
d Pharmacodynamic assessment groups only. 
e PK analysis in Part A will initially only be conducted for groups receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the event of PK data 
being quantifiable at doses ≥ 12 µg and if supported by bioanalytical stability data. 
 
 
 


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Study Plan – Part B (Multiple Dose) 
 
Screening 
Day -1 
Days 1-15 
Day 18 
(± 2 days) 
Day 22 
(± 2 days) 
Day 25 
(± 2 days) 
Day 29 
(± 2 days) 
Poststudy 
(Day 57 
± 2 days) 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
X 
X 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
Cotinine test 
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
FSH and serum pregnancy 
testa 
X 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
X 
 
 
X 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
Check-out 
 
 
Day 15 (48 hours postdose) 
 
 
 
 
 
Non-residential visit 
X 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
Days 1, 4, 7, 10, and 13 
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording  
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, 
pulse rate, respiratory rate, 
and body temperature 
X 
 
Day 1: predose, 1, 2, 4 and 8 hours 
postdose 
Day 2, Day 4 (postdose), Day 5, Day 7 
(postdose), Day 9, Day 10 (postdose), 
Day 12, Day 13: predose, 1, 2, 4 and 8 
hours postdose, and Day 15 
X 
X 
X 
X 
X 


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Screening 
Day -1 
Days 1-15 
Day 18 
Day 22 
Day 25 
Day 29 
Poststudy 
(Day 57 
± 2 days) 
Heat pain threshold test 
(heat pain threshold and 
heat pain tolerance) 
X 
 
Day 1 and Day 13: predose, 1, 2, 4, 8, 
24 hours postdose 
 
 
 
 
 
Supine 12-lead ECG 
X 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Days 2, 5, 9, 12, 17 
 
X 
 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
Days 1, 4, 7, 10, 13 
 
X 
 
X 
X 
Injection site assessment  
 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Pharmacokinetics: 
 
 
 
 
 
 
 
 
Blood samplingb 
 
 
Day 1 and Day 13: Pre dose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
X 
X 
X 
X 
X 


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Protocol Reference: OLP-1002-001 
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Abbreviations: BMI = body mass index; ECG = electrocardiogram; FSH = follicle-stimulating hormone. 
a Female subjects only; a positive urine pregnancy test results will be confirmed with a serum pregnancy test. 
b  PK timepoints will be reviewed based on emerging data and may be updated. 
 


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Appendix 7: Protocol Amendment Summary of Changes 
Protocol Amendment 6 (Version 5; 27 September 2019) 
This substantial amendment has been issued to increase the maximum dose in this study, 
which will be administered in 3 additional groups to Part A (Groups A9, A10, and A11), and 
1 additional group to Part B (Group B4). Further non-clinical data on the ability of OLP-1002 
to reverse inflammatory allodynia induced by the FCA model in rats have also been included 
in Section 1, and the project physician has been updated. 
For the additional groups, the maximum administered dose in this study will exceed the 
previously stated maximum dose of 20 µg. The justification for this is as follows: 
• The NOAEL for a 60-kg human has 96- and 76-fold safety margins to the Cmax and 
AUC0-∞, respectively, for the proposed additional single dose of 40 µg (Group A9), 
48- and 38-fold safety margins to the Cmax and AUC0-∞, respectively, for the proposed 
additional single dose of 80 µg (Group A10), respectively, and 24- and 19-fold safety 
margins to the Cmax and AUC0-∞, respectively, for the proposed additional single dose 
of 160 µg (Group A11), respectively. 
• Single doses of OLP-1002 up to 20 ug have been safe and well tolerated in Groups A1 
to A8. 
• The NOAEL for a 60-kg human has 42- and 20-fold safety margins to the Cmax and 
AUC0-tau ss, respectively, for the proposed dose for Group B4 of 5 x 20 µg. Based on 
the predicted accumulation of 3.7-fold, this dose level will not exceed the NOAEL. 
• In vivo, single dose of 10,000 pmol/kg (10 nmol/kg/dose; 46.2 µg/kg/dose) or less 
were found to inhibit FCA-induced inflammatory pain and there were no clinically 
adverse findings. The equivalent dose for a 60-kg human is 44 µg, which is therefore 
a dose at which biological effect is anticipated. 
• Predicted safety margins for Cmax and AUC0-∞ (Part A) and AUC0-tau, ss (Part B) for the 
new groups are deemed to be acceptable (see Table 1 and Table 2). 
A detailed summary of changes is presented below. Deleted text is shown in strikethrough, 
and new text is shown in bold. Additionally, the synopsis was updated to reflect changes to 
the body of the protocol, the table of contents and list of tables and figures were updated, the 
date and version number were updated, and minor editorial corrections were made. 
Change 
Justification 
Study Identification 
Project physician updated from 
 
 to 
 
Updated due to a 
change in study 
personnel. 


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Protocol Reference: OLP-1002-001 
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Change 
Justification 
Section 1.2.2 
When evaluated for their ability to reverse the inflammatory pain in 
rats inflicted with Freund's Complete Adjuvant (FCA)-induced severe 
paw inflammation, OLP-1002 at 300 pmol/kg and OLP-1002R at 
100 pmol/kg significantly reversed the thermal hyperalgesia, and both 
were more effective than pregabalin 30 mg/kg. Two further studies 
investigating OLP-1002R at concentrations up to 10,000 pmol/kg 
using the FCA model showed a reversal of inflammatory 
allodynia in rats. Both studies demonstrated that maintenance of 
a steady state of efficacy over time was dose dependent, with the 
dose of 100 pmol/kg being sufficient over 1 day/30 hours 
postdose, and the higher doses of 1000 pmol/kg and 10,000 
pmol/kg being the most suitable up to 3 days/96 hours postdose. 
Assuming that thermal withdrawal latency time of the normal 
control group was equivalent to 100% allodynia inhibition and 
that of the negative control group was equivalent to 100% 
allodynia induction, allodynia inhibition efficacy by OLP-1002R 
was estimated to be 20.65% ~ 45.48% and 34.21% ~ 58.72 % in 
the 2 studies. During both studies, no abnormalities or clinical 
findings were observed. 
New non-clinical data 
added to justify the 
therapeutic dose for 
OLP-1002. 
Section 3.1.1 
Part A will comprise a single-dose, sequential-group design. Overall, 
4468 healthy subjects will be studied in 811 groups. Up to 3 
additional groups (24 subjects in total) may be included for further 
assessment of safety, tolerability, PK, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter 
the study within 28 days prior to the first dose administration. 
Potential subjects for Groups A2, A4, and A6, A9, A10, and A11 
will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will 
reside at the Clinical Research Unit (CRU) from Day -2 (2 days 
before dosing) to Day 3. All subjects will return for non-residential 
visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 2 days), and 
for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional 
non-residential visits may be required. The number of additional 
visits per subject will not exceed 3 and will not extend beyond 
Day 28 (± 2 days). 
Doses will be administered in an escalating manner following 
satisfactory review of safety and tolerability data up to Day 10 (216 
Text updated to 
include Groups A9, 
A10, and A11. 


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Change 
Justification 
hours postdose) from the lower dose levels. For doses ≥ 12 µg, PK 
data will also be reviewed up to Day 7 prior to dose escalation. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 
3 subjects will receive OLP-1002 and 1 subject will receive placebo. 
To assess PD parameters, Groups A2, A4, and A6, A9, A10, and A11 
will consist of 8 subjects; 6 subjects will receive OLP-1002 and 
2 subjects will receive placebo. 
Figure 1 
Figure updated to include Groups A9, A10, and A11. 
Groups A9 to A11 may be included if required; dose levels will not 
exceed the maximum proposed dose of 20 µg. 
Three Six groups consist of 8 subjects (6 active: 2 placebo); all other 
groups will consist of 4 subjects (3 active: 1 placebo). 
Figure and footnote 
updated based on the 
change in maximum 
dose, and the inclusion 
of Groups A9, A10, 
and A11.  
Section 3.1.2 
Part B will comprise a multiple-dose, sequential-group study. 
Overall, 2432 subjects will be studied in 34 groups (Groups B1 to 
B34), with each group consisting of 8 subjects. Up to 32 additional 
groups (2416 subjects in total) may be included for further 
assessment of safety and tolerability (Section 3.3).  
Potential subjects will be screened to assess their eligibility to enter 
the study within 28 days prior to the first dose administration. Each 
subject will participate in 1 treatment period only and reside at the 
CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (± 
2 days), 22 (± 2 days), 25 (± 2 days), and 29 (± 2 days), and for a 
poststudy visit on Day 57 (± 2 days). 
In each of Groups B1 to B34, 6 subjects will receive OLP-1002 and 2 
subjects will receive placebo. 
Text updated to 
include Group B4. 
Figure 2 
Figure updated to include Group B4. 
All doses will be confirmed based on results of Part A; dose levels will 
not exceed the maximum proposed dose of 20 µg and previous 
groups in Part B. Groups B45 to and B6 will be included if required.
Figure and footnote 
updated based on the 
change in maximum 
dose, and the inclusion 
of Group B4. 
Section 3.3 
The maximum dose for any additional group will not exceed 20 µg. 
Up to 3 further groups of 8 subjects (6 active: 2 placebo) may be 
included in Part A, and uUp to 32 additional groups of 8 subjects 
Text updated 
following inclusion of 
Groups A9, A10, A11, 
and B4. 


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Change 
Justification 
(6 active: 2 placebo) may be included in Part B. The requirement for 
additional groups will be agreed with the Sponsor and documented in 
the Trial Master File (TMF). 
Section 3.4 
In order to assess the PD effects of OLP-1002, 36 groups in Part A 
will include 8 subjects (6 active; 2 placebo). 
Text updated 
following the inclusion 
of Groups A9, A10, 
and A11. 
Section 3.4 
A could potentiallyAdditional optimization of the PK analysis has  
delivered an LLOQ of around 0.1 ng/mL with the limit of detection 
being 0.2 ng/mL. 
Added to include 
information regarding 
developments in the 
PK analysis of OLP-
1002. 
Section 3.4.2 
Pharmacodynamic assessments will be conducted for subjects in 
Groups A2, A4, and A6, A9, A10, and A11. 
Text updated 
following the inclusion 
of Groups A9, A10, 
and A11. 
Section 3.5.1 
The dose of 462.29 µg/kg/dose corresponds to human equivalent 
doses (HEDs) of 74.8 µg/kg/dose, which gives a maximum 
recommended starting dose (MRSD) of 444 µg for a 60-kg human 
and thus a 15000-fold safety margin to the proposed starting dose of 
30 ng and 222.8-fold margin to the proposed maximum daily dose of 
20160 µg. Additionally the NOAEL dose in the cynomolgus monkey 
was identified as 100 nmol/kg/dose (462.29 µg/kg/dose), which gives 
a higher HED of 150 µg/kg/dose. 
In vivo, doses of 10 pmol/kg/dose (0.0462µg/kg/dose) or less were 
found to inhibit peripheral acute inflammatory pain. The equivalent 
human dose for a 60-kg human is 44 ng, thus a dose at which 
minimal biological effect is anticipated has been selected as the 
starting dose of 30 ng. 
Based on further in vivo studies in the rat (see Section 1.2.2), 
single doses of 10,000 pmol/kg (10 nmol/kg/dose; 46.2 ug/kg/dose) 
or less were found to inhibit FCA-induced inflammatory pain 
and there were no clinically adverse findings. The equivalent dose 
for a 60-kg human is 44 µg, and this is therefore a dose at which 
biological effect is anticipated. 
Text updated based on 
new non-clinical data 
to specify the 
anticipated therapeutic 
dose level in humans. 
Table 1 
Data for 40 µg, 80 µg, and 160 µg added to table. 
Table updated to 
include data for the 
increased dose levels 
in Part A. 


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Change 
Justification 
Table 2 
Data for 40 µg added to table. 
Table updated to 
include data for the 
increased dose level in 
Part B. 
Table 3 
Dose levels for Groups A9, A10, and A11 added to table. 
Table updated 
following inclusion of 
Groups A9, A10, and 
A11. 
Section 3.5.3 
For Part B, dose levels, dosing frequency, and dosing duration will be 
decided, in consultation with the Sponsor, on the basis of data from 
Part A of the study. Since predictions of human exposure of OLP-
1002 suggest that OLP-1002 concentrations may be not be 
quantifiable and human data have been estimated from a single 
species, it is proposed that the highest dose in the multiple-ascending-
dose part will be up to 50% of the highest dose in the single-
ascending-dose part (ie, if the highest dose in the single-ascending-
dose part is 20160 µg, the highest dose in the multiple-ascending-
dose part will be 1080 µg). Therefore, if the predicted accumulation 
of 3.7-fold occurs, the highest exposure in the multiple-ascending-
dose pPart B will not exceed ~2-fold the maximum exposure in the 
single-ascending-dose part. 
Group B4 may be dosed concurrently with Group A10 (80 µg), 
following the dose escalation meeting for Group A9 (40 µg). The 
predicted Cmax and AUC0-∞ for a single dose of 40 µg are 
0.258 ng/mL and 1.673 ng.h/mL, respectively (Table 1). Assuming 
3.7-fold accumulation, the predicted Cmax and AUC0-∞ at the 20 µg 
dose level in Group B4 are 0.294 ng/mL and 3.15 ng.h/mL, 
respectively (Table 2). Exposure in Group B4, therefore, is not 
predicted to exceed ~2-fold the maximum exposure in Group A9. 
If additional groups (A9-11 or B3-6B5 and B6) are required, the 
maximum daily dose administered will not exceed 20 µg and 
predicted systemic exposure will not exceed that stated in the dose 
escalation stopping criteria [Section 3.7]) based on available PK data. 
Justification added for 
conducting Groups 
A10 and B4 
concurrently. 
Section 3.6 
For escalation to doses >≥ 12 µg, PK data up to Day 7 
(144 hours postdose) will also be reviewed. All available safety, 
tolerability, and PK data from previous groups will be reviewed 
prior to dose escalation. 
 
Updated for 
consistency with 
section 3.1.1 
 


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Change 
Justification 
In Part B, doses will be administered in an escalating manner 
following satisfactory review of safety, tolerability, and PK data 
up to Day 22 (216 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and 
may be lower than the starting dose. Available safety, 
tolerability, and PK data from all previous groups will be 
reviewed prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 
4 subjects (Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups 
A2, A4, and A6, A9, A10, and A11) have been reviewed from the 
previous lower dose group, such that data from a minimum of 3 or 
4 subjects, respectively, who have received OLP-1002 will be used to 
make the dose-escalation decision. 
 
 
 
 
Text updated 
following the inclusion 
of Groups A9, A10, 
and A11. 
Section 3.7 
• 
The dose will not exceed 20 µg or the sSystemic exposure for 
any individual subject is predicted to exceed a Cmax of 
24.9 ng/mL (plasma) and/or an AUC0-24 of 128 ng.h/mL; i.e., 
systemic exposure will be no greater than the NOAEL in the 
most sensitive species (100,000 pmol/kg in rat [462 µg/kg]). 
Text updated due to 
the increased 
maximum dose level. 
Section 5.2 
For subjects in Groups A2, A4, and A6, A9, A10, and A11, dosing 
will be on the opposite arm to the intradermal capsaicin test. At dose 
levels of ≥40 µg (Groups A9, A10, and A11), doses may be 
administered as multiple SC injections in the same location (ie, 2 
SC injections in the upper arm). 
The highest doses of 
40 µg, 80 µg, and 
160 µg may be 
administered as 
multiple SC injections 
due to the volume of 
the dose. 
Section 6.2 
Chilli pepper/hot sauce will not be allowed for 48 hours prior to 
Check-in for all subjects. Subjects in Groups A2, A4, and A6, A9, 
A10, and A11 will not be allowed chilli pepper/hot sauce for 
48 hours prior to their pre-screening visit. 
Text updated 
following the inclusion 
of Groups A9, A10, 
and A11. 
Section 6.6 
Subjects in Groups A2, A4, and A6, A9, A10, and A11 will not be 
allowed to shower within 1 hour prior to the capsaicin-evoked pain 
tests at prescreening, predose, and postdose. 
Text updated 
following the inclusion 
of Groups A9, A10, 
and A11. 
Section 7.2 
Capsaicin intradermal test will be performed for subjects in 
Groups A2, A4, and A6, A9, A10, and A11. Each subject will be 
Text updated 
following the inclusion 
of Groups A9, A10, 
and A11. 


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Change 
Justification 
tested at a pre-screening visit before being tested twice during the 
study (1 predose and 1 postdose). 
Section 8.1 
No formal statistical assessment, in terms of sample size, has been 
conducted as this is the first time OLP-1002 is being administered to 
humans. However, the number of subjects in each part of the present 
study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. As part 
of Protocol Version 5, 3 additional groups will be included in Part 
A (Groups A9, A10, and A11) and 1 additional group will be 
included in Part B (Group B4). In order to achieve PD endpoints in 
Part A, additional subjects will be included in 3 groups (8 subjects in 
total; 6 active: 2 placebo). Up to 3 additional groups may be added to 
Part A, consisting of either 4 subjects (3 active; 1 placebo) or 8 
subjects (6 active; 2 placebo). Up to 32 additional groups of 
8 subjects may be added to Part B (6 active; 2 placebo). 
Text updated 
following the inclusion 
of Groups A9, A10, 
A11, and B4. 
Protocol Amendment 5 (Version 4; 26 March 2019) 
This substantial amendment has been issued to update the Principal Investigator from 
 
 to 
.  
A detailed summary of changes is presented below. For each section, deleted text is shown in 
strikethrough, and new text is shown in bold.  
Title Page 
Principal Investigator: 
 was replaced by 
 
 
Investigator Agreement 
was replaced by 
 
 
Study Identification 
 was replaced by 
 
 
Tel:
 was replaced by 
 


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Protocol Amendment 4 (Version 3; 29 January 2019) 
This substantial amendment has been issued to update the female contraception criteria to 
allow female subjects to use alternative forms of contraception including the combined oral 
contraceptive pill, combined hormonal patch, and combined hormonal vaginal ring. 
Additionally, it has been clarified that only a serum pregnancy test will be conducted at 
Screening. 
A detailed summary of changes is presented below. For each section, deleted text is shown in 
strikethrough, and new text is shown in bold: 
Appendix 4 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception. Female subjects of childbearing potential must be willing to use 2 
methods (1 primary highly effective and 1 secondary method) of birth control from the 
time of signing the informed consent form until 90 days after the Follow-up visit. 
Primary highly effective (non-barrier) methods of contraception include:  
• hormone injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as 
prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  
• hormonal or non-hormonal intrauterine device with appropriate re-insertion 
period (as prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole 
partner for the female subject). 
Appendix 6 
Hormone panel was replaced by FSH and serum pregnancy test in the study plan for 
Part A and Part B for clarity. 
A footnote was added to the study plan for Part A and Part B to specify that the FSH 
and serum pregnancy test will be conducted for female subjects only. 
Urine pregnancy test at Screening removed for Part A and Part B. 


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Protocol Amendment 3 (Version 2.2; 12 December 2018) 
This non-substantial amendment has been issued to include a clinical laboratory assessment 
on Day -2 in Part A. 
Appendix 3 
Additional clinical laboratory sample added to Part A. Total blood volume withdrawn 
in Part A updated to 124.5 mL. 
Appendix 6 
Study Plan (Part A) 
Clinical chemistry, haematology, and urinalysis assessment added on Day -2. 
Protocol Amendment 2 (Version 2.1; 29 November 2018) 
This non-substantial amendment has been issued to correct minor inconsistencies in PK 
sampling timepoints, data cut off for dose escalation, clinical laboratory assessment 
timepoints, and the synopsis. Additionally, details of the injection site assessments have been 
added to the protocol. 
A detailed summary of changes is presented below. For each section, deleted text is shown in 
strikethrough, and new text is shown in bold: 
Synopsis: Endpoints 
Text added: 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 
12-lead ECGs, vital signs measurements, injection site assessment, heat pain threshold and 
tolerance, and physical examinations. 
Section 3.6 
Previously read: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
Now reads: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 10 (216 hours postdose) from groups that received lower doses of OLP-1002. 


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Section 7.3.8 
Entire section added to describe injection site assessments. 
Appendix 3 
Total blood volume for PK analysis (76 mL) added. 
Appendix 6 - Schedule of assessments Part A 
24 hour postdose continuous ECG recording timepoint added. 
Appendix 6 - Schedule of assessments Part B 
Clinical chemistry, haematology, and urinalysis for Days 1-15 previously read: 
Days 2, 4, 7, 10,13 
Clinical chemistry, haematology, and urinalysis for Days 1-15 now reads: 
Days 2, 5, 9, 12, 17 
 
PK blood sampling for Days 1-15 previously read: 
Day 1 and Day 15: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 8, 11, 15 Predose 
PK blood sampling for Days 1-15 now reads: 
Day 1 and Day 13: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
Protocol Amendment 1 (Version 2; 02 October 2018) 
This amendment has been generated following the non-acceptance of the original protocol 
(version 1) by the Medicines and Healthcare products Regulatory Agency (MHRA) on 20 
September 2018. All changes made have been in response to comments provided by the 
MHRA. 
The primary changes in this amendment are: 
1. Inclusion of PK sampling in Parts A and B: 
• PK objective and exploratory endpoints added (Section 2). 
• Discussion of PK included Section 3.4. 
• PK stopping criteria added to Section 3.7. 


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• PK assessments included in Section 7.1. 
• PK population and analysis (Section 8.2.1). 
• Blood volumes updated to include samples for PK assessments (Appendix 3). 
2. Exclusion and stopping criteria updated 
• Women who are pregnant or breastfeeding have been excluded from the study 
(Section 4.2). 
• Liver function tests, tachycardia, and hypertension stopping criteria have been 
updated (Section 3.7 and Section 4.4). 
• Stopping criteria for SAEs and serious AEs have been added (Section 3.7 and 
Section 4.4). 
3. Safety, tolerability, and PK data up to Day 22 in Part B will be reviewed prior to dose 
escalation (Section 3.1.2). 
4. Sentinel dosing included in Part B (Section 3.1.2). 
5. It has been specified that the maximum dose for additional groups will not exceed 20 
µg (Section 3.5.3). 
Minor changes: 
1. Additional clinical laboratory evaluations have been included on Day 14 in Part A. 
2. The definition of the Safety population has been updated to include all subjects who 
receive OLP-1002. 
3. Typographical errors and formatting errors were corrected, as necessary. 
A detailed summary of changes is presented below. For each section, deleted text is shown in 
strikethrough, and new text is shown in bold: 
Section 1.6 
Previously read: 
This information, together with the pharmacodynamic (PD data, will help establish the 
doses and dosing regimen suitable for future studies in patients. 
Now reads: 
This information, together with the pharmacodynamic (PD) and pharmacokinetic 
(PK) data, will help establish the doses and dosing regimen suitable for future studies 
in patients. 
Section 2.1  
Objective added: 


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Where possible, single and/or multiple subcutaneous dose pharmacokinetics of 
OLP-1002 in healthy subjects will be determined. 
Section 2.2.1 
Endpoint added: 
• demonstrate that exposure to OLP-1002 does not exceed pre-defined 
exposure limits from non-clinical studies. 
Section 2.2.2 
Endpoints added: 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-1002 
are as follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from time 
zero to infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable 
concentration (AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 


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Other PK parameters may also be added if deemed necessary. 
Section 3.1.1 
Previously read: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study within 
28 days prior to the first dose administration. Potential subjects for Groups A2, A4, and 
A6 will attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will 
return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 
2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential 
visits may be required. The number of additional visits per subject will not exceed 3 
and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 7 (144 hours postdose) from the lower dose 
levels. 
Now reads: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, PK, and PD 
(Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study within 
28 days prior to the first dose administration. Potential subjects for Groups A2, A4, and 
A6 will attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will 
return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 
2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential 
visits may be required. The number of additional visits per subject will not exceed 3 
and will not extend beyond Day 28 (± 2 days). 


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Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 10 (216 hours postdose) from the lower dose 
levels. For doses ≥ 12 µg, PK data will also be reviewed up to Day 7 prior to dose 
escalation. 
Figure 1 – footnote 
Text added:  
Groups A9 to A11 may be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Figure 2 – footnote 
Text added: 
Groups B4 to B6 will be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Section 3.1.2 
Previously read: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. There will be no sentinel dosing in Part B. For all subjects, a single 
subcutaneous dose will be administered on Days 1, 4, 7, 10, and 13. The dosing 
frequency in Part B may be changed following review of data from groups in Part A 
(Section 3.4).  
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 18 (120 hours post-final dose) from the lower 
dose levels. Part B may start after a review of the safety and tolerability for Groups A1 
to A6. The total daily dose administered will not exceed the highest single dose given 
in Part A. 
Now reads: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. For all subjects, a single subcutaneous dose will be administered on 
Days 1, 4, 7, 10, and 13. Prior to each dosing occasion a physician will review the 
available safety and tolerability data from each subject to confirm it is acceptable to 
continue dosing. The dosing frequency in Part B may be changed following review of 
data from groups in Part A (Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to 
OLP-1002 at steady state is predicted to exceed exposures that have been shown to 


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be safe and well tolerated in earlier groups in Parts A or B. In the event of sentinel 
dosing, 2 subjects (1 active, 1 placebo) will be dosed at least 4 days prior to the 
remaining 6 subjects (5 active: 1 placebo). Safety data for the sentinel subjects 
from at least 2 additional doses will be reviewed prior to dosing the remaining 
subjects (i.e. sentinel subjects’ safety data after doses 1 and 2 will be reviewed 
prior to the remaining subjects receiving dose 1). In addition, safety data from 
each subject will be reviewed by a physician prior to each dose to approve 
continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from the 
lower dose levels. Part B may start after a review of the safety, tolerability, and 
available PK data for Groups A1 to A6. The total daily dose administered will not 
exceed the highest single dose given in Part A. 
Section 3.3 
Previously read: 
Following review of the safety, tolerability, and PD data, additional dose groups may 
be added to the study. 
Now reads: 
Following review of the safety, tolerability, PK, and PD data (where systemic 
exposure is not expected to exceed that stated in the dose escalation stopping 
criteria [Section 3.7]), additional dose groups may be added to the study. The 
maximum dose for any additional group will not exceed 20 µg. 
Section 3.4 
Previously read: 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD effects 
of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 placebo). A full 
review of the safety and tolerability data from Part A will be performed to determine 
the dose regimen for Part B. Part B may start after a full review of all safety and 
tolerability data from Group A1 to A6. A review of PD data may also be performed, at 
the discretion of the Investigator. Details of the dosing regimen and duration used for 
Part B of the study will be documented in the TMF. 


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Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis will not be conducted in this study. The bioanalytical method 
used for preclinical species has a lower limit of quantification (LLOQ) of 5 ng/mL. The 
increased sample volume possible from humans (compared to small animals) may 
afford an approximate 10-fold increase in sensitivity with possibly an additional 5-fold 
increase from the use of a more sensitive mass spectrometer. This could potentially 
deliver an LLOQ of around 0.1 ng/mL. It is apparent from the predicted plasma 
concentrations (see Section 3.5.2) that only a small number of samples around Cmax at 
the highest doses would be quantifiable and that a conventional approach to 
pharmacokinetic will not achieve a full definition of the plasma concentration vs time 
profile or enable an estimation of the terminal phase. Thus, the additional burden of 
sampling procedures would not be justified by the quality of the data which it would 
generate. 
Now reads:  
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, and 
PK data up to Day 7 will be reviewed for all groups receiving ≥ 12 µg OLP-1002. 
In Part B, safety, tolerability and PK data up to Day 22 will be reviewed for all 
dose groups. As the t1/2 of OLP-1002 is predicted to be approximately 180 hours 
(based on non-clinical data) review of safety data up to Day 10 (Part A) and Day 
22 (Part B) is considered sufficient to ensure data from at least one half-life is 
included in the review. In addition, as plasma exposures are anticipated to be low, 
it is expected that it will only be possible to perform an assessment of peak 
concentrations (Cmax) and therefore PK data to Day 7 (Part A) and Day 22 (Part 
B) will be sufficient. Additionally, a cumulative safety review will occur such that 
additional emerging safety data from earlier groups will be considered when 
making a dose escalation decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD effects 
of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 placebo). A full 
review of the safety and tolerability data from Part A will be performed to determine 
the dose regimen for Part B. Part B may start after a full review of all safety and 
tolerability data from Group A1 to A6. A review of PD data may also be performed, at 
the discretion of the Investigator. Details of the dosing regimen and duration used for 
Part B of the study will be documented in the TMF. 


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Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower 
dose groups occurring in the event of PK data being quantifiable at doses ≥ 12 µg 
and if supported by bioanalytical stability data. Dose escalation decisions for doses 
<12 µg in Part A will not require PK data. The rationale for this is that maximum 
plasma concentrations at 12 µg are expected to be approximately 0.078 ng/mL and 
the bioanalytical method used for preclinical species has a lower limit of quantification 
(LLOQ) of 5 ng/mL. The increased sample volume possible from humans (compared 
to small animals) may afford an approximate 10-fold increase in sensitivity with 
possibly an additional 5-fold increase from the use of a more sensitive mass 
spectrometer. This could potentially deliver an LLOQ of around 0.1 ng/mL. Therefore, 
even with the increased assay sensitivity plasma levels from doses at or below 
12 µg are not expected to be quantifiable. It is apparent from the predicted plasma 
concentrations (see Section 3.5.2) that only a small number of samples around Cmax at 
the highest dose would be quantifiable and that a conventional approach to 
pharmacokinetic will not achieve a full definition of the plasma concentration vs time 
profile or enable an estimation of the terminal phase. In addition the planned dose 
levels have a high safety margin when comparing the predicted exposures to the 
exposures at the NOAEL (see Section 3.5.2), with the 12 µg dose level having an 
expected 312-fold and 255-fold safety margin based on Cmax and AUC0-∞, 
respectively. Therefore if exposure is significantly higher than predicted it is not 
expected to exceed the PK stopping criteria.  
 
Section 3.4.1 
Previously read: 
In Part B, all subjects in a group will be dosed on the same day. Accumulation of OLP-
1002 is expected following multiple doses, based on the preclinical data, and will be 
taken into account when determining the doses for Part B (see Section 3.5.3). 
Now reads:  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 at 
steady state is predicted to exceed exposures that have been shown to be safe and 
well tolerated in earlier groups in Parts A or B. When used, two subjects (1 active; 
1 placebo), will be dosed 4 days prior to the remaining 6 subjects (5 active; 2 
placebo). The 2 sentinel subjects will always be 2 doses ahead of the remaining 
subjects (ie. sentinel subjects will receive dose 2 before the remaining subjects 
receive dose 1). Subjects in groups where exposure is not predicted to exceed that 
tested in Part A will be dosed on the same day. Accumulation of OLP-1002 is 
expected following multiple doses, based on the preclinical data, and will be taken into 


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account when determining the doses for Part B (see Section 3.5.3). If it is not possible 
to quantify exposure it will be assumed that multiple dosing results in a 4-fold 
accumulation based on the predicted t1/2 of 180h. 
Section 3.5.3 
Text added: 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose 
administered will not exceed 20 µg and predicted systemic exposure will not 
exceed that stated in the dose escalation stopping criteria [Section 3.7]) based on 
available PK data. 
Section 3.6 
Previously read:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to Day 7 
(144 hours postdose) from groups that received lower doses of OLP-1002. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety and tolerability data up to Day 18 (120 hours post-final dose) from 
groups that received lower doses of OLP-1002. Doses may be reduced and may be 
lower than the starting dose. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups 
A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have been reviewed 
from the previous lower dose group, such that data from a minimum of 5 subjects, who 
have received OLP-1002 will be used to make the dose-escalation decision. Dose 
escalation in Part B will only occur if data from a minimum of 6 subjects have been 
reviewed from the previous lower dose group, such that data from a minimum of 
4 subjects who have received OLP-1002 will be used to make the dose-escalation 
decision. 
Now reads:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to Day 7 
(144 hours postdose) from groups that received lower doses of OLP-1002. For 
escalation to doses > 12 µg, PK data up to Day 7 (144 hours postdose) will also be 
reviewed. All available safety, tolerability, and PK data from previous groups will 
be reviewed prior to dose escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) 
from groups that received lower doses of OLP-1002. Doses may be reduced and may 


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be lower than the starting dose. Available safety, tolerability, and PK data from all 
previous groups will be reviewed prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups 
A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have been reviewed 
from the previous lower dose group, such that data from a minimum of 3 or 4 subjects, 
respectively, who have received OLP-1002 will be used to make the dose-escalation 
decision. Dose escalation in Part B will only occur if data from a minimum of 
6 subjects have been reviewed from the previous lower dose group, such that data from 
a minimum of 4 subjects who have received OLP-1002 will be used to make the dose-
escalation decision. 
 
Section 3.7 
Previously read: 
In Parts A and B, following consultation with the Sponsor, dose escalation will be 
stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping of 
dose escalation. 
• There is evidence of clinically significant increases in liver function tests 
(aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and 
total bilirubin) defined as 3 times the upper limit of normal in 3 or more 
subjects in a group (confirmed with repeat testing). 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose 
for Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat 
measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in at 
least 2 subjects in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in at 
least 2 subjects in a group. 
Now reads: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping of 
dose escalation. 


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• One or more subjects experience an SAE that is considered to be related to 
OLP-1002. 
• Two or more subjects in the same group experience severe non-serious AEs 
(ie. severe non-serious AEs considered as, at least, possibly related to 
OLP-1002 administration), independent of whether the AEs are within or 
not within the same system organ class.  
• There is evidence of clinically significant increases in aspartate 
aminotransferase, alanine aminotransferase or alkaline phosphatase (defined as 
3 times the upper limit of normal), or total bilirubin (defined as 2 times the 
upper limit of normal) that are considered to be related to OLP-1002 in 2 
or more subjects in a group. Results will be confirmed with repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose 
for Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat 
measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in ≥1 
subject in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in ≥1 
subject in a group. 
• The dose will not exceed 20 µg or the systemic exposure for any individual 
subject is predicted to exceed a Cmax of 24.9 ng/mL (plasma) and/or an 
AUC0-24 of 128 ng/mL; i.e., systemic exposure will be no greater than the 
NOAEL in the most sensitive species (100,000 pmol/kg in rat [462 µg/kg]). 
 
Section 4.2 
Exclusion criteria added: 
4. 
Female subjects who are pregnant or breastfeeding. 
Section 4.4 
Previously read: 
• any clinically relevant sign or symptom that, in the opinion of the Investigator 
(or designee), warrants subject withdrawal 
Now reads: 


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• any clinically relevant sign or symptom that, in the opinion of the Investigator 
(or designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least possibly 
related to OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE 
considered to at least possibly related to OLP-1002 administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for Part A 
or Day 1 predose for Part B) and/or absolute QTcF 
values > 500 msec (confirmed by repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position 
(confirmed by 2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg and/or 
diastolic blood pressure > 110 mmHg) in the resting supine position 
(confirmed by 2 repeat measurements). 
Section 7.1 
Section added: 
7.1  Pharmacokinetic Assessments 
7.1.1 Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times 
indicated in the Schedule of Assessments (Appendix 6). Furthermore, additional 
blood samples may be taken from each subject per treatment period, with the 
maximum volume of blood withdrawn per subject not exceeding the limit detailed 
in Appendix 3. Any changes to the scheduled times of PK assessments will be 
agreed with the Sponsor and documented in the TMF. Samples taken from 
subjects who received placebo will not be analyzed. 
In Part A, only samples collected from subjects that received >12 µg OLP-1002 
will be initially analyzed. If PK data is quantifiable at concentrations of OLP-1002 
>12 µg, samples from lower dose groups will be retrospectively analyzed. In Part 
B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate 
documents. 


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Section 8.2 
Previously read: 
8.2.1 Pharmacodynamic population 
The PD population will include all subjects who received at least 1 dose of study 
treatment OLP-1002 or placebo and for whom PD can be evaluated. 
8.2.2 Safety Population 
The safety population will include all subjects who received at least 1 dose of study 
treatment or placebo and have at least 1 postdose safety assessment. 
Now reads: 
8.2.1 Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of OLP-
1002 that have evaluable PK data and have had no AEs or protocol deviations 
considered to impact PK. 
8.2.2 Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-1002 
or placebo and for whom PD can be evaluated. 
8.2.3 Safety Population 
The safety population will include all subjects who received at least 1 dose of 
OLP-1002 or placebo. 
8.3 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma and urine 
concentration data, using commercial software such as Phoenix® WinNonlin®. 
Plasma concentrations of OLP-1002 and PK parameters will be listed and 
summarized using descriptive statistics. Individual and arithmetic mean OLP-
1002 concentration-time profiles will also be presented graphically. 
Appendix 3 
Table updated: 
Part A 
 


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Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis* 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
33.5109.5  
Part B 
 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
78.5194.5  
 
 
Appendix 6 
PK and Blood sampling rows added to the schedule of events for Part A and Part B. In 
the Schedule of events for Part A, footnote e was added. In the Schedule of events for 
Part B, footnote b was added. 
Clinical chemistry, hematology, and urinalysis was added to the Schedule of events for 
Part A on Day 14.  
 
 


TITLE PAGE 
Protocol 
OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single 
and Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, 
and Pharmacodynamic Study in Healthy Male and Female Subjects 
Protocol Status: Final 
Protocol Date: 26 March 2019 
Protocol Version: 4 
Investigational Product: OLP-1002 
Protocol Reference Number: OLP-1002-001 
Covance Study Number: 8379789 
EudraCT Number: 2018-003085-13 
Sponsor: 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung-gu, Yongin, Gyeonggi 17015 
Republic of Korea 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street  
Leeds, LS2 9LH 
United Kingdom 
Sponsor Signatory: 
 
Principal Investigator: 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP-1002-001 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
  
 
Protocol Version 4, 26 March 2019 
Date 
Page 2 of81 
Protocol Version 4, 26 March 2019
Page 2 of 82


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
 
Principal Jnvestigator 
Protocol Version 4, 26 March 2019 
Date 
Page 3 of 82 
Protocol Version 4, 26 March 2019
Page 3 of 82


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Protocol Version 4, 26 March 2019 
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STUDY IDENTIFICATION 
Sponsor 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Study Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Medical Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Medical Monitor 
(24-hour emergency 
medical contact) 
 
 
 
 
 
Study Site 
Covance Clinical Research Unit Ltd. 
Springfield House, 
Hyde Street, 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
Project Physician 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 


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Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
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United Kingdom 
 
Clinical Laboratory 
 
 
 
Statistician 
 
Covance 


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SYNOPSIS 
Title of study: OLP-1002 – A first-in-human, double-blind, placebo-controlled, single and multiple 
subcutaneous dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy 
male and female subjects 
Objectives:  
The primary objective of the study is to assess the safety and tolerability of single and multiple 
subcutaneous doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the pharmacodynamic effect of OLP-1002 
following single subcutaneous doses in healthy volunteers using a capsaicin pain model, and to 
monitor the effects of a single subcutaneous doses of OLP-1002 on cardiac QT interval. Where 
possible, single and/or multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy 
subjects will be determined. 
Study design: 
This will be a double-blind, randomized, placebo-controlled, single and multiple subcutaneous dose 
study conducted in 2 parts, including healthy male and female subjects. 
Number of subjects: 
Part A: 44 subjects will be studied in 8 groups (5 groups of 4 and 3 groups of 8). 
Part B: 24 subjects will be studied in 3 groups (Groups B1 to B3). 
Up to 24 additional subjects may be recruited into Part A and Part B of the study if required. 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged between 18 and 60 years (inclusive) with a body mass index 
between 18.0 and 28.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test product: OLP-1002 
Proposed dose levels for Part A: 30 ng, 120 ng, 400 ng, 1.2 µg, 3 µg, 6 µg, 12 µg, and 20 µg. 
Proposed dose levels for Part B: the doses for Part B will be decided in consultation with the 
Sponsor and on the basis of data from Part A of the study. The highest dose in Part B will be up to 
50% of the highest dose in Part A. 
Administration route: subcutaneous 
Reference product and mode of administration: 
Reference product: placebo 
Administration route: subcutaneous 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 8 weeks for Part A and 
approximately 12 weeks for Part B. 


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Endpoints: 
Pharmacodynamics: 
In Part A, the analgesic effect of OLP-1002 will be investigated in 3 groups consisting of 8 subjects 
(6 active: 2 placebo) using experimental capsaicin-evoked pain methods. Measurement of 
capsaicin-evoked pain will be performed at pre-screening, baseline and on Day 2, and secondary 
hyperalgesia at 5 and 30 minutes post-capsaicin injection. Continuous electrocardiogram (ECG) 
recording will be conducted to investigate the effect of OLP-1002 on cardiac function. 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 12-lead 
ECGs, vital signs measurements, injection site assessment, heat pain threshold and tolerance, and 
physical examinations. 
Pharmacokinetics: 
In Part A, the following PK parameters will be determined where possible: area under the plasma 
concentration-time curve (AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the 
time of the last quantifiable concentration (AUC0-tlast), maximum observed plasma concentration 
(Cmax), time of the maximum observed plasma concentration (tmax), and apparent plasma terminal 
elimination half-life (t1/2). PK analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups 
occurring in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by 
bioanalytical stability data. 
In Part B, the following PK parameters will be determined where possible: AUC over a dosing 
interval (AUC0-τ), AUC0-∞, Cmax, minimum observed plasma concentration (Cmin), tmax, t1/2, observed 
accumulation ratio based on AUC0-τ (RAAUC0-τ), observed accumulation ratio based on Cmax 
(RACmax), and Temporal change parameter (TCP). PK samples from all groups in Part B will be 
analyzed. 
Statistical methods: 
Pharmacodynamics: 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of pharmacodynamic data is planned. 
Safety: 
Safety parameters will be listed and summarized using descriptive statistics. No formal statistical 
analysis of safety data is planned. 
Pharmacokinetics: 
Individual plasma concentrations and PK parameters of OLP-1002 will be listed and summarized 
using descriptive statistics. Individual and mean OLP-1002 concentration-time profiles will be 
presented graphically. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................12 
1.1. 
Overview ................................................................................................................12 
1.2. 
Summary of Nonclinical Pharmacology ................................................................12 
1.2.1. 
In Vitro Pharmacology Studies ....................................................................12 
1.2.2. 
In Vivo Pharmacology Studies ....................................................................13 
1.2.3. 
Ex Vivo Pharmacology Studies ...................................................................14 
1.3. 
Summary of Safety Pharmacology ........................................................................15 
1.4. 
Summary of Toxicology ........................................................................................15 
1.5. 
Summary of Nonclinical Pharmacokinetics ...........................................................16 
1.6. 
Study Rationale ......................................................................................................17 
1.7. 
Benefit-risk Assessment .........................................................................................17 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................17 
2.1. 
Objectives ..............................................................................................................17 
2.2. 
Endpoints ...............................................................................................................17 
2.2.1. 
Primary Endpoints .......................................................................................17 
2.2.2. 
Exploratory Endpoints .................................................................................18 
3. 
INVESTIGATIONAL PLAN ..........................................................................................19 
3.1. 
Overall Study Design and Plan ..............................................................................19 
3.1.1. 
Part A ...........................................................................................................19 
3.1.2. 
Part B ...........................................................................................................21 
3.2. 
Start of Study and End of Study Definitions .........................................................22 
3.3. 
Additional Groups ..................................................................................................22 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................22 
3.4.1. 
Dose Interval ................................................................................................24 
3.4.2. 
Pharmacodynamic Assessment ....................................................................24 
3.5. 
Selection of Doses in the Study .............................................................................25 
3.5.1. 
Starting Dose ................................................................................................25 
3.5.2. 
Exposure ......................................................................................................26 
3.5.3. 
Proposed Doses ............................................................................................27 
3.6. 
Dose Escalation ......................................................................................................28 


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3.7. 
Dose Escalation Stopping Criteria .........................................................................29 
4. 
SELECTION OF STUDY POPULATION .....................................................................30 
4.1. 
Inclusion Criteria ...................................................................................................30 
4.2. 
Exclusion Criteria ..................................................................................................30 
4.3. 
Subject Number and Identification ........................................................................32 
4.4. 
Subject Withdrawal and Replacement ...................................................................32 
4.5. 
Study Termination .................................................................................................33 
5. 
STUDY TREATMENTS .................................................................................................33 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................33 
5.2. 
Study Treatment Administration ............................................................................33 
5.3. 
Randomization .......................................................................................................33 
5.4. 
Blinding..................................................................................................................34 
5.5. 
Treatment Compliance ...........................................................................................34 
5.6. 
Drug Accountability...............................................................................................34 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................35 
6.1. 
Concomitant Therapies ..........................................................................................35 
6.2. 
Diet .........................................................................................................................35 
6.3. 
Smoking .................................................................................................................35 
6.4. 
Exercise ..................................................................................................................35 
6.5. 
Blood Donation ......................................................................................................36 
6.6. 
Other Restrictions ..................................................................................................36 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................36 
7.1. 
Pharmacokinetic Assessments ...............................................................................36 
7.1.1. 
Sample Collection and Processing ...............................................................36 
7.1.2. 
Analytical Methodology ..............................................................................37 
7.2. 
Pharmacodynamic Assessments ............................................................................37 
7.2.1. 
Capsaicin-evoked Pain Model .....................................................................37 
7.2.2. 
Secondary Hyperalgesia ...............................................................................37 
7.3. 
Safety and Tolerability Assessments .....................................................................37 
7.3.1. 
Adverse Events ............................................................................................37 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................38 
7.3.3. 
Vital Signs ....................................................................................................38 
7.3.4. 
Electrocardiogram ........................................................................................39 
7.3.5. 
Heat Pain Threshold Test .............................................................................39 
7.3.6. 
Physical Examination...................................................................................40 
7.3.7. 
Body Weight and Height .............................................................................40 
7.3.8. 
Injection Site Assessments ...........................................................................40 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................42 
8.1. 
Determination of Sample Size ...............................................................................42 


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8.2. 
Analysis Populations ..............................................................................................42 
8.2.1. 
Pharmacokinetic Population ........................................................................42 
8.2.2. 
Pharmacodynamic Population .....................................................................42 
8.2.3. 
Safety Population .........................................................................................42 
8.3. 
Pharmacokinetic Analyses .....................................................................................42 
8.4. 
Pharmacodynamic Analyses ..................................................................................43 
8.5. 
Safety Analysis ......................................................................................................43 
9. 
REFERENCES ................................................................................................................43 
10.  APPENDICES .................................................................................................................45 
Appendix 1: Adverse Event Reporting ..............................................................................46 
Appendix 2: Clinical Laboratory Evaluations ...................................................................50 
Appendix 3: Total Blood Volume ......................................................................................51 
Appendix 4: Contraception Guidance ................................................................................52 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................55 
Appendix 6: Schedule of Assessments ..............................................................................58 
Appendix 7: Protocol Amendment Summary of Changes .................................................66 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 ..........................................26 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 ......................................27 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
27 
Figure 1: 
Study Schematic (Part A)...........................................................................20 
Figure 2: 
Study Schematic (Part B) ...........................................................................22 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve extrapolated to infinity 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
postdose 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
DN 
Dose normalized 
DRG 
dorsal root ganglion 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Emax 
maximum pain intensity 
FCA 
Freund's Complete Adjuvant 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SNL 
spinal nerve ligation 
t1/2 
elimination half-life 
tEmax 
time of maximum pain intensity 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
VAS 
Visual Analogic Scale 
VGSC 
voltage-gated sodium channel 


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1. INTRODUCTION 
1.1. 
Overview 
OLP-1002 is a novel peptide nucleic acid (PNA) derivative which acts as a specific voltage-
gated sodium channel (VGSC) protein (Nav1.7) inhibitor, and is being developed by OliPass 
for the treatment of pain. 
The Nav1.7 protein is a subtype of VGSCs. Nav1.7 is particularly important in nociception 
and pain signaling, with congenital loss-of-function mutations in Nav1.7 resulting in the 
inability to experience pain. Selective Nav1.7 inhibitors are believed to have the potential to 
treat severe pain safely1. The active sites of VGSC subtypes are virtually indistinguishable by 
their 3-dimensional structure and thus the discovery of selective Nav1.7 small molecule 
inhibitors has been extremely challenging. Since inhibition of Nav1.5 subtype elicits long QT 
cardiotoxicity, inhibition of Nav1.5 subtype should be avoided at therapeutic doses. 
To date, there are several Nav1.7 inhibitors claimed to be selective that have been evaluated 
in human subjects: 
• Vixotrigine (formerly known as raxatrigine) inhibits Nav1.7 as well as other VGSC 
subtypes. Vixotrigine is in phase III clinical development for trigeminal neuralgia. 
Due to the limited Nav1.7 selectivity over Nav1.5, vixotrigine was evaluated primarily 
in patients with a low heart risk. 
• Funapide is a Nav1.7 inhibitor with limited Nav1.7 selectivity, and was in phase IIb 
clinical trials as of July 2014. Although funapide showed analgesic activity in a small 
number of erythromelalgia patients, dose-limiting adverse events (AEs), including 
dizziness and somnolence, were observed2. The central nervous system (CNS) AEs 
were due to its poor Nav1.7 selectivity. 
• PF-05089771 is a Nav1.7 selective inhibitor with a claimed Nav1.7 selectivity of 
> 2000-fold versus other subtypes of sodium channel and was evaluated in patients of 
erythromelalgia or dental pain. It is thought low drug concentrations achieved in the 
target tissue could be a possible explanation for its poor analgesic activity in human 
patients3. 
OLP-1002 is fully complementary to a 14-mer RNA sequence spanning the junction of 
intron 4 and exon 5 in the human SCN9A pre-mRNA which codes for the Nav1.7 channel. 
OLP-1002 yields SCN9A mRNA splice variant(s) encoding variant Nav1.7 protein(s) lacking 
the sodium channel activity (ie, a non-functional channel), thereby inhibiting Nav1.7 channel 
function. 
1.2. 
Summary of Nonclinical Pharmacology 
1.2.1. 
In Vitro Pharmacology Studies 
Overall, results from the in vitro pharmacology studies showed OLP-1002 elicits responses 
consistent with its designed function4. It inhibits SCN9A mRNA expression and yields the 


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Nav1.7 variant protein or proteins lacking sodium channel activity. Its effects are highly 
selective, which may provide for an improved margin of safety compared to other Nav1.7 
inhibitors. 
OLP-1002 at 1 to 100 zM in PC3 prostate carcinoma cells induced exon skipping and yielded 
SCN9A mRNA splice variant(s) encoding a Nav1.7 variant protein or proteins lacking 
sodium channel activity.  
In rat dorsal root ganglion (DRG) neuronal cells, OLP-1002 at 1000 zM inhibited Nav1.7 
protein expression by > 50%, while OLP-1002R at 100 and 1000 zM inhibited Nav1.7 
expression almost completely. As OLP-1002R is fully complementary to rat SCN9A pre-
mRNA, OLP-1002R would be predicted to be more potent than OLP-1002 in this cell type. 
SCN9A mRNA expression level was evaluated by quantitative polymerase chain reaction 
(qPCR). OLP-1002 inhibited the expression of the SCN9A mRNA in PC3 cells with sub-
attomolar potency.  
In SH-SY5Y human neuroblastoma cells stimulated with tumor necrosis factor (TNF)-1α to 
upregulate the expression of SCN9A mRNA, OLP-1002 decreased expression by 46% to 
49% at 1 fM to 10 pM. In rat DRG neuronal cells, OLP-1002 at 1 fM significantly decreased 
SCN9A mRNA expression by 54%. 
In rat DRG neuronal cells, OLP-1002 markedly and significantly inhibited the sodium current 
by 77% at 0.1 aM and 73% at 1 aM, while for OLP-1002R, the inhibition was 66% at 0.1 aM 
and 70% at 1 aM. Given that rat DRG neuronal cells express various subtypes of sodium 
channel, the observed inhibitions of 66% to 77% correspond to the complete knockout of the 
Nav1.7 sodium channel subtype with OLP-1002 or OLP-1002R. 
The Nav1.7 selectivity over Nav1.5 was evaluated in H9C2 rat cardiomyocytes which are 
known to abundantly express the rat Nav1.5 sodium channel subtype. Following incubation 
with OLP-1002 or OLP-1002R at 1 aM or 1 pM, there were no notable decreases in the 
sodium current. Considering that OLP-1002 and OLP-1002R inhibit the expression of Nav1.7 
protein at 1 aM or lower in rat DRG neuronal cells, the Nav1.7 selectivity of OLP-1002 and 
OLP-1002R over Nav1.5 is estimated to be in excess of one million-fold. Such a large Nav1.7 
selectivity over Nav1.5 has not been realized with small molecule Nav1.7 inhibitors, 
suggesting that OLP-1002 potentially offers pain management with much greater 
cardiovascular safety. 
1.2.2. 
In Vivo Pharmacology Studies 
Spinal nerve ligation (SNL) has been widely applied as a rat model for neuropathic pain. 
OLP-1002 and OLP-1002R were found to be very potent, but highly variable in potency, in 
reversing neuropathic allodynia in this model. Analyses of the therapeutic potency strongly 
suggested that a marked proportion of subcutaneously (SC) administered OLP-1002 or OLP-
1002R may have been topically delivered directly to the spinal nerves exposed in the dorsal 
cavity created during the SNL modelling. In addition, the variability of the therapeutic 
potency may be due to a variable degree of healing of the SNL surgery wound. If an animal 


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recovers slowly, the animal tends to be left with a dorsal cavity. Therefore, estimations of 
potency in these studies with this model should be treated with caution. 
In one study using the SNL model, allodynia in rats was slowly and gradually reversed by 
OLP-1002 SC administered at nominal doses of 1, 3, and 6 pmol/kg once every 2 days (due 
to adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). As the onset time for pain reduction was 4 days, 
the doses used were not sufficient for fast onset of activity. In this study, the animals should 
have reasonably recovered from the dorsal wound, and therefore less susceptible to topical 
delivery directly to the exposed spinal nerves. However, in another study in this model, when 
OLP-1002 was intraperitoneally (IP) administered once every 3 days to avoid the likelihood 
of local delivery to the spinal nerves, OLP-1002 surprisingly reversed the allodynia at 
5 fmol/kg, and was superior or comparable to pregabalin 30 mg/kg, a gold standard for 
neuropathic pain studies. The high potency shown at 5 fmol/kg IP strongly suggests the 
possibility that OLP-1002 is efficiently absorbed by the enteric nervous system, travels to the 
spinal cord, and then redistributes to the spinal nerves of the SNL ligation. This opens the 
possibility of efficient oral delivery of OLP-1002 to the spinal cord. 
When evaluated for their ability to reverse the inflammatory pain in rats inflicted with 
Freund's Complete Adjuvant (FCA)-induced severe paw inflammation, OLP-1002 at 
300 pmol/kg and OLP-1002R at 100 pmol/kg significantly reversed the thermal hyperalgesia, 
and both were more effective than pregabalin 30 mg/kg. 
Paw burn injury induces hyperalgesia in rats and is known to upregulate Nav1.7 expression in 
the L5 and L6 DRGs of the affected side. Burn injury induces a far weaker degree of paw 
inflammation than FCA-induced paw inflammation. OLP-1002 SC administered inhibited the 
thermal hyperalgesia in paw burn injury in a dose-dependent manner. At 25 fmol/kg, OLP-
1002 did not inhibit thermal hyperalgesia. Although OLP-1002 at 625 fmol/kg significantly 
inhibited the thermal hyperalgesia, the efficacy was moderate and weaker than pregabalin 
30 mg/kg. This suggests that SC dosing does not offer the local topical delivery to spinal 
nerves in this model as seen in rats without a dorsal cavity wound. In this study, the Nav1.7 
expression in the DRG of the burn injury side significantly decreased by 58% with 
625 fmol/kg OLP-1002, validating the target engagement for analgesic activity. 
An intraplantar injection of formalin induces severe acute pain. The contributors to acute pain 
are known to be complex and require further elucidation. However, acute peripheral 
inflammation is known to contribute much to Phase II Pain (pain from 10 to 40 min after the 
formalin injection). In this model, OLP-1002 significantly inhibited Phase II Pain at 
comparable or saturated efficacy when SC administered at 10 to 100 pmol/kg (due to 
adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). Thus peripheral acute inflammatory pain could be 
treated with 10 pmol/kg or less. 
1.2.3. 
Ex Vivo Pharmacology Studies 
One day post-SC injection, OLP-1002 and OLP-1002R at 100 pmol/kg significantly inhibited 
the expression of Nav1.7 protein by 39% and 57%, respectively, in the spinal cord of rats 
subjected to SNL.  


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In other rats subjected to SNL, OLP-1002R slowly and gradually reversed the allodynia in a 
dose-dependent manner. OLP-1002R at 30 fmol/kg (the highest dose administered) had the 
greatest effect, but the dose was not high enough to elicit full therapeutic efficacy. 
OLP-1002R inhibited expression of Nav1.7 protein in these animals, most notably at 1 
fmol/kg, and decreased SCN9A mRNA expression by approximately 40% at 1 to 30 fmol/kg. 
The observed inhibitions were largely consistent with the in vivo therapeutic activity 
findings. 
Taking all the in vivo and ex vivo findings together, OLP-1002R was concluded to inhibit 
neuropathic allodynia by inhibiting the expression of the SCN9A mRNA and the Nav1.7 
protein. 
1.3. 
Summary of Safety Pharmacology 
In vitro, OLP-1002 did not inhibit the human ether-à-go-go-related gene (hERG) channel 
current expressed in human embryonic kidney (HEK) cells at the highest concentration tested 
2 μM (the limit of the validated analytical method for OLP-1002). 
In the in vivo safety pharmacology studies, OLP-1002 SC administered at dose levels up to 
100 nmol/kg had no effect on body temperature, neurological function, or respiratory 
function in rats, and had no significant toxic effect on cardiovascular function in cynomolgus 
monkeys. 
1.4. 
Summary of Toxicology 
In rats, following twice-weekly SC dosing for 13 weeks, OLP-1002-related microscopic 
findings included pigment accumulation in the kidney of males administered 
100 nmol/kg/dose and females administered ≥ 10 nmol/kg/dose, foreign material and 
vacuolated macrophage infiltrates in males and/or females administered ≥ 1 nmol/kg/dose, 
and an increased incidence and/or severity of mononuclear cell infiltrates at the injection sites 
in males and/or females administered ≥ 10 nmol/kg/dose. These findings persisted through 
the recovery phase in animals administered 100 nmol/kg/dose. However, the effects were 
considered non-adverse due to their mild severity and lack of impact on animal health and 
wellbeing. The no-observed-adverse-effect level (NOAEL) was 100 nmol/kg/dose. This dose 
level corresponded to maximum observed plasma concentration (Cmax) and area under the 
plasma concentration-time curve (AUC) from 0 to 24 hours postdose (AUC0-24) values of 
27.6 ng/mL and 174 ng·hr/mL, respectively, in males and 24.9 ng/mL and 128 ng·hr/mL, 
respectively, in females on Day 88 of the dosing phase. 
In cynomolgus monkeys, following twice-weekly SC dosing for 13 weeks, OLP-1002-related 
microscopic findings included mononuclear cell infiltrates at the SC injection sites of animals 
administered ≥ 10 nmol/kg/dose. This finding was not resolved with the completion of the 
recovery phase. However, the effects of 100 nmol/kg/dose were considered non-adverse due 
to the mild severity of findings and the lack of impact on animal health and wellbeing. The 
NOAEL was 100 nmol/kg/dose (equivalent to 462.29 µg/kg/dose), which corresponded to 
Cmax and AUC from 0 to 72 hours postdose (AUC0-72) values of 121 ng/mL and 
2840 ng·hr/mL in males, respectively, and 216 ng/mL and 4840 ng·hr/mL in females, 
respectively, on Day 88 of the dosing phase. 


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The genotoxic and mutagenic potential of OLP-1002 was evaluated with standard Good 
Laboratory Practice (GLP) via in vitro bacterial mutagenicity and chromosomal aberration 
studies, and was found to be negative. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
In rats, following a single SC dose of 14C-OLP-1002, the time of maximum observed 
concentration (Tmax) was 0.5 to 1 hour for both radioactivity and parent compound. Plasma 
concentrations of total radioactivity were quantifiable through the last sampling time of 72 
hours postdose, but was variable for the parent compound. The elimination half-life (t1/2) of 
total radioactivity from plasma was 23 hours. Total radioactivity distributed into tissues, 
including those of the CNS protected by the blood-brain barrier. 14C-OLP-1002-derived total 
radioactivity was not rapidly excreted from rats, with minimal amounts present in urine and 
feces. The bulk of the total radioactivity remained in carcasses, primarily in kidneys (cortex 
and medulla) and liver. Parent 14C-OLP-1002 was present in plasma and tissues, but 
concentrations declined over time and were substantially lower than total radioactivity 
concentrations at the later sampling times.  
After a single SC administration of 14C-OLP-1002 to rats, the highest concentrations of total 
radioactivity were retained predominantly in the liver (10.4% to 13.3% of the dose), kidney 
cortex (3.47% to 4.96%), and kidney medulla (1.10% to 1.59% of the dose) through 168 
hours postdose. For all other tissues, the total amounts of total radioactivity were 
substantially less, ranging from 0.0000203% in the 5th DRG to 0.327% in the spleen. 
Radioactivity was excreted slowly via both the renal and fecal routes of elimination. Total 
average recoveries of radioactivity in urine and feces through 336 hours postdose accounted 
for 2.31% and 1.75% of the administered radioactivity, respectively. The bulk of the 
administered total radioactivity was retained in the rat carcasses through 168, 336, 504, and 
840 hours postdose. The kidney cortex, kidney medulla, and liver were the 3 tissues that 
retained the greatest amounts of the administered radioactivity. 
Following a 16.1-µg/kg dose in rats, the plasma concentrations were still quantifiable at 
72 hours postdose and the rate of elimination was slow, with t1/2 17.5 hours. It was not 
possible to accurately define the elimination phase for the 2.67- and 5.28-µg/kg dose levels. 
In cynomolgus monkeys, following a single SC dose of 14C-OLP-1002, Tmax ranged from 
0.25 to 1 hour for both total radioactivity and parent compound. Concentrations of total 
radioactivity were sustained in blood and plasma through the last sampling time of 144 hours 
postdose. Concentrations of parent compound were sustained in plasma through the last 
sampling time of 144 hours postdose in 2 of 3 monkeys, and were similar to plasma total 
radioactivity concentrations at 8 hours postdose. From 24 to 144 hours postdose, plasma 
concentrations of total radioactivity were substantially higher than for parent 14C-OLP-1002 
plasma concentrations.  
The mean Cmax of parent 14C-OLP-1002 in plasma was 1.96 ng/mL. The mean plasma Tmax 
was 0.833 hours. Plasma exposure of parent 14C-OLP-1002 based on AUC extrapolated to 
infinity (AUC0-∞), was 12.7 ng·h/mL. After reaching Cmax, plasma concentrations of parent 
14C-OLP-1002 declined with a mean t1/2 of 84 hours. 


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1.6. 
Study Rationale 
This is the first time OLP-1002 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when OLP-1002 is administered SC as single 
and multiple doses to healthy subjects. This information, together with the pharmacodynamic 
(PD) and pharmacokinetic (PK) data, will help establish the doses and dosing regimen 
suitable for future studies in patients. The analgesic effects of OLP-1002 on a capsaicin-
induced pain model will also be investigated. 
1.7. 
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 investigational medicinal product 
(IMP), although there may also be some discomfort from collection of blood samples and 
other study procedures. For subjects in the PD assessment groups in Part A there will be 
some additional discomfort from the capsaicin test. More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with OLP-1002 may be 
found in the Investigator’s Brochure4. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is to assess the safety and tolerability of single and 
multiple SC doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the PD effect of OLP-1002 following 
single SC doses in healthy volunteers using a capsaicin pain model, and to monitor the effects 
of single SC doses of OLP-1002 on cardiac QT interval. Where possible, single and/or 
multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy subjects will be 
determined. 
2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of AEs 
• vital signs measurements (blood pressure, pulse rate, respiratory rate) 
• 12-lead electrocardiogram (ECG) parameters 
• incidence of clinical laboratory abnormalities, based on clinical chemistry, 
hematology, and urinalysis test results 
• physical examinations 
• injection site assessment. 


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• demonstrate that exposure to OLP-1002 does not exceed pre-defined exposure limits 
from non-clinical studies. 
2.2.2. 
Exploratory Endpoints 
The following exploratory objectives will be assessed:  
• pain intensity and duration will be assessed by AUC, maximum pain intensity (Emax), 
and time of maximum pain intensity (tEmax), calculated using a capsaicin-evoked pain 
model. The exploratory endpoint of secondary hyperalgesia will be assessed by the 
area of secondary area of hyperalgesia (Part A only). 
• continuous (24-hour) ECG monitoring will be recorded in this study and archived for 
potential future analysis of OLP-1002 effects on the QT interval (Part A). 
• heat pain threshold measurements and heat pain tolerance measurements. 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from time zero to 
infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable concentration 
(AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK: 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 


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Other PK parameters may also be added if deemed necessary. 
3. INVESTIGATIONAL PLAN 
This will be a double-blind, randomized, placebo-controlled, single and multiple SC dose 
study conducted in 2 parts. 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy subjects will 
be studied in 8 groups. Up to 3 additional groups (24 subjects in total) may be included for 
further assessment of safety, tolerability, PK, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Potential subjects for Groups A2, A4, and A6 will 
attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will return 
for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 2 days), and for a 
poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential visits 
may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 10 (216 hours postdose) from the lower dose levels. For doses 
≥ 12 µg, PK data will also be reviewed up to Day 7 prior to dose escalation. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 3 subjects will receive 
OLP-1002 and 1 subject will receive placebo. To assess PD parameters, Groups A2, A4, and 
A6 will consist of 8 subjects; 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo.  
Sentinel dosing will be employed for all groups in Part A. To maintain the blind in a 
4-subject group, the first subject will be dosed 48 hours before the second subject, and the 
second subject will be dosed 48 hours prior to the third and fourth subjects. In PD assessment 
groups, 2 subjects (1 active: 1 placebo) will be dosed 48 hours before the remaining 6 
subjects (5 active: 1 placebo). 
An overview of the study design is shown in Figure 1.


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Figure 1: 
Study Schematic (Part A) 
Group A1 
(30 ng SC)
3 active:
1 placebo
Group A2
(120 ng SC)
6 active:
2 placebo
Group A3
(400 ng SC)
3 active:
1 placebo
Group A4
(1.2 µg SC)
6 active:
2 placebo
Group A5
(3 µg SC)
3 active:
1 placebo
Group A6
(6 µg SC)
6 active:
2 placebo
Group A7
(12 µg SC)
3 active:
1 placebo
Group A8
(20 µg SC)
3 active:
1 placebo
Group A9
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A10
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A11
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
Groups A9 to A11 may be included if required; dose levels will not exceed the maximum proposed dose of 20 µg. 
Three groups consist of 8 subjects (6 active: 2 placebo); all other groups will consist of 4 subjects (3 active: 1 placebo).


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The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 8 weeks. 
3.1.2. 
Part B 
Part B will comprise a multiple-dose, sequential-group study. Overall, 24 subjects will be 
studied in 3 groups (Groups B1 to B3), with each group consisting of 8 subjects. Up to 
3 additional groups (24 subjects in total) may be included for further assessment of safety and 
tolerability (Section 3.3).  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (± 2 days), 22 (± 2 days), 25 
(± 2 days), and 29 (± 2 days), and for a poststudy visit on Day 57 (± 2 days). 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo. For all subjects, a single subcutaneous dose will be administered on Days 1, 4, 7, 10, 
and 13. Prior to each dosing occasion a physician will review the available safety and 
tolerability data from each subject to confirm it is acceptable to continue dosing. The dosing 
frequency in Part B may be changed following review of data from groups in Part A 
(Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to OLP-1002 at 
steady state is predicted to exceed exposures that have been shown to be safe and well 
tolerated in earlier groups in Parts A or B. In the event of sentinel dosing, 2 subjects (1 active, 
1 placebo) will be dosed at least 4 days prior to the remaining 6 subjects (5 active: 1 placebo). 
Safety data for the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 1 and 2 will be 
reviewed prior to the remaining subjects receiving dose 1). In addition, safety data from each 
subject will be reviewed by a physician prior to each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of safety, 
tolerability, and PK data up to Day 22 (216 hours post-final dose) from the lower dose levels. 
Part B may start after a review of the safety, tolerability, and available PK for Groups A1 to 
A6. The total daily dose administered will not exceed the highest single dose given in Part A. 
An overview of the study design is shown in Figure 2. 


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Figure 2: 
Study Schematic (Part B) 
Group B1
(TBC SC)
6 active:
2 placebo
Group B2 
(TBC SC)
6 active:
2 placebo
Group B3
(TBC SC)
6 active:
2 placebo
Group B4
(TBC SC)
6 active:
2 placebo
Group B5 
(TBC SC)
6 active:
2 placebo
Group B6
(TBC SC)
6 active:
2 placebo
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
All doses will be confirmed based on results of Part A; dose levels will not exceed the maximum proposed dose 
of 20 µg..  
Groups B4 to B6 will be included if required. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 12 weeks. 
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
 Start of Study and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, PK, and PD data (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]), 
additional dose groups may be added to the study. The maximum dose for any additional 
group will not exceed 20 µg. Up to 3 further groups of 8 subjects (6 active: 2 placebo) may 
be included in Part A, and up to 3 additional groups of 8 subjects (6 active: 2 placebo) may be 
included in Part B. The requirement for additional groups will be agreed with the Sponsor 
and documented in the Trial Master File (TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For both parts of the study, a sequential-group, ascending-dose design has been chosen for 
safety reasons as OLP-1002 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Subcutaneous doses have been 
chosen for both parts of the study, as this is the intended clinical route of administration. 
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, and PK data up 
to Day 7 will be reviewed for all groups receiving ≥ 12 µg OLP-1002. In Part B, safety, 
tolerability and PK data up to Day 22 will be reviewed for all dose groups. As the t1/2 of 
OLP-1002 is predicted to be approximately 180 hours (based on non-clinical data) review of 


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safety data up to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma exposures are 
anticipated to be low, it is expected that it will only be possible to perform an assessment of 
peak concentrations (Cmax) and therefore PK data to Day 7 (Part A) and Day 22 (Part B) will 
be sufficient. Additionally, a cumulative safety review will occur such that additional 
emerging safety data from earlier groups will be considered when making a dose escalation 
decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of females 
of childbearing potential is in accordance with International Council for Harmonisation (ICH) 
M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be sufficient in 
order to determine safety and tolerability. In order to assess the PD effects of OLP-1002, 
3 groups in Part A will include 8 subjects (6 active; 2 placebo). A full review of the safety 
and tolerability data from Part A will be performed to determine the dose regimen for Part B. 
Part B may start after a full review of all safety and tolerability data from Group A1 to A6. A 
review of PD data may also be performed, at the discretion of the Investigator. Details of the 
dosing regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 57-day 
follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups receiving 
≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring 
in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. Dose escalation decisions for doses <12 µg in Part A will not require PK data. 
The rationale for this is that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical species has a 
lower limit of quantification (LLOQ) of 5 ng/mL. The increased sample volume possible 
from humans (compared to small animals) may afford an approximate 10-fold increase in 
sensitivity with possibly an additional 5-fold increase from the use of a more sensitive mass 
spectrometer. This could potentially deliver an LLOQ of around 0.1 ng/mL. Therefore, even 
with the increased assay sensitivity plasma levels from doses at or below 12 µg are not 
expected to be quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose would be 
quantifiable and that a conventional approach to pharmacokinetic will not achieve a full 
definition of the plasma concentration vs time profile or enable an estimation of the terminal 
phase. In addition the planned dose levels have a high safety margin when comparing the 
predicted exposures to the exposures at the NOAEL (see Section 3.5.2), with the 12 µg dose 
level having an expected 312-fold and 255-fold safety margin based on Cmax and AUC0-∞, 
respectively. Therefore, if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
 
 


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This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
Continuous ECG monitoring will be recorded in this study and archived for potential future 
analysis of OLP-1002 effects on the QT interval, with a view of supporting a potential 
thorough QT study waiver. 
3.4.1. 
Dose Interval 
Following thorough review of all available nonclinical data (pharmacological and 
toxicological), dosing in Part A for groups consisting of 4 subjects will be such that there will 
be 48 hours between the first and second subjects, and 48 hours between the second and 
remaining 2 subjects in each group. For groups in Part A consisting of 8 subjects, 2 subjects 
(1 active: 1 placebo) will be dosed 48 hours prior to the remaining 6 subjects.  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 at steady state 
is predicted to exceed exposures that have been shown to be safe and well tolerated in earlier 
groups in Parts A or B. When used, two subjects (1 active; 1 placebo), will be dosed 4 days 
prior to the remaining 6 subjects (5 active; 2 placebo). The 2 sentinel subjects will always be 
2 doses ahead of the remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not predicted to 
exceed that tested in Part A will be dosed on the same day. Accumulation of OLP-1002 is 
expected following multiple doses, based on the preclinical data, and will be taken into 
account when determining the doses for Part B (see Section 3.5.3). If it is not possible to 
quantify exposure it will be assumed that multiple dosing results in a 4-fold accumulation 
based on the predicted t1/2 of 180h.  
In Parts A and B, there will be a minimum interval of a 10-minute gap between dosing 
subjects (when dosed on the same day). Continuation to dose the remaining subjects in a 
group will be at the Investigator’s discretion. 
3.4.2. 
Pharmacodynamic Assessment 
Pharmacodynamic assessments will be conducted for subjects in Groups A2, A4, and A6. 
Human experimental pain models using healthy volunteers can be used to assess the effect of 
a drug or treatment under controlled clinical conditions. Capsaicin is a vanilloid responsible 
for the pungent taste of hot peppers. In mammalian species, capsaicin-induced pain is 
mediated through Group C nerve fibers following activation of vanilloid 1 transient receptor 
potential (TRPV1) channels5. Nav1.7 has been implicated in controlling neuropeptide release 
from C-fibers, and suppression of capsaicin-induced neurogenic flair has been demonstrated 
by an NAv1.7 inhibitor6. 


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Several studies have used intradermal capsaicin for human experimental pain studies7,8. It has 
been possible to demonstrate dose-dependent responses, with intradermal injections of 
100 μg generally agreed to be the ideal dosage for these studies. Intradermal injection of 
capsaicin causes a brief stinging/burning pain at the injection site (spontaneous pain) 
followed by development of secondary hyperalgesia, which can be assessed using equipment 
such as Von Frey hairs. A study by Gazerani et al.5 found that the response was site-specific 
and while peak pain intensity and duration were greatest in the forehead it was found that 
areas of visible flare and secondary hyperalgesia were significantly larger in the forearm, 
making the forearm the most suitable site for experimentation. 
Covance CRU, Leeds, UK in 2009 performed a validation study using intradermal capsaicin 
(Covance CRU Study: 9999-004) with between-subject and within-subject variability 
demonstrating that the assessments can be reliably conducted to assess pharmacological 
response. 
For these reasons, it has been decided to: 
• Measure both capsaicin-evoked pain and secondary hyperalgesia. 
• Limit the number of capsaicin tests to 3 for each subject (pre-screening, baseline, and 
48 hours postdose) 
• Exclude subjects who have pain <3 or >9 (using a Visual Analogic Scale [VAS]) at 
the pre-screening visit from PD assessment groups. 
3.5. 
Selection of Doses in the Study 
3.5.1. 
Starting Dose 
The rat has been identified as the most sensitive species in a 13-week SC toxicity study with 
a 4-week recovery phase (Covance study no. 8355564). The NOAEL was the 
100 nmol/kg/dose (462.29 µg/kg/dose). This dose level resulted in Cmax of 27.6 ng/mL and 
24.9 ng/mL in males and females, respectively, and AUC0-24 of 174 ng.h/mL and 
128 ng.h/mL in males and females, respectively4. As the exposure was lower in the female 
rats these data have been used to calculate the safety margins. 
The dose of 462.29 µg/kg/dose corresponds to human equivalent doses (HEDs) of 
74.8 µg/kg/dose, which gives a maximum recommended starting dose (MRSD) of 444 µg for 
a 60-kg human and thus a 15000-fold safety margin to the proposed starting dose of 30 ng 
and 22-fold margin to the proposed maximum dose of 20 µg. Additionally the NOAEL dose 
in the cynomolgus monkey was identified as 100 nmol/kg/dose (462.29 µg/kg/dose), which 
gives a higher HED of 150 µg/kg/dose. 
In vivo, doses of 10 pmol/kg/dose (0.0462µg/kg/dose) or less were found to inhibit peripheral 
acute inflammatory pain. The equivalent human dose for a 60-kg human is 44 ng, thus a dose 
at which minimal biological effect is anticipated has been selected as the starting dose of 
30 ng. 


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3.5.2. 
Exposure 
Human exposures have been estimated from the pharmacokinetics in the cynomolgus 
monkey since a non-human primate represents the most closely related species. 
Approximately dose-proportional exposure was seen in the 13-week toxicity study (Covance 
study no. 8355565) and 14C pharmacokinetic study (Covance study no. 8355568) over a dose 
range of approximately 1.1 to 100 nmol/kg (5.06 to 462.29 µg/kg)4. However, the lowest 
dose (5.06 µg/kg) from the 14C study has been used to estimate the human exposures as it is 
closest to the proposed human dose range and has the sufficient quantifiable data. 
The assumptions made in the human exposure estimation were that human exposure would 
be similar to the cynomolgus monkey and that exposure would be linear with dose. Following 
a dose of 5.06 µg/kg in the cynomolgus monkey, the Cmax was 1.96 ng/mL and AUC0-∞ was 
12.7 ng.h/mL. The extrapolated exposures at the planned human doses are shown in Table 1 
with margins calculated to the exposures at the NOAEL in the female rat. 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 
Human dose 
Single dose to human 
Safety margins for single dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax 
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin  
to Cmax 
Margin  
to AUC0-∞ 
0.03 
0.000500 
0.000194 
0.00125 
129000 
102000 
0.12 
0.00200 
0.000775 
0.00502 
32100 
25500 
0.4 
0.00667 
0.00258 
0.0167 
9640 
7650 
1.2 
0.0200 
0.0077 
0.0502 
3210 
2550 
3 
0.0500 
0.0194 
0.125 
1290 
1020 
6 
0.100 
0.0387 
0.251 
643 
510 
12 
0.200 
0.0775 
0.502 
321 
255 
20 
0.333 
0.129 
0.837 
193 
153 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
The dosing interval currently anticipated for the multiple-ascending-dose part of this study is 
72 hours or 96 hours. Thus the average dosing interval (82 hours) is similar to the half-life 
determined in the monkey 14C study of 84 hours. Dosing at approximately once per half-life 
would be anticipated to result in accumulation of around 2-fold. However, higher levels of 
accumulation were observed (2.28-fold for Cmax and 3.76-fold for AUC0-24) on Day 88 at the 
top dose group (100 nmol/kg, 462.28 µg/kg) in the 13-week cynomologus monkey toxicity 
study following twice-weekly dosing (every 72 or 96 hours). Calculations were performed to 
estimate the likely human half-life using a standard 1-point allometric approach from the 14C 
cynomolgus monkey pharmacokinetic study data. The exponents used were 0.75 for apparent 
total plasma clearance (CL/F) and 1 for apparent volume of distribution (Vz/F) values 
combined with the average body weight of the animal (3.1 kg) and scaling to a 60 kg human 
9–11. This resulted in a human half-life estimate of 180 h which in turn gave an accumulation 
estimate of 3.7-fold based upon a dosing interval of 82 h. This further supports the use of the 
greater than 2-fold accumulation from the 13-week cynomolgus study to estimate exposure 
following multiple dosing. Multiplication of the exposure estimates for the single ascending 


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dose by 2.28 for Cmax and 3.76 for AUC resulted in exposure estimates for multiple 
dosing presented in Table 2. 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 
Human dose 
Multiple dose to human 
Safety margins for multiple dose 
(µg) 
(µg/kg) 
Predicted 
Cmax  
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin 
to Cmax 
Margin 
to AUC0-τ,ss 
0.03 
0.000500 
0.000442 
0.00472 
56000 
27000 
0.12 
0.00200 
0.00177 
0.0189 
14100 
6800 
0.4 
0.00667 
0.00589 
0.0629 
4230 
2030 
1.2 
0.0200 
0.017663 
0.189 
1410 
680 
3 
0.0500 
0.0442 
0.472 
560 
270 
6 
0.100 
0.0883 
0.944 
282 
136 
12 
0.200 
0.177 
1.89 
141 
68 
20 
0.333 
0.294 
3.15 
85 
41 
30 
0.500 
0.442 
4.72 
56 
27 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
3.5.3. 
Proposed Doses 
The proposed IMP dose levels for Parts A and B are shown in Table 3. 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
Study Part 
Group 
Dose (OLP-1002) 
Part A 
A1 
30 ng or placebo 
A2 
120 ng or placebo 
A3 
400 ng or placebo 
A4 
1.2 µg or placebo 
A5 
3 µg or placebo 
A6 
6 µg or placebo 
A7 
12 µg or placebo 
A8 
20 µg or placebo 
A9* 
TBC or placebo 
A10* 
TBC or placebo 
A11* 
TBC or placebo 
Part B 
B1 
TBC or placebo 
B2 
TBC or placebo 
B3 
TBC or placebo 
B4* 
TBC or placebo 
B5* 
TBC or placebo 
B6* 
TBC or placebo 
Abbreviations: TBC = to be confirmed 
* groups to be included if required.


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In Parts A and B, there should not be an increase of > 3-fold between dose levels above 
120 ng. 
For Part B, dose levels, dosing frequency, and dosing duration will be decided, in 
consultation with the Sponsor, on the basis of data from Part A of the study. Since predictions 
of human exposure of OLP-1002 suggest that OLP-1002 concentrations may be not be 
quantifiable and human data have been estimated from a single species, it is proposed that the 
highest dose in the multiple-ascending-dose part will be up to 50% of the highest dose in the 
single-ascending-dose part (ie, if the highest dose in the single-ascending-dose part is 20 µg, 
the highest dose in the multiple-ascending-dose part will be 10 µg). Therefore, if the 
predicted accumulation of 3.7-fold occurs, the highest exposure in the multiple-ascending-
dose part will not exceed ~2-fold the maximum exposure in the single-ascending-dose part. 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose administered will 
not exceed 20 µg and predicted systemic exposure will not exceed that stated in the dose 
escalation stopping criteria [Section 3.7]) based on available PK data. 
Details of all doses administered in Parts A and B of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
In Part A, doses will be administered in an escalating manner following satisfactory review 
by the Sponsor and Investigator of the safety, and tolerability data up to Day 10 (216 hours 
postdose) from groups that received lower doses of OLP-1002. For escalation to doses 
> 12 µg, PK data up to Day 7 (144 hours postdose) will also be reviewed. All available 
safety, tolerability, and PK data from previous groups will be reviewed prior to dose 
escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and may be lower than the starting 
dose. Available safety, tolerability, and PK data from all previous groups will be reviewed 
prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups A1, 
A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have been reviewed from the 
previous lower dose group, such that data from a minimum of 3 or 4 subjects, respectively, 
who have received OLP-1002 will be used to make the dose-escalation decision. Dose 
escalation in Part B will only occur if data from a minimum of 6 subjects have been reviewed 
from the previous lower dose group, such that data from a minimum of 4 subjects who have 
received OLP-1002 will be used to make the dose-escalation decision. 
The justification for this is as follows: 
•
The study drug is of a known pharmacological class for which the on-target effects in
humans are well characterized. Based upon nonclinical data, no clinically important
off-target effects are expected within the proposed dose range.


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• A minimum of 3 subjects receiving the active drug is considered sufficient to 
characterize the safety profile for OLP-1002. 
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarizing 
results from all available safety assessments, will be sent to the Sponsor and a dose-escalation 
meeting will occur prior to the start of each successive group. Any clinically significant 
results will be discussed with the Sponsor before dose escalation continues. Interim PD data 
may also be reviewed on an ongoing basis. In the event of a disagreement between Sponsor 
and Investigator on the dose-escalation decision, the decision of the Investigator will be 
upheld. 
3.7. 
Dose Escalation Stopping Criteria 
In Parts A and B, following consultation with the Sponsor, dose escalation will be stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in 
a group that, in the opinion of the Investigator, warrant stopping of dose escalation. 
• One or more subjects experience an SAE that is considered to be related to OLP-1002. 
• Two or more subjects in the same group experience severe non-serious AEs (ie. 
severe non-serious AEs considered as, at least, possibly related to OLP-1002 
administration), independent of whether the AEs are within or not within the same 
system organ class.  
• There is evidence of clinically significant increases in aspartate aminotransferase, 
alanine aminotransferase or alkaline phosphatase (defined as 3 times the upper limit 
of normal), or total bilirubin (defined as 2 times the upper limit of normal) that are 
considered to be related to OLP-1002 in 2 or more subjects in a group. Results will be 
confirmed with repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose for 
Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat measurement) 
in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 110 mmHg) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• The dose will not exceed 20 µg or the systemic exposure for any individual subject is 
predicted to exceed a Cmax of 24.9 ng/mL (plasma) and/or an AUC0-24 of 128 ng/mL; 
i.e., systemic exposure will be no greater than the NOAEL in the most sensitive 
species (100,000 pmol/kg in rat [462 µg/kg]). 


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If the sponsor deems it appropriate to resume dosing after the internal safety review, it 
can be done after the approval of a substantial protocol amendment. 
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. Healthy male or females of any race, between 18 and 60 years of age, inclusive. 
2. Body mass index (BMI) between 18.0 and 28.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, single 12-lead ECG (resting heart rate > 45 bpm and 
< 90 bpm), vital signs measurements, and clinical laboratory evaluations (congenital 
nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome based on total 
and direct bilirubin] is not acceptable) at Screening as assessed by the Investigator (or 
designee).  
4. Willing to abide by the contraception requirements 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: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. Any of the following: 
• QTcF > 450 ms confirmed by repeat measurement. 
• QRS duration > 110 ms confirmed by repeat measurement. 
• PR interval > 220 ms confirmed by repeat measurement. 
• findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
• history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalemia, family history of long QT syndrome). 
4. Female subjects who are pregnant or breastfeeding. 
5. History of alcoholism or drug/chemical abuse within 1 year prior to Screening. 


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6. Alcohol consumption of > 21 units per week for males and >14 units per week for 
females. 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. 
7. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
8. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
9. Active skin conditions such as dermatitis, allergy, eczema, psoriasis, or abnormal 
healing. 
10. Tattoos, scars, or moles that in the opinion of the Investigator are likely to interfere 
with dosing or study assessments at any of the potential injection sites. 
11. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days or 5 half-lives of the investigational product, 
whichever is longer, prior to Check-in. 
12. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 
13. Use or intend to use any prescription medications/products other than hormone-
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptive concomitant medications within 14 days prior to Check-in, unless 
deemed acceptable by the Investigator (or designee). 
14. 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). 
15. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee) and/or 
Sponsor have given their prior consent. 
16. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.  
17. Receipt of blood products within 60 days prior to Check-in. 
18. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening.  
19. Poor peripheral venous access. 
20. Have previously completed or withdrawn from this study or any other study 
investigating OLP-1002, and have previously received the investigational product. 
21. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
22. Part A – PD assessment groups only 
• Subjects considered non-acceptable responders to the intradermal capsaicin 
test at screening, defined as maximum VAS score of < 3.0 or > 9.0. 


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4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomization. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, in Part A, Subjects 101, 102, 
etc., in Part B Subjects 201, 202, etc.). Replacement subjects (Section 4.4) will be assigned a 
subject number corresponding to the number of the subject he/she is replacing plus 1000 
(eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least possibly related to 
OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE considered to 
at least possibly related to OLP-1002 administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements). 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the 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 stabilized. 


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Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• 
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) 
• 
medical or ethical reasons affecting the continued performance of the study 
• 
difficulties in the recruitment of subjects 
• 
cancelation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Vials of OLP-1002 Injection Solution 100 µg/mL (1.5 mL in 5-mL vials) and the Diluent for 
OLP-1002 Injection Solution (5 mL in 10-mL vials) will be supplied by the Sponsor, along 
with the batch/lot number and Certificate of Analysis. The Diluent for OLP-1002 Injection 
Solution will also be used as the Placebo formulation. A certificate of batch certification and 
release, authorized by a Qualified Person in the European Union (EU) will also be issued, by 
a Covance CRU Qualified Person, for each batch of IMP imported into the EU. 
The IMPs will be stored according to the instructions on the label at the CRU in a location 
that is locked with restricted access. 
Dose solutions (OLP-1002 Injection Solution diluted with the Diluent for OLP-1002 
Injection Solution) will be prepared by Covance CRU Pharmacy staff in accordance with 
instructions provided in the Pharmacy Manual. The Placebo formulation will be the Diluent 
for OLP-1002 Injection Solution without further manipulation. 
5.2. 
Study Treatment Administration 
Subjects will be administered the IMP in numerical order. OLP-1002 will be administered by 
SC injection in the upper arm. If subcutaneous dosing of OLP-1002 in the upper arm is not 
possible, the subject may be dosed in the abdomen at the Investigator’s discretion. For 
subjects in Groups A2, A4, and A6, dosing will be on the opposite arm to the intradermal 
capsaicin test. 
5.3. 
Randomization 
The randomization code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. In Part A, 1 subject in groups 


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consisting of 4 subjects, and 2 subjects in groups consisting of 8 subjects, will be randomly 
assigned to receive placebo. In Part B, 2 subjects per group will be randomly assigned to 
receive placebo. All other subjects in a group will be randomized to receive OLP-1002. 
Prior to the start of the study, a copy of the master randomization code will be supplied into 
the Covance CRU pharmacy staff (in sealed envelopes). 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo solution will be identical in appearance to the OLP-1002. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 
To maintain the blind, the Investigator will be provided with sealed randomization 
code-break envelopes for each subject, containing details of their treatment. These individual 
sealed envelopes will be kept in a limited access area that is accessible 24 hours a day. In 
order to manage subject safety or to support dose-escalation decisions (in the event of 
possibly treatment-related SAEs or severe AEs), the decision to unblind resides solely with 
the Investigator. Whenever possible, and providing it does not interfere with or delay any 
decision in the best interest of the subject, the Investigator will discuss the intended code-
break with the Sponsor. If it becomes necessary to break the code during the study, the date, 
time, and reason will be recorded in the subject’s source data and on the individual envelope 
and will be witnessed by a second person. 
5.5. 
Treatment Compliance 
All doses of IMP will be administered by suitably qualified study site staff. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription medications/products from 14 days prior to 
dosing until the Follow-up visit, and non-prescription medications/products from 7 days prior 
to dosing until the Follow-up visit, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone-replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary 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 standardized 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 safety laboratory tests. On dosing days, 
subjects will receive a light breakfast approximately 2 hours prior to dosing. Meals will be 
provided as appropriate at other times and water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Check-in until the Follow-up visit. 
Xanthine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until Discharge from the site. Xanthine-containing foods and beverages will also not be 
allowed form 36 hours before non-residential site visits. 
Chili pepper/hot sauce will not be allowed for 48 hours prior to Check-in for all subjects. 
Subjects in Groups A2, A4, and A6 will not be allowed chili pepper/hot sauce for 48 hours 
prior to their pre-screening visit. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until 
Discharge. Following discharge, up to 2 units/day of alcohol are permitted until 36 hours 
before each non-residential visit and 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 3 days before Check-in until the 
Follow-up visit and will otherwise maintain their normal level of physical activity during this 


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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. Subjects should not be in receipt of blood products for 
60 days prior to check-in. 
6.6. 
Other Restrictions 
Subjects in Groups A2, A4, and A6 will not be allowed to shower within 1 hour prior to the 
capsaicin-evoked pain tests at prescreening, predose, and postdose. 
Subjects will not be allowed to apply moisturizing creams or oils to the dosing site within 
1 hour prior to dosing, or to the assessment site within 1 hour prior to the capsaicin-evoked 
pain test.  
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): 
•
dosing
•
vital signs
•
blood samples
•
cardiac monitoring/ECG extractions
•
any other procedures.
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments (Appendix 6). Furthermore, additional blood samples may be taken 
from each subject per treatment period, with the maximum volume of blood withdrawn per 
subject not exceeding the limit detailed in Appendix 3. Any changes to the scheduled times of 
PK assessments will be agreed with the Sponsor and documented in the TMF. Samples taken 
from subjects who received placebo will not be analyzed. 
In Part A, PK analysis will initially only be conducted for groups receiving ≥ 12 µg 
OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the 


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event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 
7.2. 
Pharmacodynamic Assessments 
Capsaicin intradermal test will be performed for subjects in Groups A2, A4, and A6. Each 
subject will be tested at a pre-screening visit before being tested twice during the study (1 
predose and 1 postdose). 
7.2.1. 
Capsaicin-evoked Pain Model 
The capsaicin model will be conducted by intradermal injection of capsaicin (100 μg in 
100 μL of sterile saline containing 8% [w/w] Tween 80) into the skin of the anterior aspect of 
the forearm, midway between the elbow and the wrist. The bleb area (wheal) will be a sign of 
local plasma extravasation. An assessment of the pain intensity related to capsaicin injection 
will be estimated by repeated use of a VAS from injection to 5 minutes post-injection or until 
the pain intensity returned to zero. The AUC, Emax, and tEmax will be calculated and reported 
using dedicated software. 
7.2.2. 
Secondary Hyperalgesia 
The area of secondary hyperalgesia will be quantified with a 60-g weighted von Frey hair, by 
stimulating along 8 linear paths (4 vectors crossing at the location of the injection site) 
arranged vertically and horizontally around the stimulation site in 5-mm steps (starting 
approximately 6 cm away from the injection site). The area of secondary hyperalgesia will be 
evaluated at 5 and 30 minutes post-capsaicin injection. 
7.3. 
Safety and Tolerability Assessments 
Safety and tolerability assessments will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). Timepoints may be adjusted based on an ongoing review of the 
data, and additional assessments may be conducted if deemed necessary by the Investigator 
or designee. 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs 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 


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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. 
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 drug. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a follicle-stimulating hormone (FSH) test and 
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. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and 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. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. 
Subjects must be supine for at least 5 minutes before blood pressure, pulse rate, and 
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7.3.4. 
Electrocardiogram 
7.3.4.1. 
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: 
• QTcF value > 500 msec 
• QTcF change from the mean baseline (Day 1 predose) is > 60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.3.4.2. 
Continuous (24-hour) Electrocardiogram 
At the times indicated in the Schedule of Assessments (Appendix 6), continuous (24-hour) 
ECGs will be performed.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint. Each extraction will last for 5 minutes. 
Environmental distractions (eg, television, playing games, radio, conversation) should be 
avoided during the pre-ECG time window.  
Continuous 24-hour ECGs are not planned for Part B of the study but may be implemented if 
any clinically significant findings are identified in the data from Part A. 
7.3.5. 
Heat Pain Threshold Test 
Heat pain threshold tests will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). 
A computer-controlled thermal sensory analyzer device will be used to measure the heat pain 
threshold and tolerance level of the subjects. The heat pain assessments will be conducted on 
the subject’s thigh. 
Heat Pain Threshold: 
For heat pain threshold measurements, the thermode will be placed directly on the skin of the 
right thigh, within an area selected before the start of the experiment and defined by surgical 
marking. The thermode will have a baseline temperature of 32 °C, and will be programmed to 
gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 


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their dominant hand, to indicate when the heat pain threshold (first sensation of heat pain) is 
reached by pushing a button. At that time, the test will be stopped and the temperature 
returned to baseline within 1 second. This process will be repeated a further 2 times, with an 
interval of at least 1 minute between measurements (from start to start). The computer will 
record the average value of 3 experiments. 
Heat Pain Tolerance: 
For heat pain tolerance measurements, the thermode will be placed within the same surgically 
marked skin area of the anterior side of the right thigh, which was used to assess heat pain 
threshold. The thermode will have a baseline temperature of 32 °C, and will be programmed 
to gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 
their dominant hand, to indicate when the heat-evoked pain has reached an intensity that is no 
longer tolerable, by pushing a button. At that time, the test will be stopped and the 
temperature returned to baseline within 1 second. This process will be repeated a further 
2 times, with an interval of at least 1 minute between measurements (from start to start). The 
computer will record the average value of 3 experiments. 
Safety Precautions 
As there is a risk that OLP-1002 may affect the heat pain threshold, Covance CRU will put 
appropriate safety measures in place to ensure that subjects are not exposed to extremes of 
temperature when taking a shower or consuming hot drinks. During the heat pain safety 
assessments, the cut-off temperature for either test is 53 °C in order to prevent skin injury. 
7.3.6. 
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.  
7.3.7. 
Body Weight and Height 
Body weight (in underclothes) and height will be recorded at the times indicated in the 
Schedule of Assessments in Appendix 6. BMI will be calculated using the following formula: 
BMI = body weight (kg)      (kg/m2) 
(height [m])2
7.3.8. 
Injection Site Assessments 
Injection site assessments will be made at the times indicated in the Study Plan (Appendix 6). 
Assessments will involve evaluation of the dosing site for the following criteria:  
• Pain will be evaluated according to the following scale:


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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Does not 
interfere with 
activity 
Interferes with 
activity or 
repeated use of 
non-narcotic 
pain reliever 
Prevents daily 
activity or 
repeated use of 
narcotic pain 
reliever 
Requires 
medical 
intervention 
greater than 
analgesia  
 
• Redness will be assessed by estimating the size of the red patch at the injection site across 
its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm 
51-100 mm 
More than 100 
mm 
Requires 
medical 
intervention 
greater than 
analgesia  
• Swelling will be assessed by estimating the size of the raised area around the injection site 
across its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm and 
does not 
interfere with 
activity 
51-100 mm or 
interferes with 
activity 
More than 100 
mm and 
prevents daily 
activity 
Requires 
medical 
intervention 
greater than 
analgesia 
In addition, how the swelling affects the subject in their daily routing activities will be 
considered. 
• Tenderness will be evaluated using the following scale: 


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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Mild pain to 
touch 
Moderate Pain 
to touch 
Severe pain to 
touch 
Requires 
medical 
intervention 
greater than 
analgesia 
• Bruising and ulceration will be evaluated as being present or absent. 
Local tolerability ratings of ≥Grade 3 and the presence of ulceration will be recorded as an 
adverse event.  
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time OLP-1002 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. In order to achieve PD endpoints 
in Part A, additional subjects will be included in 3 groups (8 subjects in total; 6 active: 
2 placebo). Up to 3 additional groups may be added to Part A, consisting of either 4 subjects 
(3 active; 1 placebo) or 8 subjects (6 active; 2 placebo). Up to 3 additional groups of 
8 subjects may be added to Part B (6 active; 2 placebo). 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of OLP-1002 that 
have evaluable PK data and have had no AEs or protocol deviations considered to impact PK. 
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo and for whom PD can be evaluated. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo. 
8.3. 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma concentration data, 
using commercial software such as Phoenix® WinNonlin®. Plasma concentrations of 


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OLP-1002 and PK parameters will be listed and summarized using descriptive statistics. 
Individual and arithmetic mean OLP-1002 concentration-time profiles will also be presented 
graphically. 
8.4. 
Pharmacodynamic Analyses 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No 
formal statistical analysis of PD data is planned. 
8.5. 
Safety Analysis 
Safety parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 
9. REFERENCES 
1.  Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A 
channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 
14;444(7121):894–8.  
2.  Goldberg YP, Price N, Namdari R, Cohen CJ, Lamers MH, Winters C, et al. Treatment of 
Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel 
blocker. Pain. 2012 Jan;153(1):80–5.  
3.  Jones HM, Butt RP, Webster RW, Gurrell I, Dzygiel P, Flanagan N, et al. Clinical Micro-
Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of 
Human Nav1.7 Voltage-Dependent Sodium Channels. Clin Pharmacokinet. 
2016;55(7):875–87.  
4.  Investigator Brochure - OLP-1002. 2018.  
5.  Gazerani P, Andersen OK, Arendt-Nielsen L. Site-specific, dose-dependent, and sex-
related responses to the experimental pain model induced by intradermal injection of 
capsaicin to the foreheads and forearms of healthy humans. J Orofac Pain. 
2007;21(4):289–302.  
6.  Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, et al. 
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in 
Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE 
[Internet]. 2016 Apr 6 [cited 2018 Jun 15];11(4). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822888/ 
7.  Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-
dependent pain, allodynia, and hyperalgesia in humans. J Investig Med Off Publ Am Fed 
Clin Res. 2006 Jul;54(5):238–44.  


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8.  Anderson WS, Sheth RN, Bencherif B, Frost JJ, Campbell JN. Naloxone increases pain 
induced by topical capsaicin in healthy human volunteers. Pain. 2002 Sep;99(1–2):207–
16.  
9.  Pharmacokinetics and Metabolism in Drug Design, 3rd Edition [Internet]. Wiley.com. 
[cited 2018 Aug 21]. Available from: https://www.wiley.com/en-
us/Pharmacokinetics+and+Metabolism+in+Drug+Design%2C+3rd+Edition-p-
9783527329540 
10.  Mahmood I. Pharmacokinetic allometric scaling of antibodies: application to the first-in-
human dose estimation. J Pharm Sci. 2009 Oct;98(10):3850–61.  
11.  Offman E, Edginton AN. Pharmacokinetic Time Course Scaling of a Subcutaneously 
Administered Pegylated Peptide Conjugate for a First-in-Human Investigation. Eur J 
Drug Metab Pharmacokinet. 2017 Feb;42(1):69–78.  
 
 


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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 unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but posing no 
significant or permanent risk of harm to the subject. 
• 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 drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
• 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. 
• 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. 
• Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized 
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 
stabilized. 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: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize 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 Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization 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 
Covance Drug Safety Services (DSS) Europe, Maidenhead, UK are 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 facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the Safety 
Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of the 
SAE within 2 working days of the initial notification to DSS. Drug Safety Services 
will delete any information from the SAE report forms that may identify the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined in 
the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions 
and forward to the Ethics Committee, Medicines and Healthcare Products Regulatory 
Agency, Principal 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. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfill regulatory requirements any pregnancy reported by female subjects or 


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the female partners of male subjects should be reported following the SAE process to collect 
data on the outcome for both mother and fetus. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Urea 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
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  
Serologya: 
Drug screenb: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
MDMA 
Alcohol breath test 
Follicle-stimulating hormonea  
Serum pregnancy test (human 
chorionic gonadotropin)a 
Urine pregnancy testc 
a Only analyzed at Screening. 
b Only analyzed at Screening and Check-in. 
c A positive urine pregnancy test will be confirmed with a serum pregnancy test. 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 51 of 82 
Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
Part A 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
6 
45 
Serology 
3.5 
1 
3.5 
Total: 
124.5  
Part B 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
194.5  
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
during the study will not exceed that donated during a standard blood donation 
(approximately 500 mL). 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 52 of 82 
Appendix 4: Contraception Guidance 
Definitions 
Females of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Females of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 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-estrogens, or selective estrogen 
receptor modulators.  
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. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary and 1 secondary method) of birth control from the time of signing the informed 
consent form until 90 days after the Follow-up visit. Primary (non-barrier) methods of 
contraception include:  
• hormone injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 53 of 82 
• hormonal or non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject). 
Secondary (barrier) methods of contraception include:  
• male condom with spermicide 
• female condom with spermicide  
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects can only choose a cervical cap or diaphragm if they have already had a 
prescription and fitting by their healthcare provider to ensure protocol requirements are met. 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in until 90 days after the Follow-up 
visit. Acceptable methods of contraception include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide 
• vasectomised male subject (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success). 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 54 of 82 
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. 
Sexual Abstinence and Same-sex Relationships 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 55 of 82 
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: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with Clinical Research Unit personnel, subjects will sign 
2 copies of the ICF in the presence of a suitably trained member of staff to indicate that they 
are freely giving their informed consent. One copy will be given to the subject, and the other 
will be maintained in the subject’s records. 
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 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 56 of 82 
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 Organization (CRO) auditors or other 
authorized personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All 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.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality tolerance 
thresholds, controls, and mitigation plans will be documented in a risk management 
register. Additional details of quality checking to be performed on the data may be 
included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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. 
• 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.  


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 57 of 82 
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 Code of Federal 
Regulations 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 the Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled and randomized subject, according to the 
eCRF completion instructions. The Sponsor, or CRO, will review the supporting source 
documentation against the data entered into the eCRFs to verify the accuracy of the electronic 
data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 
information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 58 of 82 
Appendix 6: Schedule of Assessments 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 59 of 82 
Study Plan – Part A (Single Dose) 
 
Pre- 
screening
d 
Screening 
Day
-2 
Day 
 -1 
Days 1 to 3 
Day 4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
 
X 
X
 
 
 
 
 
 
Alcohol breath test 
 
X 
X
 
 
 
 
 
 
Cotinine test 
 
X 
X 
 
 
 
 
 
 
Serology 
 
X 
 
 
 
 
 
 
 
 
FSH and serum pregnancy 
testa 
 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
 
X 
 
 
 
 
 
 
X 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
Day 3 
(48 hours 
postdose) 
 
 
 
 
 
Non-residential visit 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
 
 
Day 1 
(0 hours)  
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 60 of 82 
Supine blood pressure, pulse 
rate, respiratory rate, and 
body temperature 
 
X 
 
 
Predose, 1, 2, 
4, 8, 24 (± 
1 hour), and 
48 hours 
postdose 
X 
X 
X 
X 
X 
 
 
Pre- 
screening
d 
Screening 
Day 
-2
Day 
 -1
Days 1 to 3 
Day 4
Day 7 
(± 2 days)
Day 10 
(± 2 days)
Day 14 
(± 2 days)
Poststudy 
(Day 28 
± 2 days) 
Supine 12-lead ECG 
 
X 
 
 
Predose, 4, 24 
(± 1 hour) 
and 48 hours 
postdose 
 
X 
 
X 
X 
Continuous ECG 
extractionb,c 
 
 
 
-24,  
-23.5,  
-23,   
-22.5,  
-22,  
-21.5,  
-21,  
-20, 
-18,  
-16,   
-12 
hours 
Day 1: 
Predose, 0.5, 
1, 1.5, 2, 2.5, 
3, 4, 6, 8, 12 
and 24 hours 
 
 
 
 
 
 
Heat pain threshold test 
(heat pain threshold and heat 
pain tolerance) 
 
 
 
 
Day 1: 
predose, 2, 4, 
12, and 24 
hours 
postdose (± 
1 hour) 
 
 
 
 
 
Clinical chemistry, 
haematology, and urinalysis 
 
X 
X 
 
48 hours 
postdose 
 
X 
 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 61 of 82 
Height and BMI 
 
X 
 
 
 
 
 
 
 
 
Body weight  
 
X 
X 
 
 
 
 
 
 
X 
Physical examination 
 
X
 
 
 
 
 
Symptom-directed physical 
examination 
 
Prior to 
discharge 
 
X 
 
X 
X 
 
Pre- 
screening
d 
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 4
Day 7 
(± 2 days)
Day 10 
(± 2 days)
Day 14 
(± 2 days)
Poststudy 
(Day 28 
± 2 days) 
Injection site assessment  
 
Predose, 1, 2, 
4, 8, 24, 48 
hours 
postdose 
 
X 
 
X 
X 
Pharmacokineticse 
 
 
 
 
 
 
 
 
 
 
Blood sampling 
 
 
 
 
Predose, 0.5, 
1, 1.5, 2, 3, 4, 
6, 8, 12, 16, 
24, 36 and 
48 hours 
postdose 
X 
X 
X 
X 
X 
Pharmacodynamicsd: 
 
 
 
 
 
 
 
 
 
 
Intradermal capsaicin test 
(capsaicin-evoked pain and 
secondary hyperalgesia 
measurement) 
X 
 
X 
 
Day 2 (The 
area of 
secondary 
area of 
hyperalgesia 
will be 
evaluated at 5 
and 30 
minutes post-
capsaicin 
injection) 
 
 
 
 
 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 62 of 82 
Abbreviations: BMI = body mass index; ECG = electrocardiogram; FSH = follicle-stimulating hormone. 
a Female subjects only; a positive urine pregnancy test result will be confirmed with a serum pregnancy test. 
b All times are relative to dosing with OLP-1002. 
c Continuous ECG recording may begin at approximately 25 hours before dosing to allow for checks to be completed prior to the first extraction timepoint and will continue for 24 hours 
postdose, ie, until after the last timepoint for ECG extraction (24 hours postdose). At timepoints for ECG extractions, subjects will be supinely resting for a total of 15 minutes (10-minute supine 
rest period, 5-minute extraction). Data will be archived for potential future analysis and will not be available for review during the study. 
d Pharmacodynamic assessment groups only. 
e PK analysis in Part A will initially only be conducted for groups receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the event of PK data 
being quantifiable at doses ≥ 12 µg and if supported by bioanalytical stability data. 
 
 
 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 63 of 82 
Study Plan – Part B (Multiple Dose) 
 
Screening
Day -1 
Days 1-15 
Day 18 
(± 2 days) 
Day 22 
(± 2 days) 
Day 25 
(± 2 days) 
Day 29 
(± 2 days) 
Poststudy 
(Day 57 
± 2 days) 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
X 
X 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
Cotinine test 
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
FSH and serum pregnancy 
testa 
X 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
X 
 
 
X 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
Check-out 
 
 
Day 15 (48 hours postdose) 
 
 
 
 
 
Non-residential visit 
X 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
Days 1, 4, 7, 10, and 13 
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording  
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, 
pulse rate, respiratory rate, 
and body temperature 
X 
 
Day 1: predose, 1, 2, 4 and 8 hours 
postdose 
Day 2, Day 4 (postdose), Day 5, Day 7 
(postdose), Day 9, Day 10 (postdose), 
Day 12, Day 13: predose, 1, 2, 4 and 8 
hours postdose, and Day 15 
X 
X 
X 
X 
X 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 64 of 82 
 
 
Screening
Day -1
Days 1-15
Day 18
Day 22
Day 25
Day 29
Poststudy 
(Day 57 
± 2 days) 
Heat pain threshold test 
(heat pain threshold and 
heat pain tolerance) 
X 
 
Day 1 and Day 13: predose, 1, 2, 4, 8, 
24 hours postdose 
 
 
 
 
 
Supine 12-lead ECG 
X 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Days 2, 5, 9, 12, 17 
 
X 
 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
Days 1, 4, 7, 10, 13 
 
X 
 
X 
X 
Injection site assessment  
 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Pharmacokinetics:
 
 
 
 
 
 
 
Blood samplingb 
 
 
Day 1 and Day 13: Pre dose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
X 
X 
X 
X 
X 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 65 of 82 
Abbreviations: BMI = body mass index; ECG = electrocardiogram; FSH = follicle-stimulating hormone. 
a Female subjects only; a positive urine pregnancy test results will be confirmed with a serum pregnancy test. 
b  PK timepoints will be reviewed based on emerging data and may be updated. 
 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 66 of 82 
Appendix 7: Protocol Amendment Summary of Changes 
Protocol Amendment 5 (Version 4; 26 March 2019) 
This substantial amendment has been issued to update the Principal Investigator from 
 to 
.  
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold.  
Title Page 
Principal Investigator: 
 was replaced by 
 
 
Investigator Agreement 
 was replaced by 
 
 
Study Identification 
 was replaced by 
 
 
Tel: 
 was replaced by 
 
Protocol Amendment 4 (Version 3; 29 January 2019) 
This substantial amendment has been issued to update the female contraception 
criteria to allow female subjects to use alternative forms of contraception including 
the combined oral contraceptive pill, combined hormonal patch, and combined 
hormonal vaginal ring. Additionally, it has been clarified that only a serum pregnancy 
test will be conducted at Screening. 
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Appendix 4 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception. Female subjects of childbearing potential must be willing to use 2 
methods (1 primary highly effective and 1 secondary method) of birth control from 
the time of signing the informed consent form until 90 days after the Follow-up 
visit. Primary highly effective (non-barrier) methods of contraception include:  
• hormone injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as 
prescribed) 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 67 of 82 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation 
of occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  
• hormonal or non-hormonal intrauterine device with appropriate re-insertion 
period (as prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to 
the Screening visit, with verbal confirmation of surgical success, and the 
sole partner for the female subject). 
Appendix 6 
Hormone panel was replaced by FSH and serum pregnancy test in the study plan 
for Part A and Part B for clarity. 
A footnote was added to the study plan for Part A and Part B to specify that the 
FSH and serum pregnancy test will be conducted for female subjects only. 
Urine pregnancy test at Screening removed for Part A and Part B. 
 
Protocol Amendment 3 (Version 2.2; 12 December 2018) 
This non-substantial amendment has been issued to include a clinical laboratory 
assessment on Day -2 in Part A. 
Appendix 3 
Additional clinical laboratory sample added to Part A. Total blood volume 
withdrawn in Part A updated to 124.5 mL. 
Appendix 6 
Study Plan (Part A) 
Clinical chemistry, haematology, and urinalysis assessment added on Day -2. 
Protocol Amendment 2 (Version 2.1; 29 November 2018) 
This non-substantial amendment has been issued to correct minor inconsistencies in 
PK sampling timepoints, data cut off for dose escalation, clinical laboratory 
assessment timepoints, and the synopsis. Additionally, details of the injection site 
assessments have been added to the protocol. 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 68 of 82 
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Synopsis: Endpoints 
Text added: 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 
12-lead ECGs, vital signs measurements, injection site assessment, heat pain threshold 
and tolerance, and physical examinations. 
 
Section 3.6 
Previously read: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
Now reads: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 10 (216 hours postdose) from groups that received lower doses of OLP-1002. 
Section 7.3.8 
Entire section added to describe injection site assessments. 
Appendix 3 
Total blood volume for PK analysis (76 mL) added. 
Appendix 6 - Schedule of assessments Part A 
24 hour postdose continuous ECG recording timepoint added. 
Appendix 6 - Schedule of assessments Part B 
Clinical chemistry, haematology, and urinalysis for Days 1-15 previously read: 
Days 2, 4, 7, 10,13 
Clinical chemistry, haematology, and urinalysis for Days 1-15 now reads: 
Days 2, 5, 9, 12, 17 
 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 4, 26 March 2019 
Page 69 of 82 
PK blood sampling for Days 1-15 previously read: 
Day 1 and Day 15: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 8, 11, 15 Predose 
PK blood sampling for Days 1-15 now reads: 
Day 1 and Day 13: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
Protocol Amendment 1 (Version 2; 02 October 2018) 
This amendment has been generated following the non-acceptance of the original 
protocol (version 1) by the Medicines and Healthcare products Regulatory Agency 
(MHRA) on 20 September 2018. All changes made have been in response to 
comments provided by the MHRA. 
The primary changes in this amendment are: 
1. Inclusion of PK sampling in Parts A and B: 
• PK objective and exploratory endpoints added (Section 2). 
• Discussion of PK included Section 3.4. 
• PK stopping criteria added to Section 3.7. 
• PK assessments included in Section 7.1. 
• PK population and analysis (Section 8.2.1). 
• Blood volumes updated to include samples for PK assessments 
(Appendix 3). 
2. Exclusion and stopping criteria updated 
• Women who are pregnant or breastfeeding have been excluded from 
the study (Section 4.2). 
• Liver function tests, tachycardia, and hypertension stopping criteria 
have been updated (Section 3.7 and Section 4.4). 
• Stopping criteria for SAEs and serious AEs have been added 
(Section 3.7 and Section 4.4). 
3. Safety, tolerability, and PK data up to Day 22 in Part B will be reviewed prior 
to dose escalation (Section 3.1.2). 
4. Sentinel dosing included in Part B (Section 3.1.2). 
5. It has been specified that the maximum dose for additional groups will not 
exceed 20 µg (Section 3.5.3). 


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Minor changes: 
1. Additional clinical laboratory evaluations have been included on Day 14 in 
Part A. 
2. The definition of the Safety population has been updated to include all 
subjects who receive OLP-1002. 
3. Typographical errors and formatting errors were corrected, as necessary. 
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Section 1.6 
Previously read: 
This information, together with the pharmacodynamic (PD data, will help establish 
the doses and dosing regimen suitable for future studies in patients. 
Now reads: 
This information, together with the pharmacodynamic (PD) and pharmacokinetic 
(PK) data, will help establish the doses and dosing regimen suitable for future 
studies in patients. 
Section 2.1  
Objective added: 
Where possible, single and/or multiple subcutaneous dose pharmacokinetics of 
OLP-1002 in healthy subjects will be determined. 
Section 2.2.1 
Endpoint added: 
• demonstrate that exposure to OLP-1002 does not exceed pre-defined 
exposure limits from non-clinical studies. 
Section 2.2.2 
Endpoints added: 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from 
time zero to infinity (AUC0-∞) (actual and dose normalized [DN]) 


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o AUC from time zero to the time of the last quantifiable 
concentration (AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and 
DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 
Other PK parameters may also be added if deemed necessary. 
Section 3.1.1 
Previously read: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 


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Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 7 (144 hours postdose) from the lower dose 
levels. 
Now reads: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, PK, and PD 
(Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 10 (216 hours postdose) from the lower dose 
levels. For doses ≥ 12 µg, PK data will also be reviewed up to Day 7 prior to 
dose escalation. 
Figure 1 – footnote 
Text added:  
Groups A9 to A11 may be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Figure 2 – footnote 
Text added: 
Groups B4 to B6 will be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 


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Section 3.1.2 
Previously read: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. There will be no sentinel dosing in Part B. For all subjects, a single 
subcutaneous dose will be administered on Days 1, 4, 7, 10, and 13. The dosing 
frequency in Part B may be changed following review of data from groups in Part 
A (Section 3.4).  
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 18 (120 hours post-final dose) from the lower 
dose levels. Part B may start after a review of the safety and tolerability for Groups 
A1 to A6. The total daily dose administered will not exceed the highest single dose 
given in Part A. 
Now reads: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. For all subjects, a single subcutaneous dose will be administered 
on Days 1, 4, 7, 10, and 13. Prior to each dosing occasion a physician will review 
the available safety and tolerability data from each subject to confirm it is 
acceptable to continue dosing. The dosing frequency in Part B may be changed 
following review of data from groups in Part A (Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to 
OLP-1002 at steady state is predicted to exceed exposures that have been 
shown to be safe and well tolerated in earlier groups in Parts A or B. In the 
event of sentinel dosing, 2 subjects (1 active, 1 placebo) will be dosed at least 
4 days prior to the remaining 6 subjects (5 active: 1 placebo). Safety data for 
the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 
1 and 2 will be reviewed prior to the remaining subjects receiving dose 1). In 
addition, safety data from each subject will be reviewed by a physician prior to 
each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from the 
lower dose levels. Part B may start after a review of the safety, tolerability, and 
available PK data for Groups A1 to A6. The total daily dose administered will not 
exceed the highest single dose given in Part A. 
Section 3.3 
Previously read: 
Following review of the safety, tolerability, and PD data, additional dose groups 
may be added to the study. 


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Now reads: 
Following review of the safety, tolerability, PK, and PD data (where systemic 
exposure is not expected to exceed that stated in the dose escalation stopping 
criteria [Section 3.7]), additional dose groups may be added to the study. The 
maximum dose for any additional group will not exceed 20 µg. 
Section 3.4 
Previously read: 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis will not be conducted in this study. The bioanalytical 
method used for preclinical species has a lower limit of quantification (LLOQ) of 
5 ng/mL. The increased sample volume possible from humans (compared to small 
animals) may afford an approximate 10-fold increase in sensitivity with possibly an 
additional 5-fold increase from the use of a more sensitive mass spectrometer. This 
could potentially deliver an LLOQ of around 0.1 ng/mL. It is apparent from the 
predicted plasma concentrations (see Section 3.5.2) that only a small number of 
samples around Cmax at the highest doses would be quantifiable and that a 
conventional approach to pharmacokinetic will not achieve a full definition of the 
plasma concentration vs time profile or enable an estimation of the terminal phase. 
Thus, the additional burden of sampling procedures would not be justified by the 
quality of the data which it would generate. 
Now reads:  
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, 
and PK data up to Day 7 will be reviewed for all groups receiving ≥ 12 µg 
OLP-1002. In Part B, safety, tolerability and PK data up to Day 22 will be 
reviewed for all dose groups. As the t1/2 of OLP-1002 is predicted to be 
approximately 180 hours (based on non-clinical data) review of safety data up 


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to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma 
exposures are anticipated to be low, it is expected that it will only be possible 
to perform an assessment of peak concentrations (Cmax) and therefore PK data 
to Day 7 (Part A) and Day 22 (Part B) will be sufficient. Additionally, a 
cumulative safety review will occur such that additional emerging safety data 
from earlier groups will be considered when making a dose escalation decision.
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower 
dose groups occurring in the event of PK data being quantifiable at doses ≥ 12 
µg and if supported by bioanalytical stability data. Dose escalation decisions 
for doses <12 µg in Part A will not require PK data. The rationale for this is 
that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical 
species has a lower limit of quantification (LLOQ) of 5 ng/mL. The increased 
sample volume possible from humans (compared to small animals) may afford an 
approximate 10-fold increase in sensitivity with possibly an additional 5-fold 
increase from the use of a more sensitive mass spectrometer. This could potentially 
deliver an LLOQ of around 0.1 ng/mL. Therefore, even with the increased assay 
sensitivity plasma levels from doses at or below 12 µg are not expected to be 
quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose 
would be quantifiable and that a conventional approach to pharmacokinetic will not 
achieve a full definition of the plasma concentration vs time profile or enable an 
estimation of the terminal phase. In addition the planned dose levels have a high 
safety margin when comparing the predicted exposures to the exposures at the 
NOAEL (see Section 3.5.2), with the 12 µg dose level having an expected 312-
fold and 255-fold safety margin based on Cmax and AUC0-∞, respectively. 
Therefore if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
 


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Section 3.4.1 
Previously read: 
In Part B, all subjects in a group will be dosed on the same day. Accumulation of 
OLP-1002 is expected following multiple doses, based on the preclinical data, and 
will be taken into account when determining the doses for Part B (see 
Section 3.5.3). 
Now reads:  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 
at steady state is predicted to exceed exposures that have been shown to be safe 
and well tolerated in earlier groups in Parts A or B. When used, two subjects 
(1 active; 1 placebo), will be dosed 4 days prior to the remaining 6 subjects 
(5 active; 2 placebo). The 2 sentinel subjects will always be 2 doses ahead of the 
remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not 
predicted to exceed that tested in Part A will be dosed on the same day. 
Accumulation of OLP-1002 is expected following multiple doses, based on the 
preclinical data, and will be taken into account when determining the doses for Part 
B (see Section 3.5.3). If it is not possible to quantify exposure it will be assumed 
that multiple dosing results in a 4-fold accumulation based on the predicted t1/2 
of 180h. 
Section 3.5.3 
Text added: 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose 
administered will not exceed 20 µg and predicted systemic exposure will not 
exceed that stated in the dose escalation stopping criteria [Section 3.7]) based 
on available PK data. 
Section 3.6 
Previously read:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety and tolerability data up to Day 18 (120 hours post-final dose) from 
groups that received lower doses of OLP-1002. Doses may be reduced and may be 
lower than the starting dose. 


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Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 5 subjects, who have received OLP-1002 will be used to make the dose-
escalation decision. Dose escalation in Part B will only occur if data from a 
minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
Now reads:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
For escalation to doses > 12 µg, PK data up to Day 7 (144 hours postdose) will 
also be reviewed. All available safety, tolerability, and PK data from previous 
groups will be reviewed prior to dose escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) 
from groups that received lower doses of OLP-1002. Doses may be reduced and 
may be lower than the starting dose. Available safety, tolerability, and PK data 
from all previous groups will be reviewed prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 3 or 4 subjects, respectively, who have received OLP-1002 will be used to make 
the dose-escalation decision. Dose escalation in Part B will only occur if data from 
a minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
 
Section 3.7 
Previously read: 
In Parts A and B, following consultation with the Sponsor, dose escalation will be 
stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping 
of dose escalation. 
• There is evidence of clinically significant increases in liver function tests 
(aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase 
and total bilirubin) defined as 3 times the upper limit of normal in 3 or more 
subjects in a group (confirmed with repeat testing). 


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• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in 
at least 2 subjects in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in 
at least 2 subjects in a group. 
Now reads: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping 
of dose escalation. 
• One or more subjects experience an SAE that is considered to be 
related to OLP-1002. 
• Two or more subjects in the same group experience severe non-serious 
AEs (ie. severe non-serious AEs considered as, at least, possibly related 
to OLP-1002 administration), independent of whether the AEs are 
within or not within the same system organ class.  
• There is evidence of clinically significant increases in aspartate 
aminotransferase, alanine aminotransferase or alkaline phosphatase (defined 
as 3 times the upper limit of normal), or total bilirubin (defined as 2 times 
the upper limit of normal) that are considered to be related to OLP-
1002 in 2 or more subjects in a group. Results will be confirmed with 
repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in 
≥1 subject in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in 
≥1 subject in a group. 
• The dose will not exceed 20 µg or the systemic exposure for any 
individual subject is predicted to exceed a Cmax of 24.9 ng/mL (plasma) 
and/or an AUC0-24 of 128 ng/mL; i.e., systemic exposure will be no 
greater than the NOAEL in the most sensitive species (100,000 pmol/kg 
in rat [462 µg/kg]). 


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Section 4.2 
Exclusion criteria added: 
4. 
Female subjects who are pregnant or breastfeeding. 
Section 4.4 
Previously read: 
• any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal 
Now reads: 
• any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least 
possibly related to OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE 
considered to at least possibly related to OLP-1002 
administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN),
o QTcF increases > 60 msec compared to baseline (predose for 
Part A or Day 1 predose for Part B) and/or absolute QTcF 
values > 500 msec (confirmed by repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position 
(confirmed by 2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg 
and/or diastolic blood pressure > 110 mmHg) in the resting 
supine position (confirmed by 2 repeat measurements). 
Section 7.1 
Section added: 
7.1  Pharmacokinetic Assessments 
7.1.1 Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times 
indicated in the Schedule of Assessments (Appendix 6). Furthermore, 
additional blood samples may be taken from each subject per treatment 
period, with the maximum volume of blood withdrawn per subject not 
exceeding the limit detailed in Appendix 3. Any changes to the scheduled times 


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of PK assessments will be agreed with the Sponsor and documented in the 
TMF. Samples taken from subjects who received placebo will not be analyzed. 
In Part A, only samples collected from subjects that received >12 µg OLP-1002 
will be initially analyzed. If PK data is quantifiable at concentrations of OLP-
1002 >12 µg, samples from lower dose groups will be retrospectively analyzed. 
In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated 
analytical procedures. Specifics of the analytical methods will be provided in 
separate documents. 
Section 8.2 
Previously read: 
8.2.1 Pharmacodynamic population 
The PD population will include all subjects who received at least 1 dose of study 
treatment OLP-1002 or placebo and for whom PD can be evaluated. 
8.2.2 Safety Population 
The safety population will include all subjects who received at least 1 dose of study 
treatment or placebo and have at least 1 postdose safety assessment. 
Now reads: 
8.2.1 Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of 
OLP-1002 that have evaluable PK data and have had no AEs or protocol 
deviations considered to impact PK. 
8.2.2 Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-
1002 or placebo and for whom PD can be evaluated. 
8.2.3 Safety Population 
The safety population will include all subjects who received at least 1 dose of 
OLP-1002 or placebo. 
8.3 
Pharmacokinetic Analyses 


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Noncompartmental PK analysis will be performed on individual plasma and 
urine concentration data, using commercial software such as Phoenix® 
WinNonlin®. Plasma concentrations of OLP-1002 and PK parameters will be 
listed and summarized using descriptive statistics. Individual and arithmetic 
mean OLP-1002 concentration-time profiles will also be presented graphically. 
Appendix 3 
Table updated: 
Part A 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis* 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
33.5109.5 
Part B 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
78.5194.5 
Appendix 6 
PK and Blood sampling rows added to the schedule of events for Part A and Part B. 
In the Schedule of events for Part A, footnote e was added. In the Schedule of 
events for Part B, footnote b was added. 


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Clinical chemistry, hematology, and urinalysis was added to the Schedule of events 
for Part A on Day 14.  
 
 


TITLE PAGE 
Protocol 
OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single 
and Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, 
and Pharmacodynamic Study in Healthy Male and Female Subjects 
Protocol Status: Final 
Protocol Date: 29 January 2019 
Protocol Version: 3 
Investigational Product: OLP-1002 
 
Protocol Reference Number: OLP-1002-001 
Covance Study Number: 8379789 
EudraCT Number: 2018-003085-13 
 
 
Sponsor: 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung-gu, Yongin, Gyeonggi 17015 
Republic of Korea 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street  
Leeds, LS2 9LH 
United Kingdom 
 
 
Sponsor Signatory: 
 
 
Principal Investigator: 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP-I 002-001 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
  
 
Protocol Version 3, 29 January 2019 
Date 
Page 2of80 


Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP-1002-00 I 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
 
Principal Investigator 
Protocol Version 3, 29 January 2019 
\ f\-rJ 2-cp I q 
Date 
Page 3 of SO 


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STUDY IDENTIFICATION 
Sponsor 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Study Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Medical Contact 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Medical Monitor 
(24-hour emergency 
medical contact) 
 
 
 
 
Study Site 
Covance Clinical Research Unit Ltd. 
Springfield House, 
Hyde Street, 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
Project Physician 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
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United Kingdom 
 
Clinical Laboratory 
 
 
 
Statistician 
 
Covance 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 6 of 80 
SYNOPSIS 
Title of study: OLP-1002 – A first-in-human, double-blind, placebo-controlled, single and multiple 
subcutaneous dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy 
male and female subjects 
Objectives:  
The primary objective of the study is to assess the safety and tolerability of single and multiple 
subcutaneous doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the pharmacodynamic effect of OLP-1002 
following single subcutaneous doses in healthy volunteers using a capsaicin pain model, and to 
monitor the effects of a single subcutaneous doses of OLP-1002 on cardiac QT interval. Where 
possible, single and/or multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy 
subjects will be determined. 
Study design: 
This will be a double-blind, randomized, placebo-controlled, single and multiple subcutaneous dose 
study conducted in 2 parts, including healthy male and female subjects. 
Number of subjects: 
Part A: 44 subjects will be studied in 8 groups (5 groups of 4 and 3 groups of 8). 
Part B: 24 subjects will be studied in 3 groups (Groups B1 to B3). 
Up to 24 additional subjects may be recruited into Part A and Part B of the study if required. 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged between 18 and 60 years (inclusive) with a body mass index 
between 18.0 and 28.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test product: OLP-1002 
Proposed dose levels for Part A: 30 ng, 120 ng, 400 ng, 1.2 µg, 3 µg, 6 µg, 12 µg, and 20 µg. 
Proposed dose levels for Part B: the doses for Part B will be decided in consultation with the 
Sponsor and on the basis of data from Part A of the study. The highest dose in Part B will be up to 
50% of the highest dose in Part A. 
Administration route: subcutaneous 
Reference product and mode of administration: 
Reference product: placebo 
Administration route: subcutaneous 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 8 weeks for Part A and 
approximately 12 weeks for Part B. 


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Protocol Reference: OLP-1002-001 
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Endpoints: 
Pharmacodynamics: 
In Part A, the analgesic effect of OLP-1002 will be investigated in 3 groups consisting of 8 subjects 
(6 active: 2 placebo) using experimental capsaicin-evoked pain methods. Measurement of 
capsaicin-evoked pain will be performed at pre-screening, baseline and on Day 2, and secondary 
hyperalgesia at 5 and 30 minutes post-capsaicin injection. Continuous electrocardiogram (ECG) 
recording will be conducted to investigate the effect of OLP-1002 on cardiac function. 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 12-lead 
ECGs, vital signs measurements, injection site assessment, heat pain threshold and tolerance, and 
physical examinations. 
Pharmacokinetics: 
In Part A, the following PK parameters will be determined where possible: area under the plasma 
concentration-time curve (AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the 
time of the last quantifiable concentration (AUC0-tlast), maximum observed plasma concentration 
(Cmax), time of the maximum observed plasma concentration (tmax), and apparent plasma terminal 
elimination half-life (t1/2). PK analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups 
occurring in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by 
bioanalytical stability data. 
In Part B, the following PK parameters will be determined where possible: AUC over a dosing 
interval (AUC0-τ), AUC0-∞, Cmax, minimum observed plasma concentration (Cmin), tmax, t1/2, observed 
accumulation ratio based on AUC0-τ (RAAUC0-τ), observed accumulation ratio based on Cmax 
(RACmax), and Temporal change parameter (TCP). PK samples from all groups in Part B will be 
analyzed. 
Statistical methods: 
Pharmacodynamics: 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of pharmacodynamic data is planned. 
Safety: 
Safety parameters will be listed and summarized using descriptive statistics. No formal statistical 
analysis of safety data is planned. 
Pharmacokinetics: 
Individual plasma concentrations and PK parameters of OLP-1002 will be listed and summarized 
using descriptive statistics. Individual and mean OLP-1002 concentration-time profiles will be 
presented graphically. 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................12 
1.1. 
Overview ................................................................................................................12 
1.2. 
Summary of Nonclinical Pharmacology ................................................................12 
1.2.1. 
In Vitro Pharmacology Studies ....................................................................12 
1.2.2. 
In Vivo Pharmacology Studies ....................................................................13 
1.2.3. 
Ex Vivo Pharmacology Studies ...................................................................14 
1.3. 
Summary of Safety Pharmacology ........................................................................15 
1.4. 
Summary of Toxicology ........................................................................................15 
1.5. 
Summary of Nonclinical Pharmacokinetics...........................................................16 
1.6. 
Study Rationale ......................................................................................................17 
1.7. 
Benefit-risk Assessment.........................................................................................17 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................17 
2.1. 
Objectives ..............................................................................................................17 
2.2. 
Endpoints ...............................................................................................................17 
2.2.1. 
Primary Endpoints .......................................................................................17 
2.2.2. 
Exploratory Endpoints .................................................................................18 
3. 
INVESTIGATIONAL PLAN ..........................................................................................19 
3.1. 
Overall Study Design and Plan ..............................................................................19 
3.1.1. 
Part A ...........................................................................................................19 
3.1.2. 
Part B ...........................................................................................................21 
3.2. 
Start of Study and End of Study Definitions .........................................................22 
3.3. 
Additional Groups ..................................................................................................22 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................22 
3.4.1. 
Dose Interval ................................................................................................24 
3.4.2. 
Pharmacodynamic Assessment ....................................................................24 
3.5. 
Selection of Doses in the Study .............................................................................25 
3.5.1. 
Starting Dose ................................................................................................25 
3.5.2. 
Exposure ......................................................................................................26 
3.5.3. 
Proposed Doses ............................................................................................27 


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3.6. 
Dose Escalation ......................................................................................................28 
3.7. 
Dose Escalation Stopping Criteria .........................................................................29 
4. 
SELECTION OF STUDY POPULATION .....................................................................30 
4.1. 
Inclusion Criteria ...................................................................................................30 
4.2. 
Exclusion Criteria ..................................................................................................30 
4.3. 
Subject Number and Identification ........................................................................32 
4.4. 
Subject Withdrawal and Replacement ...................................................................32 
4.5. 
Study Termination .................................................................................................33 
5. 
STUDY TREATMENTS .................................................................................................33 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................33 
5.2. 
Study Treatment Administration............................................................................33 
5.3. 
Randomization .......................................................................................................33 
5.4. 
Blinding..................................................................................................................34 
5.5. 
Treatment Compliance ...........................................................................................34 
5.6. 
Drug Accountability...............................................................................................34 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................35 
6.1. 
Concomitant Therapies ..........................................................................................35 
6.2. 
Diet .........................................................................................................................35 
6.3. 
Smoking .................................................................................................................35 
6.4. 
Exercise ..................................................................................................................35 
6.5. 
Blood Donation ......................................................................................................36 
6.6. 
Other Restrictions ..................................................................................................36 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................36 
7.1. 
Pharmacokinetic Assessments ...............................................................................36 
7.1.1. 
Sample Collection and Processing ...............................................................36 
7.1.2. 
Analytical Methodology ..............................................................................37 
7.2. 
Pharmacodynamic Assessments ............................................................................37 
7.2.1. 
Capsaicin-evoked Pain Model .....................................................................37 
7.2.2. 
Secondary Hyperalgesia...............................................................................37 
7.3. 
Safety and Tolerability Assessments .....................................................................37 
7.3.1. 
Adverse Events ............................................................................................37 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................38 
7.3.3. 
Vital Signs ....................................................................................................38 
7.3.4. 
Electrocardiogram ........................................................................................39 
7.3.5. 
Heat Pain Threshold Test .............................................................................39 
7.3.6. 
Physical Examination...................................................................................40 
7.3.7. 
Body Weight and Height .............................................................................40 
7.3.8. 
Injection Site Assessments ...........................................................................40 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................42 


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8.1. 
Determination of Sample Size ...............................................................................42 
8.2. 
Analysis Populations ..............................................................................................42 
8.2.1. 
Pharmacokinetic Population ........................................................................42 
8.2.2. 
Pharmacodynamic Population .....................................................................42 
8.2.3. 
Safety Population .........................................................................................42 
8.3. 
Pharmacokinetic Analyses .....................................................................................42 
8.4. 
Pharmacodynamic Analyses ..................................................................................43 
8.5. 
Safety Analysis ......................................................................................................43 
9. 
REFERENCES ................................................................................................................43 
10. APPENDICES .................................................................................................................45 
Appendix 1: Adverse Event Reporting ..............................................................................46 
Appendix 2: Clinical Laboratory Evaluations ...................................................................50 
Appendix 3: Total Blood Volume......................................................................................51 
Appendix 4: Contraception Guidance ................................................................................52 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................55 
Appendix 6: Schedule of Assessments ..............................................................................58 
Appendix 7: Protocol Amendment Summary of Changes .................................................65 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 ..........................................26 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 ......................................27 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
....................................................................................................................27 
Figure 1: 
Study Schematic (Part A)...........................................................................20 
Figure 2: 
Study Schematic (Part B) ...........................................................................22 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve extrapolated to infinity 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours postdose 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
DN 
Dose normalized 
DRG 
dorsal root ganglion 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Emax 
maximum pain intensity 
FCA 
Freund's Complete Adjuvant 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SNL 
spinal nerve ligation 
t1/2 
elimination half-life 
tEmax 
time of maximum pain intensity 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
VAS 
Visual Analogic Scale 
VGSC 
voltage-gated sodium channel 


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1. INTRODUCTION 
1.1. 
Overview 
OLP-1002 is a novel peptide nucleic acid (PNA) derivative which acts as a specific voltage-
gated sodium channel (VGSC) protein (Nav1.7) inhibitor, and is being developed by OliPass 
for the treatment of pain. 
The Nav1.7 protein is a subtype of VGSCs. Nav1.7 is particularly important in nociception 
and pain signaling, with congenital loss-of-function mutations in Nav1.7 resulting in the 
inability to experience pain. Selective Nav1.7 inhibitors are believed to have the potential to 
treat severe pain safely1. The active sites of VGSC subtypes are virtually indistinguishable by 
their 3-dimensional structure and thus the discovery of selective Nav1.7 small molecule 
inhibitors has been extremely challenging. Since inhibition of Nav1.5 subtype elicits long QT 
cardiotoxicity, inhibition of Nav1.5 subtype should be avoided at therapeutic doses. 
To date, there are several Nav1.7 inhibitors claimed to be selective that have been evaluated 
in human subjects: 
• Vixotrigine (formerly known as raxatrigine) inhibits Nav1.7 as well as other VGSC 
subtypes. Vixotrigine is in phase III clinical development for trigeminal neuralgia. 
Due to the limited Nav1.7 selectivity over Nav1.5, vixotrigine was evaluated primarily 
in patients with a low heart risk. 
• Funapide is a Nav1.7 inhibitor with limited Nav1.7 selectivity, and was in phase IIb 
clinical trials as of July 2014. Although funapide showed analgesic activity in a small 
number of erythromelalgia patients, dose-limiting adverse events (AEs), including 
dizziness and somnolence, were observed2. The central nervous system (CNS) AEs 
were due to its poor Nav1.7 selectivity. 
• PF-05089771 is a Nav1.7 selective inhibitor with a claimed Nav1.7 selectivity of 
> 2000-fold versus other subtypes of sodium channel and was evaluated in patients of 
erythromelalgia or dental pain. It is thought low drug concentrations achieved in the 
target tissue could be a possible explanation for its poor analgesic activity in human 
patients3. 
OLP-1002 is fully complementary to a 14-mer RNA sequence spanning the junction of 
intron 4 and exon 5 in the human SCN9A pre-mRNA which codes for the Nav1.7 channel. 
OLP-1002 yields SCN9A mRNA splice variant(s) encoding variant Nav1.7 protein(s) lacking 
the sodium channel activity (ie, a non-functional channel), thereby inhibiting Nav1.7 channel 
function. 
1.2. 
Summary of Nonclinical Pharmacology 
1.2.1. 
In Vitro Pharmacology Studies 
Overall, results from the in vitro pharmacology studies showed OLP-1002 elicits responses 
consistent with its designed function4. It inhibits SCN9A mRNA expression and yields the 


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Nav1.7 variant protein or proteins lacking sodium channel activity. Its effects are highly 
selective, which may provide for an improved margin of safety compared to other Nav1.7 
inhibitors. 
OLP-1002 at 1 to 100 zM in PC3 prostate carcinoma cells induced exon skipping and yielded 
SCN9A mRNA splice variant(s) encoding a Nav1.7 variant protein or proteins lacking 
sodium channel activity.  
In rat dorsal root ganglion (DRG) neuronal cells, OLP-1002 at 1000 zM inhibited Nav1.7 
protein expression by > 50%, while OLP-1002R at 100 and 1000 zM inhibited Nav1.7 
expression almost completely. As OLP-1002R is fully complementary to rat SCN9A 
pre-mRNA, OLP-1002R would be predicted to be more potent than OLP-1002 in this cell 
type. 
SCN9A mRNA expression level was evaluated by quantitative polymerase chain reaction 
(qPCR). OLP-1002 inhibited the expression of the SCN9A mRNA in PC3 cells with sub-
attomolar potency.  
In SH-SY5Y human neuroblastoma cells stimulated with tumor necrosis factor (TNF)-1α to 
upregulate the expression of SCN9A mRNA, OLP-1002 decreased expression by 46% to 
49% at 1 fM to 10 pM. In rat DRG neuronal cells, OLP-1002 at 1 fM significantly decreased 
SCN9A mRNA expression by 54%. 
In rat DRG neuronal cells, OLP-1002 markedly and significantly inhibited the sodium current 
by 77% at 0.1 aM and 73% at 1 aM, while for OLP-1002R, the inhibition was 66% at 0.1 aM 
and 70% at 1 aM. Given that rat DRG neuronal cells express various subtypes of sodium 
channel, the observed inhibitions of 66% to 77% correspond to the complete knockout of the 
Nav1.7 sodium channel subtype with OLP-1002 or OLP-1002R. 
The Nav1.7 selectivity over Nav1.5 was evaluated in H9C2 rat cardiomyocytes which are 
known to abundantly express the rat Nav1.5 sodium channel subtype. Following incubation 
with OLP-1002 or OLP-1002R at 1 aM or 1 pM, there were no notable decreases in the 
sodium current. Considering that OLP-1002 and OLP-1002R inhibit the expression of Nav1.7 
protein at 1 aM or lower in rat DRG neuronal cells, the Nav1.7 selectivity of OLP-1002 and 
OLP-1002R over Nav1.5 is estimated to be in excess of one million-fold. Such a large Nav1.7 
selectivity over Nav1.5 has not been realized with small molecule Nav1.7 inhibitors, 
suggesting that OLP-1002 potentially offers pain management with much greater 
cardiovascular safety. 
1.2.2. 
In Vivo Pharmacology Studies 
Spinal nerve ligation (SNL) has been widely applied as a rat model for neuropathic pain. 
OLP-1002 and OLP-1002R were found to be very potent, but highly variable in potency, in 
reversing neuropathic allodynia in this model. Analyses of the therapeutic potency strongly 
suggested that a marked proportion of subcutaneously (SC) administered OLP-1002 or 
OLP-1002R may have been topically delivered directly to the spinal nerves exposed in the 
dorsal cavity created during the SNL modelling. In addition, the variability of the therapeutic 
potency may be due to a variable degree of healing of the SNL surgery wound. If an animal 


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recovers slowly, the animal tends to be left with a dorsal cavity. Therefore, estimations of 
potency in these studies with this model should be treated with caution. 
In one study using the SNL model, allodynia in rats was slowly and gradually reversed by 
OLP-1002 SC administered at nominal doses of 1, 3, and 6 pmol/kg once every 2 days (due 
to adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). As the onset time for pain reduction was 4 days, 
the doses used were not sufficient for fast onset of activity. In this study, the animals should 
have reasonably recovered from the dorsal wound, and therefore less susceptible to topical 
delivery directly to the exposed spinal nerves. However, in another study in this model, when 
OLP-1002 was intraperitoneally (IP) administered once every 3 days to avoid the likelihood 
of local delivery to the spinal nerves, OLP-1002 surprisingly reversed the allodynia at 
5 fmol/kg, and was superior or comparable to pregabalin 30 mg/kg, a gold standard for 
neuropathic pain studies. The high potency shown at 5 fmol/kg IP strongly suggests the 
possibility that OLP-1002 is efficiently absorbed by the enteric nervous system, travels to the 
spinal cord, and then redistributes to the spinal nerves of the SNL ligation. This opens the 
possibility of efficient oral delivery of OLP-1002 to the spinal cord. 
When evaluated for their ability to reverse the inflammatory pain in rats inflicted with 
Freund's Complete Adjuvant (FCA)-induced severe paw inflammation, OLP-1002 at 
300 pmol/kg and OLP-1002R at 100 pmol/kg significantly reversed the thermal hyperalgesia, 
and both were more effective than pregabalin 30 mg/kg. 
Paw burn injury induces hyperalgesia in rats and is known to upregulate Nav1.7 expression in 
the L5 and L6 DRGs of the affected side. Burn injury induces a far weaker degree of paw 
inflammation than FCA-induced paw inflammation. OLP-1002 SC administered inhibited the 
thermal hyperalgesia in paw burn injury in a dose-dependent manner. At 25 fmol/kg, 
OLP-1002 did not inhibit thermal hyperalgesia. Although OLP-1002 at 625 fmol/kg 
significantly inhibited the thermal hyperalgesia, the efficacy was moderate and weaker than 
pregabalin 30 mg/kg. This suggests that SC dosing does not offer the local topical delivery to 
spinal nerves in this model as seen in rats without a dorsal cavity wound. In this study, the 
Nav1.7 expression in the DRG of the burn injury side significantly decreased by 58% with 
625 fmol/kg OLP-1002, validating the target engagement for analgesic activity. 
An intraplantar injection of formalin induces severe acute pain. The contributors to acute pain 
are known to be complex and require further elucidation. However, acute peripheral 
inflammation is known to contribute much to Phase II Pain (pain from 10 to 40 min after the 
formalin injection). In this model, OLP-1002 significantly inhibited Phase II Pain at 
comparable or saturated efficacy when SC administered at 10 to 100 pmol/kg (due to 
adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). Thus peripheral acute inflammatory pain could be 
treated with 10 pmol/kg or less. 
1.2.3. 
Ex Vivo Pharmacology Studies 
One day post-SC injection, OLP-1002 and OLP-1002R at 100 pmol/kg significantly inhibited 
the expression of Nav1.7 protein by 39% and 57%, respectively, in the spinal cord of rats 
subjected to SNL.  


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In other rats subjected to SNL, OLP-1002R slowly and gradually reversed the allodynia in a 
dose-dependent manner. OLP-1002R at 30 fmol/kg (the highest dose administered) had the 
greatest effect, but the dose was not high enough to elicit full therapeutic efficacy. 
OLP-1002R inhibited expression of Nav1.7 protein in these animals, most notably at 
1 fmol/kg, and decreased SCN9A mRNA expression by approximately 40% at 1 to 30 
fmol/kg. The observed inhibitions were largely consistent with the in vivo therapeutic activity 
findings. 
Taking all the in vivo and ex vivo findings together, OLP-1002R was concluded to inhibit 
neuropathic allodynia by inhibiting the expression of the SCN9A mRNA and the 
Nav1.7 protein. 
1.3. 
Summary of Safety Pharmacology 
In vitro, OLP-1002 did not inhibit the human ether-à-go-go-related gene (hERG) channel 
current expressed in human embryonic kidney (HEK) cells at the highest concentration tested 
2 μM (the limit of the validated analytical method for OLP-1002). 
In the in vivo safety pharmacology studies, OLP-1002 SC administered at dose levels up to 
100 nmol/kg had no effect on body temperature, neurological function, or respiratory 
function in rats, and had no significant toxic effect on cardiovascular function in cynomolgus 
monkeys. 
1.4. 
Summary of Toxicology 
In rats, following twice-weekly SC dosing for 13 weeks, OLP-1002-related microscopic 
findings included pigment accumulation in the kidney of males administered 
100 nmol/kg/dose and females administered ≥ 10 nmol/kg/dose, foreign material and 
vacuolated macrophage infiltrates in males and/or females administered ≥ 1 nmol/kg/dose, 
and an increased incidence and/or severity of mononuclear cell infiltrates at the injection sites 
in males and/or females administered ≥ 10 nmol/kg/dose. These findings persisted through 
the recovery phase in animals administered 100 nmol/kg/dose. However, the effects were 
considered non-adverse due to their mild severity and lack of impact on animal health and 
wellbeing. The no-observed-adverse-effect level (NOAEL) was 100 nmol/kg/dose. This dose 
level corresponded to maximum observed plasma concentration (Cmax) and area under the 
plasma concentration-time curve (AUC) from 0 to 24 hours postdose (AUC0-24) values of 
27.6 ng/mL and 174 ng·hr/mL, respectively, in males and 24.9 ng/mL and 128 ng·hr/mL, 
respectively, in females on Day 88 of the dosing phase. 
In cynomolgus monkeys, following twice-weekly SC dosing for 13 weeks, OLP-1002-related 
microscopic findings included mononuclear cell infiltrates at the SC injection sites of animals 
administered ≥ 10 nmol/kg/dose. This finding was not resolved with the completion of the 
recovery phase. However, the effects of 100 nmol/kg/dose were considered non-adverse due 
to the mild severity of findings and the lack of impact on animal health and wellbeing. The 
NOAEL was 100 nmol/kg/dose (equivalent to 462.29 µg/kg/dose), which corresponded to 
Cmax and AUC from 0 to 72 hours postdose (AUC0-72) values of 121 ng/mL and 
2840 ng·hr/mL in males, respectively, and 216 ng/mL and 4840 ng·hr/mL in females, 
respectively, on Day 88 of the dosing phase. 


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The genotoxic and mutagenic potential of OLP-1002 was evaluated with standard Good 
Laboratory Practice (GLP) via in vitro bacterial mutagenicity and chromosomal aberration 
studies, and was found to be negative. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
In rats, following a single SC dose of 14C-OLP-1002, the time of maximum observed 
concentration (Tmax) was 0.5 to 1 hour for both radioactivity and parent compound. Plasma 
concentrations of total radioactivity were quantifiable through the last sampling time of 
72 hours postdose, but was variable for the parent compound. The elimination half-life (t1/2) 
of total radioactivity from plasma was 23 hours. Total radioactivity distributed into tissues, 
including those of the CNS protected by the blood-brain barrier. 14C-OLP-1002-derived total 
radioactivity was not rapidly excreted from rats, with minimal amounts present in urine and 
feces. The bulk of the total radioactivity remained in carcasses, primarily in kidneys (cortex 
and medulla) and liver. Parent 14C-OLP-1002 was present in plasma and tissues, but 
concentrations declined over time and were substantially lower than total radioactivity 
concentrations at the later sampling times.  
After a single SC administration of 14C-OLP-1002 to rats, the highest concentrations of total 
radioactivity were retained predominantly in the liver (10.4% to 13.3% of the dose), kidney 
cortex (3.47% to 4.96%), and kidney medulla (1.10% to 1.59% of the dose) through 
168 hours postdose. For all other tissues, the total amounts of total radioactivity were 
substantially less, ranging from 0.0000203% in the 5th DRG to 0.327% in the spleen. 
Radioactivity was excreted slowly via both the renal and fecal routes of elimination. Total 
average recoveries of radioactivity in urine and feces through 336 hours postdose accounted 
for 2.31% and 1.75% of the administered radioactivity, respectively. The bulk of the 
administered total radioactivity was retained in the rat carcasses through 168, 336, 504, and 
840 hours postdose. The kidney cortex, kidney medulla, and liver were the 3 tissues that 
retained the greatest amounts of the administered radioactivity. 
Following a 16.1-µg/kg dose in rats, the plasma concentrations were still quantifiable at 
72 hours postdose and the rate of elimination was slow, with t1/2 17.5 hours. It was not 
possible to accurately define the elimination phase for the 2.67- and 5.28-µg/kg dose levels. 
In cynomolgus monkeys, following a single SC dose of 14C-OLP-1002, Tmax ranged from 
0.25 to 1 hour for both total radioactivity and parent compound. Concentrations of total 
radioactivity were sustained in blood and plasma through the last sampling time of 144 hours 
postdose. Concentrations of parent compound were sustained in plasma through the last 
sampling time of 144 hours postdose in 2 of 3 monkeys, and were similar to plasma total 
radioactivity concentrations at 8 hours postdose. From 24 to 144 hours postdose, plasma 
concentrations of total radioactivity were substantially higher than for parent 14C-OLP-1002 
plasma concentrations.  
The mean Cmax of parent 14C-OLP-1002 in plasma was 1.96 ng/mL. The mean plasma Tmax 
was 0.833 hours. Plasma exposure of parent 14C-OLP-1002 based on AUC extrapolated to 
infinity (AUC0-∞), was 12.7 ng·h/mL. After reaching Cmax, plasma concentrations of parent 
14C-OLP-1002 declined with a mean t1/2 of 84 hours. 


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1.6. 
Study Rationale 
This is the first time OLP-1002 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when OLP-1002 is administered SC as single 
and multiple doses to healthy subjects. This information, together with the pharmacodynamic 
(PD) and pharmacokinetic (PK) data, will help establish the doses and dosing regimen 
suitable for future studies in patients. The analgesic effects of OLP-1002 on a 
capsaicin-induced pain model will also be investigated. 
1.7. 
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 investigational medicinal product 
(IMP), although there may also be some discomfort from collection of blood samples and 
other study procedures. For subjects in the PD assessment groups in Part A there will be 
some additional discomfort from the capsaicin test. More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with OLP-1002 may be 
found in the Investigator’s Brochure4. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is to assess the safety and tolerability of single and 
multiple SC doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the PD effect of OLP-1002 following 
single SC doses in healthy volunteers using a capsaicin pain model, and to monitor the effects 
of single SC doses of OLP-1002 on cardiac QT interval. Where possible, single and/or 
multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy subjects will be 
determined. 
2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of AEs 
• vital signs measurements (blood pressure, pulse rate, respiratory rate) 
• 12-lead electrocardiogram (ECG) parameters 
• incidence of clinical laboratory abnormalities, based on clinical chemistry, 
hematology, and urinalysis test results 
• physical examinations 
• injection site assessment. 


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• demonstrate that exposure to OLP-1002 does not exceed pre-defined exposure limits 
from non-clinical studies. 
2.2.2. 
Exploratory Endpoints 
The following exploratory objectives will be assessed:  
• pain intensity and duration will be assessed by AUC, maximum pain intensity (Emax), 
and time of maximum pain intensity (tEmax), calculated using a capsaicin-evoked pain 
model. The exploratory endpoint of secondary hyperalgesia will be assessed by the 
area of secondary area of hyperalgesia (Part A only). 
• continuous (24-hour) ECG monitoring will be recorded in this study and archived for 
potential future analysis of OLP-1002 effects on the QT interval (Part A). 
• heat pain threshold measurements and heat pain tolerance measurements. 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from time zero to 
infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable concentration 
(AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK: 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 


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Other PK parameters may also be added if deemed necessary. 
3. INVESTIGATIONAL PLAN 
This will be a double-blind, randomized, placebo-controlled, single and multiple SC dose 
study conducted in 2 parts. 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy subjects will 
be studied in 8 groups. Up to 3 additional groups (24 subjects in total) may be included for 
further assessment of safety, tolerability, PK, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Potential subjects for Groups A2, A4, and A6 will 
attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will return 
for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 2 days), and for a 
poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential visits 
may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 10 (216 hours postdose) from the lower dose levels. For doses 
≥ 12 µg, PK data will also be reviewed up to Day 7 prior to dose escalation. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 3 subjects will receive 
OLP-1002 and 1 subject will receive placebo. To assess PD parameters, Groups A2, A4, and 
A6 will consist of 8 subjects; 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo.  
Sentinel dosing will be employed for all groups in Part A. To maintain the blind in a 
4-subject group, the first subject will be dosed 48 hours before the second subject, and the 
second subject will be dosed 48 hours prior to the third and fourth subjects. In PD assessment 
groups, 2 subjects (1 active: 1 placebo) will be dosed 48 hours before the remaining 
6 subjects (5 active: 1 placebo). 
An overview of the study design is shown in Figure 1.


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Figure 1: 
Study Schematic (Part A) 
Group A1 
(30 ng SC)
3 active:
1 placebo
Group A2
(120 ng SC)
6 active:
2 placebo
Group A3
(400 ng SC)
3 active:
1 placebo
Group A4
(1.2 µg SC)
6 active:
2 placebo
Group A5
(3 µg SC)
3 active:
1 placebo
Group A6
(6 µg SC)
6 active:
2 placebo
Group A7
(12 µg SC)
3 active:
1 placebo
Group A8
(20 µg SC)
3 active:
1 placebo
Group A9
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A10
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A11
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
Groups A9 to A11 may be included if required; dose levels will not exceed the maximum proposed dose of 20 µg. 
Three groups consist of 8 subjects (6 active: 2 placebo); all other groups will consist of 4 subjects (3 active: 1 placebo).


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The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 8 weeks. 
3.1.2. 
Part B 
Part B will comprise a multiple-dose, sequential-group study. Overall, 24 subjects will be 
studied in 3 groups (Groups B1 to B3), with each group consisting of 8 subjects. Up to 
3 additional groups (24 subjects in total) may be included for further assessment of safety and 
tolerability (Section 3.3).  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (± 2 days), 22 (± 2 days), 
25 (± 2 days), and 29 (± 2 days), and for a poststudy visit on Day 57 (± 2 days). 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo. For all subjects, a single subcutaneous dose will be administered on Days 1, 4, 7, 10, 
and 13. Prior to each dosing occasion a physician will review the available safety and 
tolerability data from each subject to confirm it is acceptable to continue dosing. The dosing 
frequency in Part B may be changed following review of data from groups in Part A 
(Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to OLP-1002 at 
steady state is predicted to exceed exposures that have been shown to be safe and well 
tolerated in earlier groups in Parts A or B. In the event of sentinel dosing, 2 subjects (1 active, 
1 placebo) will be dosed at least 4 days prior to the remaining 6 subjects (5 active: 1 placebo). 
Safety data for the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 1 and 2 will be 
reviewed prior to the remaining subjects receiving dose 1). In addition, safety data from each 
subject will be reviewed by a physician prior to each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of safety, 
tolerability, and PK data up to Day 22 (216 hours post-final dose) from the lower dose levels. 
Part B may start after a review of the safety, tolerability, and available PK for Groups A1 to 
A6. The total daily dose administered will not exceed the highest single dose given in Part A. 
An overview of the study design is shown in Figure 2. 


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Figure 2: 
Study Schematic (Part B) 
Group B1
(TBC SC)
6 active:
2 placebo
Group B2 
(TBC SC)
6 active:
2 placebo
Group B3
(TBC SC)
6 active:
2 placebo
Group B4
(TBC SC)
6 active:
2 placebo
Group B5 
(TBC SC)
6 active:
2 placebo
Group B6
(TBC SC)
6 active:
2 placebo
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
All doses will be confirmed based on results of Part A; dose levels will not exceed the maximum proposed dose 
of 20 µg.  
Groups B4 to B6 will be included if required. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 12 weeks. 
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
 Start of Study and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, PK, and PD data (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]), additional 
dose groups may be added to the study. The maximum dose for any additional group will not 
exceed 20 µg. Up to 3 further groups of 8 subjects (6 active: 2 placebo) may be included in 
Part A, and up to 3 additional groups of 8 subjects (6 active: 2 placebo) may be included in 
Part B. The requirement for additional groups will be agreed with the Sponsor and 
documented in the Trial Master File (TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For both parts of the study, a sequential-group, ascending-dose design has been chosen for 
safety reasons as OLP-1002 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Subcutaneous doses have been 
chosen for both parts of the study, as this is the intended clinical route of administration. 
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, and PK data up 
to Day 7 will be reviewed for all groups receiving ≥ 12 µg OLP-1002. In Part B, safety, 
tolerability and PK data up to Day 22 will be reviewed for all dose groups. As the t1/2 of 


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OLP-1002 is predicted to be approximately 180 hours (based on non-clinical data) review of 
safety data up to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma exposures are 
anticipated to be low, it is expected that it will only be possible to perform an assessment of 
peak concentrations (Cmax) and therefore PK data to Day 7 (Part A) and Day 22 (Part B) will 
be sufficient. Additionally, a cumulative safety review will occur such that additional 
emerging safety data from earlier groups will be considered when making a dose escalation 
decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of females 
of childbearing potential is in accordance with International Council for Harmonisation (ICH) 
M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be sufficient in 
order to determine safety and tolerability. In order to assess the PD effects of OLP-1002, 
3 groups in Part A will include 8 subjects (6 active; 2 placebo). A full review of the safety 
and tolerability data from Part A will be performed to determine the dose regimen for Part B. 
Part B may start after a full review of all safety and tolerability data from Group A1 to A6. A 
review of PD data may also be performed, at the discretion of the Investigator. Details of the 
dosing regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 57-day 
follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups receiving 
≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring 
in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. Dose escalation decisions for doses < 12 µg in Part A will not require PK data. 
The rationale for this is that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical species has a 
lower limit of quantification (LLOQ) of 5 ng/mL. The increased sample volume possible 
from humans (compared to small animals) may afford an approximate 10-fold increase in 
sensitivity with possibly an additional 5-fold increase from the use of a more sensitive mass 
spectrometer. This could potentially deliver an LLOQ of around 0.1 ng/mL. Therefore, even 
with the increased assay sensitivity plasma levels from doses at or below 12 µg are not 
expected to be quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose would be 
quantifiable and that a conventional approach to pharmacokinetic will not achieve a full 
definition of the plasma concentration vs time profile or enable an estimation of the terminal 
phase. In addition the planned dose levels have a high safety margin when comparing the 
predicted exposures to the exposures at the NOAEL (see Section 3.5.2), with the 12 µg dose 
level having an expected 312-fold and 255-fold safety margin based on Cmax and AUC0-∞, 
respectively. Therefore, if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
 
 


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This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
Continuous ECG monitoring will be recorded in this study and archived for potential future 
analysis of OLP-1002 effects on the QT interval, with a view of supporting a potential 
thorough QT study waiver. 
3.4.1. 
Dose Interval 
Following thorough review of all available nonclinical data (pharmacological and 
toxicological), dosing in Part A for groups consisting of 4 subjects will be such that there will 
be 48 hours between the first and second subjects, and 48 hours between the second and 
remaining 2 subjects in each group. For groups in Part A consisting of 8 subjects, 2 subjects 
(1 active: 1 placebo) will be dosed 48 hours prior to the remaining 6 subjects.  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 at steady state 
is predicted to exceed exposures that have been shown to be safe and well tolerated in earlier 
groups in Parts A or B. When used, two subjects (1 active; 1 placebo), will be dosed 4 days 
prior to the remaining 6 subjects (5 active; 2 placebo). The 2 sentinel subjects will always be 
2 doses ahead of the remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not predicted to 
exceed that tested in Part A will be dosed on the same day. Accumulation of OLP-1002 is 
expected following multiple doses, based on the preclinical data, and will be taken into 
account when determining the doses for Part B (see Section 3.5.3). If it is not possible to 
quantify exposure it will be assumed that multiple dosing results in a 4-fold accumulation 
based on the predicted t1/2 of 180h.  
In Parts A and B, there will be a minimum interval of a 10-minute gap between dosing 
subjects (when dosed on the same day). Continuation to dose the remaining subjects in a 
group will be at the Investigator’s discretion. 
3.4.2. 
Pharmacodynamic Assessment 
Pharmacodynamic assessments will be conducted for subjects in Groups A2, A4, and A6. 
Human experimental pain models using healthy volunteers can be used to assess the effect of 
a drug or treatment under controlled clinical conditions. Capsaicin is a vanilloid responsible 
for the pungent taste of hot peppers. In mammalian species, capsaicin-induced pain is 
mediated through Group C nerve fibers following activation of vanilloid 1 transient receptor 
potential (TRPV1) channels5. Nav1.7 has been implicated in controlling neuropeptide release 
from C-fibers, and suppression of capsaicin-induced neurogenic flair has been demonstrated 
by an NAv1.7 inhibitor6. 


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Several studies have used intradermal capsaicin for human experimental pain studies7,8. It has 
been possible to demonstrate dose-dependent responses, with intradermal injections of 
100 μg generally agreed to be the ideal dosage for these studies. Intradermal injection of 
capsaicin causes a brief stinging/burning pain at the injection site (spontaneous pain) 
followed by development of secondary hyperalgesia, which can be assessed using equipment 
such as Von Frey hairs. A study by Gazerani et al.5 found that the response was site-specific 
and while peak pain intensity and duration were greatest in the forehead it was found that 
areas of visible flare and secondary hyperalgesia were significantly larger in the forearm, 
making the forearm the most suitable site for experimentation. 
Covance CRU, Leeds, UK in 2009 performed a validation study using intradermal capsaicin 
(Covance CRU Study: 9999-004) with between-subject and within-subject variability 
demonstrating that the assessments can be reliably conducted to assess pharmacological 
response. 
For these reasons, it has been decided to: 
• Measure both capsaicin-evoked pain and secondary hyperalgesia. 
• Limit the number of capsaicin tests to 3 for each subject (pre-screening, baseline, and 
48 hours postdose) 
• Exclude subjects who have pain < 3 or > 9 (using a Visual Analogic Scale [VAS]) at 
the pre-screening visit from PD assessment groups. 
3.5. 
Selection of Doses in the Study 
3.5.1. 
Starting Dose 
The rat has been identified as the most sensitive species in a 13-week SC toxicity study with 
a 4-week recovery phase (Covance study no. 8355564). The NOAEL was the 
100 nmol/kg/dose (462.29 µg/kg/dose). This dose level resulted in Cmax of 27.6 ng/mL and 
24.9 ng/mL in males and females, respectively, and AUC0-24 of 174 ng.h/mL and 
128 ng.h/mL in males and females, respectively4. As the exposure was lower in the female 
rats these data have been used to calculate the safety margins. 
The dose of 462.29 µg/kg/dose corresponds to human equivalent doses (HEDs) of 
74.8 µg/kg/dose, which gives a maximum recommended starting dose (MRSD) of 444 µg for 
a 60-kg human and thus a 15000-fold safety margin to the proposed starting dose of 30 ng 
and 22-fold margin to the proposed maximum dose of 20 µg. Additionally the NOAEL dose 
in the cynomolgus monkey was identified as 100 nmol/kg/dose (462.29 µg/kg/dose), which 
gives a higher HED of 150 µg/kg/dose. 
In vivo, doses of 10 pmol/kg/dose (0.0462µg/kg/dose) or less were found to inhibit peripheral 
acute inflammatory pain. The equivalent human dose for a 60-kg human is 44 ng, thus a dose 
at which minimal biological effect is anticipated has been selected as the starting dose of 
30 ng. 


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3.5.2. 
Exposure 
Human exposures have been estimated from the pharmacokinetics in the cynomolgus 
monkey since a non-human primate represents the most closely related species. 
Approximately dose-proportional exposure was seen in the 13-week toxicity study (Covance 
study no. 8355565) and 14C pharmacokinetic study (Covance study no. 8355568) over a dose 
range of approximately 1.1 to 100 nmol/kg (5.06 to 462.29 µg/kg)4. However, the lowest 
dose (5.06 µg/kg) from the 14C study has been used to estimate the human exposures as it is 
closest to the proposed human dose range and has the sufficient quantifiable data. 
The assumptions made in the human exposure estimation were that human exposure would 
be similar to the cynomolgus monkey and that exposure would be linear with dose. Following 
a dose of 5.06 µg/kg in the cynomolgus monkey, the Cmax was 1.96 ng/mL and AUC0-∞ was 
12.7 ng.h/mL. The extrapolated exposures at the planned human doses are shown in Table 1 
with margins calculated to the exposures at the NOAEL in the female rat. 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 
Human dose 
Single dose to human 
Safety margins for single dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax 
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin  
to Cmax 
Margin  
to AUC0-∞ 
0.03 
0.000500 
0.000194 
0.00125 
129000 
102000 
0.12 
0.00200 
0.000775 
0.00502 
32100 
25500 
0.4 
0.00667 
0.00258 
0.0167 
9640 
7650 
1.2 
0.0200 
0.0077 
0.0502 
3210 
2550 
3 
0.0500 
0.0194 
0.125 
1290 
1020 
6 
0.100 
0.0387 
0.251 
643 
510 
12 
0.200 
0.0775 
0.502 
321 
255 
20 
0.333 
0.129 
0.837 
193 
153 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
The dosing interval currently anticipated for the multiple-ascending-dose part of this study is 
72 hours or 96 hours. Thus the average dosing interval (82 hours) is similar to the half-life 
determined in the monkey 14C study of 84 hours. Dosing at approximately once per half-life 
would be anticipated to result in accumulation of around 2-fold. However, higher levels of 
accumulation were observed (2.28-fold for Cmax and 3.76-fold for AUC0-24) on Day 88 at the 
top dose group (100 nmol/kg, 462.28 µg/kg) in the 13-week cynomologus monkey toxicity 
study following twice-weekly dosing (every 72 or 96 hours). Calculations were performed to 
estimate the likely human half-life using a standard 1-point allometric approach from the 14C 
cynomolgus monkey pharmacokinetic study data. The exponents used were 0.75 for apparent 
total plasma clearance (CL/F) and 1 for apparent volume of distribution (Vz/F) values 
combined with the average body weight of the animal (3.1 kg) and scaling to a 60 kg human 
9–11. This resulted in a human half-life estimate of 180 h which in turn gave an accumulation 
estimate of 3.7-fold based upon a dosing interval of 82 h. This further supports the use of the 
greater than 2-fold accumulation from the 13-week cynomolgus study to estimate exposure 
following multiple dosing. Multiplication of the exposure estimates for the single ascending 


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dose by 2.28 for Cmax and 3.76 for AUC resulted in exposure estimates for multiple dosing 
presented in Table 2. 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 
Human dose 
Multiple dose to human 
Safety margins for multiple dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax  
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin 
to Cmax 
Margin 
to AUC0-τ,ss 
0.03 
0.000500 
0.000442 
0.00472 
56000 
27000 
0.12 
0.00200 
0.00177 
0.0189 
14100 
6800 
0.4 
0.00667 
0.00589 
0.0629 
4230 
2030 
1.2 
0.0200 
0.017663 
0.189 
1410 
680 
3 
0.0500 
0.0442 
0.472 
560 
270 
6 
0.100 
0.0883 
0.944 
282 
136 
12 
0.200 
0.177 
1.89 
141 
68 
20 
0.333 
0.294 
3.15 
85 
41 
30 
0.500 
0.442 
4.72 
56 
27 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
3.5.3. 
Proposed Doses 
The proposed IMP dose levels for Parts A and B are shown in Table 3. 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
Study Part 
Group 
Dose (OLP-1002) 
Part A 
A1 
30 ng or placebo 
 
A2 
120 ng or placebo 
 
A3 
400 ng or placebo 
 
A4 
1.2 µg or placebo 
 
A5 
3 µg or placebo 
 
A6 
6 µg or placebo 
 
A7 
12 µg or placebo 
 
A8 
20 µg or placebo 
 
A9* 
TBC or placebo 
 
A10* 
TBC or placebo 
 
A11* 
TBC or placebo 
 
 
 
Part B 
B1 
TBC or placebo 
 
B2 
TBC or placebo 
 
B3 
TBC or placebo 
 
B4* 
TBC or placebo 
 
B5* 
TBC or placebo 
 
B6* 
TBC or placebo 
Abbreviations: TBC = to be confirmed 
* groups to be included if required. 


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In Parts A and B, there should not be an increase of > 3-fold between dose levels above 
120 ng. 
For Part B, dose levels, dosing frequency, and dosing duration will be decided, in 
consultation with the Sponsor, on the basis of data from Part A of the study. Since predictions 
of human exposure of OLP-1002 suggest that OLP-1002 concentrations may be not be 
quantifiable and human data have been estimated from a single species, it is proposed that the 
highest dose in the multiple-ascending-dose part will be up to 50% of the highest dose in the 
single-ascending-dose part (ie, if the highest dose in the single-ascending-dose part is 20 µg, 
the highest dose in the multiple-ascending-dose part will be 10 µg). Therefore, if the 
predicted accumulation of 3.7-fold occurs, the highest exposure in the multiple-ascending-
dose part will not exceed ~2-fold the maximum exposure in the single-ascending-dose part. 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose administered will 
not exceed 20 µg and predicted systemic exposure will not exceed that stated in the dose 
escalation stopping criteria [Section 3.7]) based on available PK data. 
Details of all doses administered in Parts A and B of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
In Part A, doses will be administered in an escalating manner following satisfactory review 
by the Sponsor and Investigator of the safety, and tolerability data up to Day 10 (216 hours 
postdose) from groups that received lower doses of OLP-1002. For escalation to doses 
> 12 µg, PK data up to Day 7 (144 hours postdose) will also be reviewed. All available 
safety, tolerability, and PK data from previous groups will be reviewed prior to dose 
escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and may be lower than the starting 
dose. Available safety, tolerability, and PK data from all previous groups will be reviewed 
prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups A1, 
A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have been reviewed from the 
previous lower dose group, such that data from a minimum of 3 or 4 subjects, respectively, 
who have received OLP-1002 will be used to make the dose-escalation decision. Dose 
escalation in Part B will only occur if data from a minimum of 6 subjects have been reviewed 
from the previous lower dose group, such that data from a minimum of 4 subjects who have 
received OLP-1002 will be used to make the dose-escalation decision. 
The justification for this is as follows: 
•
The study drug is of a known pharmacological class for which the on-target effects in
humans are well characterized. Based upon nonclinical data, no clinically important
off-target effects are expected within the proposed dose range.


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•
A minimum of 3 subjects receiving the active drug is considered sufficient to
characterize the safety profile for OLP-1002.
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarizing 
results from all available safety assessments, will be sent to the Sponsor and a dose-escalation 
meeting will occur prior to the start of each successive group. Any clinically significant 
results will be discussed with the Sponsor before dose escalation continues. Interim PD data 
may also be reviewed on an ongoing basis. In the event of a disagreement between Sponsor 
and Investigator on the dose-escalation decision, the decision of the Investigator will be 
upheld. 
3.7. 
Dose Escalation Stopping Criteria 
In Parts A and B, following consultation with the Sponsor, dose escalation will be stopped if: 
•
Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in
a group that, in the opinion of the Investigator, warrant stopping of dose escalation.
•
One or more subjects experience an SAE that is considered to be related to OLP-1002.
•
Two or more subjects in the same group experience severe non-serious AEs (ie.
severe non-serious AEs considered as, at least, possibly related to OLP-1002
administration), independent of whether the AEs are within or not within the same
system organ class.
•
There is evidence of clinically significant increases in aspartate aminotransferase,
alanine aminotransferase or alkaline phosphatase (defined as 3 times the upper limit
of normal), or total bilirubin (defined as 2 times the upper limit of normal) that are
considered to be related to OLP-1002 in 2 or more subjects in a group. Results will be
confirmed with repeat testing.
•
QT interval corrected for heart rate using Fridericia’s method (QTcF)
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose for
Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat measurement)
in 2 or more subjects in a group.
•
Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥ 1 subject in a 
group.
•
Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 110 mmHg) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥ 1 subject in a 
group.
•
The dose will not exceed 20 µg or the systemic exposure for any individual subject is
predicted to exceed a Cmax of 24.9 ng/mL (plasma) and/or an AUC0-24 of 128 ng/mL;
i.e., systemic exposure will be no greater than the NOAEL in the most sensitive
species (100,000 pmol/kg in rat [462 µg/kg]).


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If the sponsor deems it appropriate to resume dosing after the internal safety review, it 
can be done after the approval of a substantial protocol amendment. 
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. Healthy male or females of any race, between 18 and 60 years of age, inclusive. 
2. Body mass index (BMI) between 18.0 and 28.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, single 12-lead ECG (resting heart rate > 45 bpm and 
< 90 bpm), vital signs measurements, and clinical laboratory evaluations (congenital 
nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome based on total 
and direct bilirubin] is not acceptable) at Screening as assessed by the Investigator (or 
designee).  
4. Willing to abide by the contraception requirements 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: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. Any of the following: 
• QTcF > 450 ms confirmed by repeat measurement. 
• QRS duration > 110 ms confirmed by repeat measurement. 
• PR interval > 220 ms confirmed by repeat measurement. 
• findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
• history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalemia, family history of long QT syndrome). 
4. Female subjects who are pregnant or breastfeeding. 
5. History of alcoholism or drug/chemical abuse within 1 year prior to Screening. 


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6. Alcohol consumption of > 21 units per week for males and > 14 units per week for 
females. 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. 
7. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
8. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
9. Active skin conditions such as dermatitis, allergy, eczema, psoriasis, or abnormal 
healing. 
10. Tattoos, scars, or moles that in the opinion of the Investigator are likely to interfere 
with dosing or study assessments at any of the potential injection sites. 
11. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days or 5 half-lives of the investigational product, 
whichever is longer, prior to Check-in. 
12. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 
13. Use or intend to use any prescription medications/products other than 
hormone-replacement therapy, oral, implantable, transdermal, injectable, or 
intrauterine contraceptive concomitant medications within 14 days prior to Check-in, 
unless deemed acceptable by the Investigator (or designee). 
14. 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). 
15. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee) and/or 
Sponsor have given their prior consent. 
16. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.  
17. Receipt of blood products within 60 days prior to Check-in. 
18. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening.  
19. Poor peripheral venous access. 
20. Have previously completed or withdrawn from this study or any other study 
investigating OLP-1002, and have previously received the investigational product. 
21. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
22. Part A – PD assessment groups only 
• Subjects considered non-acceptable responders to the intradermal capsaicin 
test at screening, defined as maximum VAS score of < 3.0 or > 9.0. 


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4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomization. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, in Part A, Subjects 101, 102, 
etc., in Part B Subjects 201, 202, etc.). Replacement subjects (Section 4.4) will be assigned a 
subject number corresponding to the number of the subject he/she is replacing plus 1000 
(eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least possibly related to 
OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE considered to 
at least possibly related to OLP-1002 administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements). 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the 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 stabilized. 


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Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• 
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) 
• 
medical or ethical reasons affecting the continued performance of the study 
• 
difficulties in the recruitment of subjects 
• 
cancelation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Vials of OLP-1002 Injection Solution 100 µg/mL (1.5 mL in 5-mL vials) and the Diluent for 
OLP-1002 Injection Solution (5 mL in 10-mL vials) will be supplied by the Sponsor, along 
with the batch/lot number and Certificate of Analysis. The Diluent for OLP-1002 Injection 
Solution will also be used as the Placebo formulation. A certificate of batch certification and 
release, authorized by a Qualified Person in the European Union (EU) will also be issued, by 
a Covance CRU Qualified Person, for each batch of IMP imported into the EU. 
The IMPs will be stored according to the instructions on the label at the CRU in a location 
that is locked with restricted access. 
Dose solutions (OLP-1002 Injection Solution diluted with the Diluent for OLP-1002 
Injection Solution) will be prepared by Covance CRU Pharmacy staff in accordance with 
instructions provided in the Pharmacy Manual. The Placebo formulation will be the Diluent 
for OLP-1002 Injection Solution without further manipulation. 
5.2. 
Study Treatment Administration 
Subjects will be administered the IMP in numerical order. OLP-1002 will be administered by 
SC injection in the upper arm. If subcutaneous dosing of OLP-1002 in the upper arm is not 
possible, the subject may be dosed in the abdomen at the Investigator’s discretion. For 
subjects in Groups A2, A4, and A6, dosing will be on the opposite arm to the intradermal 
capsaicin test. 
5.3. 
Randomization 
The randomization code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. In Part A, 1 subject in groups 


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consisting of 4 subjects, and 2 subjects in groups consisting of 8 subjects, will be randomly 
assigned to receive placebo. In Part B, 2 subjects per group will be randomly assigned to 
receive placebo. All other subjects in a group will be randomized to receive OLP-1002. 
Prior to the start of the study, a copy of the master randomization code will be supplied into 
the Covance CRU pharmacy staff (in sealed envelopes). 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo solution will be identical in appearance to the OLP-1002. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 
To maintain the blind, the Investigator will be provided with sealed randomization 
code-break envelopes for each subject, containing details of their treatment. These individual 
sealed envelopes will be kept in a limited access area that is accessible 24 hours a day. In 
order to manage subject safety or to support dose-escalation decisions (in the event of 
possibly treatment-related SAEs or severe AEs), the decision to unblind resides solely with 
the Investigator. Whenever possible, and providing it does not interfere with or delay any 
decision in the best interest of the subject, the Investigator will discuss the intended 
code-break with the Sponsor. If it becomes necessary to break the code during the study, the 
date, time, and reason will be recorded in the subject’s source data and on the individual 
envelope and will be witnessed by a second person. 
5.5. 
Treatment Compliance 
All doses of IMP will be administered by suitably qualified study site staff. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription medications/products from 14 days prior to 
dosing until the Follow-up visit, and non-prescription medications/products from 7 days prior 
to dosing until the Follow-up visit, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone-replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary 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 standardized 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 safety laboratory tests. On dosing days, 
subjects will receive a light breakfast approximately 2 hours prior to dosing. Meals will be 
provided as appropriate at other times and water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Check-in until the Follow-up visit. 
Xanthine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until Discharge from the site. Xanthine-containing foods and beverages will also not be 
allowed form 36 hours before non-residential site visits. 
Chili pepper/hot sauce will not be allowed for 48 hours prior to Check-in for all subjects. 
Subjects in Groups A2, A4, and A6 will not be allowed chili pepper/hot sauce for 48 hours 
prior to their pre-screening visit. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until 
Discharge. Following discharge, up to 2 units/day of alcohol are permitted until 36 hours 
before each non-residential visit and 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 3 days before Check-in until the 
Follow-up visit and will otherwise maintain their normal level of physical activity during this 


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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. Subjects should not be in receipt of blood products for 
60 days prior to check-in. 
6.6. 
Other Restrictions 
Subjects in Groups A2, A4, and A6 will not be allowed to shower within 1 hour prior to the 
capsaicin-evoked pain tests at prescreening, predose, and postdose. 
Subjects will not be allowed to apply moisturizing creams or oils to the dosing site within 
1 hour prior to dosing, or to the assessment site within 1 hour prior to the capsaicin-evoked 
pain test.  
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): 
•
dosing
•
vital signs
•
blood samples
•
cardiac monitoring/ECG extractions
•
any other procedures.
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments (Appendix 6). Furthermore, additional blood samples may be taken 
from each subject per treatment period, with the maximum volume of blood withdrawn per 
subject not exceeding the limit detailed in Appendix 3. Any changes to the scheduled times of 
PK assessments will be agreed with the Sponsor and documented in the TMF. Samples taken 
from subjects who received placebo will not be analyzed. 
In Part A, PK analysis will initially only be conducted for groups receiving ≥ 12 µg 
OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the 


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event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 
7.2. 
Pharmacodynamic Assessments 
Capsaicin intradermal test will be performed for subjects in Groups A2, A4, and A6. Each 
subject will be tested at a pre-screening visit before being tested twice during the study 
(1 predose and 1 postdose). 
7.2.1. 
Capsaicin-evoked Pain Model 
The capsaicin model will be conducted by intradermal injection of capsaicin (100 μg in 
100 μL of sterile saline containing 8% [w/w] Tween 80) into the skin of the anterior aspect of 
the forearm, midway between the elbow and the wrist. The bleb area (wheal) will be a sign of 
local plasma extravasation. An assessment of the pain intensity related to capsaicin injection 
will be estimated by repeated use of a VAS from injection to 5 minutes post-injection or until 
the pain intensity returned to zero. The AUC, Emax, and tEmax will be calculated and reported 
using dedicated software. 
7.2.2. 
Secondary Hyperalgesia 
The area of secondary hyperalgesia will be quantified with a 60-g weighted von Frey hair, by 
stimulating along 8 linear paths (4 vectors crossing at the location of the injection site) 
arranged vertically and horizontally around the stimulation site in 5-mm steps (starting 
approximately 6 cm away from the injection site). The area of secondary hyperalgesia will be 
evaluated at 5 and 30 minutes post-capsaicin injection. 
7.3. 
Safety and Tolerability Assessments 
Safety and tolerability assessments will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). Timepoints may be adjusted based on an ongoing review of the 
data, and additional assessments may be conducted if deemed necessary by the Investigator 
or designee. 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs 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 


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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. 
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 drug. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a follicle-stimulating hormone (FSH) test and 
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. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and 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. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. 
Subjects must be supine for at least 5 minutes before blood pressure, pulse rate, and 
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7.3.4. 
Electrocardiogram 
7.3.4.1. 
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: 
• QTcF value > 500 msec 
• QTcF change from the mean baseline (Day 1 predose) is > 60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.3.4.2. 
Continuous (24-hour) Electrocardiogram 
At the times indicated in the Schedule of Assessments (Appendix 6), continuous (24-hour) 
ECGs will be performed.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint. Each extraction will last for 5 minutes. 
Environmental distractions (eg, television, playing games, radio, conversation) should be 
avoided during the pre-ECG time window.  
Continuous 24-hour ECGs are not planned for Part B of the study but may be implemented if 
any clinically significant findings are identified in the data from Part A. 
7.3.5. 
Heat Pain Threshold Test 
Heat pain threshold tests will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). 
A computer-controlled thermal sensory analyzer device will be used to measure the heat pain 
threshold and tolerance level of the subjects. The heat pain assessments will be conducted on 
the subject’s thigh. 
Heat Pain Threshold: 
For heat pain threshold measurements, the thermode will be placed directly on the skin of the 
right thigh, within an area selected before the start of the experiment and defined by surgical 
marking. The thermode will have a baseline temperature of 32 °C, and will be programmed to 
gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 


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their dominant hand, to indicate when the heat pain threshold (first sensation of heat pain) is 
reached by pushing a button. At that time, the test will be stopped and the temperature 
returned to baseline within 1 second. This process will be repeated a further 2 times, with an 
interval of at least 1 minute between measurements (from start to start). The computer will 
record the average value of 3 experiments. 
Heat Pain Tolerance: 
For heat pain tolerance measurements, the thermode will be placed within the same surgically 
marked skin area of the anterior side of the right thigh, which was used to assess heat pain 
threshold. The thermode will have a baseline temperature of 32 °C, and will be programmed 
to gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 
their dominant hand, to indicate when the heat-evoked pain has reached an intensity that is no 
longer tolerable, by pushing a button. At that time, the test will be stopped and the 
temperature returned to baseline within 1 second. This process will be repeated a further 
2 times, with an interval of at least 1 minute between measurements (from start to start). The 
computer will record the average value of 3 experiments. 
Safety Precautions 
As there is a risk that OLP-1002 may affect the heat pain threshold, Covance CRU will put 
appropriate safety measures in place to ensure that subjects are not exposed to extremes of 
temperature when taking a shower or consuming hot drinks. During the heat pain safety 
assessments, the cut-off temperature for either test is 53 °C in order to prevent skin injury. 
7.3.6. 
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.  
7.3.7. 
Body Weight and Height 
Body weight (in underclothes) and height will be recorded at the times indicated in the 
Schedule of Assessments in Appendix 6. BMI will be calculated using the following formula: 
BMI = body weight (kg)      (kg/m2) 
                  (height [m])2 
7.3.8. 
Injection Site Assessments 
Injection site assessments will be made at the times indicated in the Study Plan (Appendix 6). 
Assessments will involve evaluation of the dosing site for the following criteria:  
• Pain will be evaluated according to the following scale: 


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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Does not 
interfere with 
activity 
Interferes with 
activity or 
repeated use of 
non-narcotic 
pain reliever 
Prevents daily 
activity or 
repeated use of 
narcotic pain 
reliever 
Requires 
medical 
intervention 
greater than 
analgesia  
 
• Redness will be assessed by estimating the size of the red patch at the injection site across 
its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm 
51-100 mm 
More than 100 
mm 
Requires 
medical 
intervention 
greater than 
analgesia  
• Swelling will be assessed by estimating the size of the raised area around the injection site 
across its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm and 
does not 
interfere with 
activity 
51-100 mm or 
interferes with 
activity 
More than 100 
mm and 
prevents daily 
activity 
Requires 
medical 
intervention 
greater than 
analgesia 
In addition, how the swelling affects the subject in their daily routing activities will be 
considered. 
• Tenderness will be evaluated using the following scale: 


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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Mild pain to 
touch 
Moderate Pain 
to touch 
Severe pain to 
touch 
Requires 
medical 
intervention 
greater than 
analgesia 
• Bruising and ulceration will be evaluated as being present or absent. 
Local tolerability ratings of ≥Grade 3 and the presence of ulceration will be recorded as an 
adverse event.  
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time OLP-1002 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. In order to achieve PD endpoints 
in Part A, additional subjects will be included in 3 groups (8 subjects in total; 6 active: 
2 placebo). Up to 3 additional groups may be added to Part A, consisting of either 4 subjects 
(3 active; 1 placebo) or 8 subjects (6 active; 2 placebo). Up to 3 additional groups of 
8 subjects may be added to Part B (6 active; 2 placebo). 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of OLP-1002 that 
have evaluable PK data and have had no AEs or protocol deviations considered to impact PK. 
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo and for whom PD can be evaluated. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo. 
8.3. 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma concentration data, 
using commercial software such as Phoenix® WinNonlin®. Plasma concentrations of 


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OLP-1002 and PK parameters will be listed and summarized using descriptive statistics. 
Individual and arithmetic mean OLP-1002 concentration-time profiles will also be presented 
graphically. 
8.4. 
Pharmacodynamic Analyses 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No 
formal statistical analysis of PD data is planned. 
8.5. 
Safety Analysis 
Safety parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 
9. REFERENCES 
1.  Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A 
channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 
14;444(7121):894–8.  
2.  Goldberg YP, Price N, Namdari R, Cohen CJ, Lamers MH, Winters C, et al. Treatment of 
Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel 
blocker. Pain. 2012 Jan;153(1):80–5.  
3.  Jones HM, Butt RP, Webster RW, Gurrell I, Dzygiel P, Flanagan N, et al. Clinical Micro-
Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of 
Human Nav1.7 Voltage-Dependent Sodium Channels. Clin Pharmacokinet. 
2016;55(7):875–87.  
4.  Investigator Brochure - OLP-1002. 2018.  
5.  Gazerani P, Andersen OK, Arendt-Nielsen L. Site-specific, dose-dependent, and sex-
related responses to the experimental pain model induced by intradermal injection of 
capsaicin to the foreheads and forearms of healthy humans. J Orofac Pain. 
2007;21(4):289–302.  
6.  Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, et al. 
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in 
Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE 
[Internet]. 2016 Apr 6 [cited 2018 Jun 15];11(4). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822888/ 
7.  Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-
dependent pain, allodynia, and hyperalgesia in humans. J Investig Med Off Publ Am Fed 
Clin Res. 2006 Jul;54(5):238–44.  


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8.  Anderson WS, Sheth RN, Bencherif B, Frost JJ, Campbell JN. Naloxone increases pain 
induced by topical capsaicin in healthy human volunteers. Pain. 2002 Sep;99(1–2):207–
16.  
9.  Pharmacokinetics and Metabolism in Drug Design, 3rd Edition [Internet]. Wiley.com. 
[cited 2018 Aug 21]. Available from: https://www.wiley.com/en-
us/Pharmacokinetics+and+Metabolism+in+Drug+Design%2C+3rd+Edition-p-
9783527329540 
10.  Mahmood I. Pharmacokinetic allometric scaling of antibodies: application to the first-in-
human dose estimation. J Pharm Sci. 2009 Oct;98(10):3850–61.  
11.  Offman E, Edginton AN. Pharmacokinetic Time Course Scaling of a Subcutaneously 
Administered Pegylated Peptide Conjugate for a First-in-Human Investigation. Eur J 
Drug Metab Pharmacokinet. 2017 Feb;42(1):69–78.  
 
 


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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 unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but posing no 
significant or permanent risk of harm to the subject. 
• 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 drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
• 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. 
• 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. 
• Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized 
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 
stabilized. 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: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize 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 Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization 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 
Covance Drug Safety Services (DSS) Europe, Maidenhead, UK are 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 facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the Safety 
Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of the 
SAE within 2 working days of the initial notification to DSS. Drug Safety Services 
will delete any information from the SAE report forms that may identify the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined in 
the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions 
and forward to the Ethics Committee, Medicines and Healthcare Products Regulatory 
Agency, Principal 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. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfill regulatory requirements any pregnancy reported by female subjects or 


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the female partners of male subjects should be reported following the SAE process to collect 
data on the outcome for both mother and fetus. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Urea 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
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  
Serologya: 
Drug screenb: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
MDMA 
Alcohol breath test 
Follicle-stimulating hormonea  
Serum pregnancy test (human 
chorionic gonadotropin)a 
Urine pregnancy testc 
a Only analyzed at Screening. 
b Only analyzed at Screening and Check-in. 
c 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. 
Part A 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
6 
45 
Serology 
3.5 
1 
3.5 
Total: 
124.5  
Part B 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
194.5  
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
during the study will not exceed that donated during a standard blood donation 
(approximately 500 mL). 


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Appendix 4: Contraception Guidance 
Definitions 
Females of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Females of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 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-estrogens, or selective estrogen 
receptor modulators.  
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. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary and 1 secondary method) of birth control from the time of signing the informed 
consent form until 90 days after the Follow-up visit. Primary (non-barrier) methods of 
contraception include:  
• hormone injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  


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• hormonal or non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject). 
Secondary (barrier) methods of contraception include:  
• male condom with spermicide 
• female condom with spermicide  
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects can only choose a cervical cap or diaphragm if they have already had a 
prescription and fitting by their healthcare provider to ensure protocol requirements are met. 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in until 90 days after the Follow-up 
visit. Acceptable methods of contraception include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide 
• vasectomised male subject (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success). 


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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. 
Sexual Abstinence and Same-sex Relationships 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 


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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: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with Clinical Research Unit personnel, subjects will sign 
2 copies of the ICF in the presence of a suitably trained member of staff to indicate that they 
are freely giving their informed consent. One copy will be given to the subject, and the other 
will be maintained in the subject’s records. 
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 


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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 Organization (CRO) auditors or other 
authorized personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All 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.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality tolerance 
thresholds, controls, and mitigation plans will be documented in a risk management 
register. Additional details of quality checking to be performed on the data may be 
included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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. 
• 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.  


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Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 Code of Federal 
Regulations 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 the Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled and randomized subject, according to the 
eCRF completion instructions. The Sponsor, or CRO, will review the supporting source 
documentation against the data entered into the eCRFs to verify the accuracy of the electronic 
data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 
information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 58 of 80 
Appendix 6: Schedule of Assessments 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 59 of 80 
Study Plan – Part A (Single Dose) 
 
Pre- 
screeningd 
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
 
X 
X 
 
 
 
 
 
 
 
Alcohol breath test 
 
X 
X 
 
 
 
 
 
 
 
Cotinine test 
 
X 
X 
 
 
 
 
 
 
 
Serology 
 
X 
 
 
 
 
 
 
 
 
FSH and serum pregnancy 
testa 
 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
 
X 
 
 
 
 
 
 
X 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
Day 3 (48 hours 
postdose) 
 
 
 
 
 
Non-residential visit 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Study drug administration: 
 
 
 
 
Day 1 (0 hours)  
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, pulse 
rate, respiratory rate, and 
body temperature 
 
X 
 
 
Predose, 1, 2, 4, 
8, 24 (± 1 hour), 
and 48 hours 
postdose 
X 
X 
X 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 60 of 80 
 
 
Pre- 
screeningd 
Screening 
Day -
2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Supine 12-lead ECG 
 
X 
 
 
Predose, 4, 24 
(± 1 hour) and 48 
hours postdose 
 
X 
 
X 
X 
Continuous ECG 
extractionb,c 
 
 
 
-24,  
-23.5,  
-23,   
-22.5,  
-22,  
-21.5,  
-21,  
-20, 
-18,  
-16,   
-12 
hours 
Day 1: Predose, 
0.5, 1, 1.5, 2, 2.5, 
3, 4, 6, 8, 12 and 
24 hours 
 
 
 
 
 
 
Heat pain threshold test 
(heat pain threshold and heat 
pain tolerance) 
 
 
 
 
Day 1: predose, 2, 
4, 12, and 24 
hours postdose (± 
1 hour) 
 
 
 
 
 
Clinical chemistry, 
haematology, and urinalysis 
 
X 
X 
 
48 hours postdose 
 
X 
 
X 
X 
Height and BMI 
 
X 
 
 
 
 
 
 
 
 
Body weight  
 
X 
X 
 
 
 
 
 
 
X 
Physical examination 
 
X 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
 
 
Prior to discharge 
 
X 
 
X 
X 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 61 of 80 
Abbreviations: BMI = body mass index; ECG = electrocardiogram; FSH = follicle-stimulating hormone. 
a Female subjects only; a positive urine pregnancy test result will be confirmed with a serum pregnancy test. 
b All times are relative to dosing with OLP-1002. 
c Continuous ECG recording may begin at approximately 25 hours before dosing to allow for checks to be completed prior to the first extraction timepoint and will continue for 24 hours 
postdose, ie, until after the last timepoint for ECG extraction (24 hours postdose). At timepoints for ECG extractions, subjects will be supinely resting for a total of 15 minutes (10-minute supine 
rest period, 5-minute extraction). Data will be archived for potential future analysis and will not be available for review during the study. 
d Pharmacodynamic assessment groups only. 
e PK analysis in Part A will initially only be conducted for groups receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the event of PK data 
being quantifiable at doses ≥ 12 µg and if supported by bioanalytical stability data. 
 
 
 
Pre- 
screeningd 
Screening 
Day -
2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Injection site assessment  
 
 
 
 
Predose, 1, 2, 4, 
8, 24, 48 hours 
postdose 
 
X 
 
X 
X 
Pharmacokineticse 
 
 
 
 
 
 
 
 
 
 
Blood sampling 
 
 
 
 
Predose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 
12, 16, 24, 36 and 
48 hours postdose 
X 
X 
X 
X 
X 
Pharmacodynamicsd: 
 
 
 
 
 
 
 
 
 
 
Intradermal capsaicin test 
(capsaicin-evoked pain and 
secondary hyperalgesia 
measurement) 
X 
 
X 
 
Day 2 (The area 
of secondary area 
of hyperalgesia 
will be evaluated 
at 5 and 30 
minutes post-
capsaicin 
injection) 
 
 
 
 
 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 62 of 80 
Study Plan – Part B (Multiple Dose) 
 
Screening 
Day -1 
Days 1-15 
Day 18 
(± 2 days) 
Day 22 
(± 2 days) 
Day 25 
(± 2 days) 
Day 29 
(± 2 days) 
Poststudy 
(Day 57 
± 2 days) 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
X 
X 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
Cotinine test 
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
FSH and serum pregnancy 
testa 
X 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
X 
 
 
X 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
Check-out 
 
 
Day 15 (48 hours postdose) 
 
 
 
 
 
Non-residential visit 
X 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
Days 1, 4, 7, 10, and 13 
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording  
X 
X 
Ongoing 
X 
X 
X 
X 
X 


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Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 63 of 80 
Supine blood pressure, 
pulse rate, respiratory rate, 
and body temperature 
X 
 
Day 1: predose, 1, 2, 4 and 8 hours 
postdose 
Day 2, Day 4 (postdose), Day 5, Day 7 
(postdose), Day 9, Day 10 (postdose), 
Day 12, Day 13: predose, 1, 2, 4 and 8 
hours postdose, and Day 15 
 
X 
X 
X 
X 
X 
 
Screening 
Day -1 
Days 1-15 
Day 18 
Day 22 
Day 25 
Day 29 
Poststudy 
(Day 57 
± 2 days) 
Heat pain threshold test 
(heat pain threshold and 
heat pain tolerance) 
X 
 
Day 1 and Day 13: predose, 1, 2, 4, 8, 
24 hours postdose 
 
 
 
 
 
Supine 12-lead ECG 
X 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Days 2, 5, 9, 12, 17 
 
X 
 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
Days 1, 4, 7, 10, 13 
 
X 
 
X 
X 
Injection site assessment  
 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 64 of 80 
Abbreviations: BMI = body mass index; ECG = electrocardiogram; FSH = follicle-stimulating hormone. 
a Female subjects only; a positive urine pregnancy test results will be confirmed with a serum pregnancy test. 
b  PK timepoints will be reviewed based on emerging data and may be updated. 
 
Pharmacokinetics: 
 
 
 
 
 
 
 
 
Blood samplingb 
 
 
Day 1 and Day 13: Pre dose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
X 
X 
X 
X 
X 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 65 of 80 
Appendix 7: Protocol Amendment Summary of Changes 
Protocol Amendment 4 (Version 3; 29 January 2019) 
This substantial amendment has been issued to update the female contraception 
criteria to allow female subjects to use alternative forms of contraception including 
the combined oral contraceptive pill, combined hormonal patch, and combined 
hormonal vaginal ring. Additionally, it has been clarified that only a serum pregnancy 
test will be conducted at Screening. 
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Appendix 4 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception. Female subjects of childbearing potential must be willing to use 2 
methods (1 primary highly effective and 1 secondary method) of birth control from 
the time of signing the informed consent form until 90 days after the Follow-up 
visit. Primary highly effective (non-barrier) methods of contraception include:  
• hormone injection (as prescribed) 
• combined oral contraceptive pill or progestin/progestogen-only pill (as 
prescribed) 
• combined hormonal patch (as prescribed) 
• combined hormonal vaginal ring (as prescribed) 
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation 
of occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  
• hormonal or non-hormonal intrauterine device with appropriate re-insertion 
period (as prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to 
the Screening visit, with verbal confirmation of surgical success, and the 
sole partner for the female subject). 
Appendix 6 
Hormone panel was replaced by FSH and serum pregnancy test in the study plan 
for Part A and Part B for clarity. 
A footnote was added to the study plan for Part A and Part B to specify that the 
FSH and serum pregnancy test will be conducted for female subjects only. 
Urine pregnancy test at Screening removed for Part A and Part B. 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 66 of 80 
 
Protocol Amendment 3 (Version 2.2; 12 December 2018) 
This non-substantial amendment has been issued to include a clinical laboratory 
assessment on Day -2 in Part A. 
Appendix 3 
Additional clinical laboratory sample added to Part A. Total blood volume 
withdrawn in Part A updated to 124.5 mL. 
Appendix 6 
Study Plan (Part A) 
Clinical chemistry, haematology, and urinalysis assessment added on Day -2. 
Protocol Amendment 2 (Version 2.1; 29 November 2018) 
This non-substantial amendment has been issued to correct minor inconsistencies in 
PK sampling timepoints, data cut off for dose escalation, clinical laboratory 
assessment timepoints, and the synopsis. Additionally, details of the injection site 
assessments have been added to the protocol. 
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Synopsis: Endpoints 
Text added: 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 
12-lead ECGs, vital signs measurements, injection site assessment, heat pain threshold 
and tolerance, and physical examinations. 
 
Section 3.6 
Previously read: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
Now reads: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 10 (216 hours postdose) from groups that received lower doses of OLP-1002. 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 67 of 80 
Section 7.3.8 
Entire section added to describe injection site assessments. 
Appendix 3 
Total blood volume for PK analysis (76 mL) added. 
Appendix 6 - Schedule of assessments Part A 
24 hour postdose continuous ECG recording timepoint added. 
Appendix 6 - Schedule of assessments Part B 
Clinical chemistry, haematology, and urinalysis for Days 1-15 previously read: 
Days 2, 4, 7, 10,13 
Clinical chemistry, haematology, and urinalysis for Days 1-15 now reads: 
Days 2, 5, 9, 12, 17 
 
PK blood sampling for Days 1-15 previously read: 
Day 1 and Day 15: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 8, 11, 15 Predose 
PK blood sampling for Days 1-15 now reads: 
Day 1 and Day 13: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
Protocol Amendment 1 (Version 2; 02 October 2018) 
This amendment has been generated following the non-acceptance of the original 
protocol (version 1) by the Medicines and Healthcare products Regulatory Agency 
(MHRA) on 20 September 2018. All changes made have been in response to 
comments provided by the MHRA. 
The primary changes in this amendment are: 
1. Inclusion of PK sampling in Parts A and B: 
• PK objective and exploratory endpoints added (Section 2). 
• Discussion of PK included Section 3.4. 
• PK stopping criteria added to Section 3.7. 
• PK assessments included in Section 7.1. 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 68 of 80 
• PK population and analysis (Section 8.2.1). 
• Blood volumes updated to include samples for PK assessments 
(Appendix 3). 
2. Exclusion and stopping criteria updated 
• Women who are pregnant or breastfeeding have been excluded from 
the study (Section 4.2). 
• Liver function tests, tachycardia, and hypertension stopping criteria 
have been updated (Section 3.7 and Section 4.4). 
• Stopping criteria for SAEs and serious AEs have been added 
(Section 3.7 and Section 4.4). 
3. Safety, tolerability, and PK data up to Day 22 in Part B will be reviewed prior 
to dose escalation (Section 3.1.2). 
4. Sentinel dosing included in Part B (Section 3.1.2). 
5. It has been specified that the maximum dose for additional groups will not 
exceed 20 µg (Section 3.5.3). 
Minor changes: 
1. Additional clinical laboratory evaluations have been included on Day 14 in 
Part A. 
2. The definition of the Safety population has been updated to include all 
subjects who receive OLP-1002. 
3. Typographical errors and formatting errors were corrected, as necessary. 
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Section 1.6 
Previously read: 
This information, together with the pharmacodynamic (PD data, will help establish 
the doses and dosing regimen suitable for future studies in patients. 
Now reads: 
This information, together with the pharmacodynamic (PD) and pharmacokinetic 
(PK) data, will help establish the doses and dosing regimen suitable for future 
studies in patients. 
Section 2.1  
Objective added: 
Where possible, single and/or multiple subcutaneous dose pharmacokinetics of 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 69 of 80 
OLP-1002 in healthy subjects will be determined. 
Section 2.2.1 
Endpoint added: 
• demonstrate that exposure to OLP-1002 does not exceed pre-defined 
exposure limits from non-clinical studies. 
Section 2.2.2 
Endpoints added: 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from 
time zero to infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable 
concentration (AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and 
DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 
Other PK parameters may also be added if deemed necessary. 


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Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 70 of 80 
Section 3.1.1 
Previously read: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 7 (144 hours postdose) from the lower dose 
levels. 
Now reads: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, PK, and PD 
(Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 10 (216 hours postdose) from the lower dose 
levels. For doses ≥ 12 µg, PK data will also be reviewed up to Day 7 prior to 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 71 of 80 
dose escalation. 
Figure 1 – footnote 
Text added:  
Groups A9 to A11 may be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Figure 2 – footnote 
Text added: 
Groups B4 to B6 will be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Section 3.1.2 
Previously read: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. There will be no sentinel dosing in Part B. For all subjects, a single 
subcutaneous dose will be administered on Days 1, 4, 7, 10, and 13. The dosing 
frequency in Part B may be changed following review of data from groups in Part 
A (Section 3.4).  
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 18 (120 hours post-final dose) from the lower 
dose levels. Part B may start after a review of the safety and tolerability for Groups 
A1 to A6. The total daily dose administered will not exceed the highest single dose 
given in Part A. 
Now reads: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. For all subjects, a single subcutaneous dose will be administered 
on Days 1, 4, 7, 10, and 13. Prior to each dosing occasion a physician will review 
the available safety and tolerability data from each subject to confirm it is 
acceptable to continue dosing. The dosing frequency in Part B may be changed 
following review of data from groups in Part A (Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to 
OLP-1002 at steady state is predicted to exceed exposures that have been 
shown to be safe and well tolerated in earlier groups in Parts A or B. In the 
event of sentinel dosing, 2 subjects (1 active, 1 placebo) will be dosed at least 
4 days prior to the remaining 6 subjects (5 active: 1 placebo). Safety data for 
the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 


Protocol 
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Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 72 of 80 
1 and 2 will be reviewed prior to the remaining subjects receiving dose 1). In 
addition, safety data from each subject will be reviewed by a physician prior to 
each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from the 
lower dose levels. Part B may start after a review of the safety, tolerability, and 
available PK data for Groups A1 to A6. The total daily dose administered will not 
exceed the highest single dose given in Part A. 
Section 3.3 
Previously read: 
Following review of the safety, tolerability, and PD data, additional dose groups 
may be added to the study. 
Now reads: 
Following review of the safety, tolerability, PK, and PD data (where systemic 
exposure is not expected to exceed that stated in the dose escalation stopping 
criteria [Section 3.7]), additional dose groups may be added to the study. The 
maximum dose for any additional group will not exceed 20 µg. 
Section 3.4 
Previously read: 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis will not be conducted in this study. The bioanalytical 
method used for preclinical species has a lower limit of quantification (LLOQ) of 


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Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
Page 73 of 80 
5 ng/mL. The increased sample volume possible from humans (compared to small 
animals) may afford an approximate 10-fold increase in sensitivity with possibly an 
additional 5-fold increase from the use of a more sensitive mass spectrometer. This 
could potentially deliver an LLOQ of around 0.1 ng/mL. It is apparent from the 
predicted plasma concentrations (see Section 3.5.2) that only a small number of 
samples around Cmax at the highest doses would be quantifiable and that a 
conventional approach to pharmacokinetic will not achieve a full definition of the 
plasma concentration vs time profile or enable an estimation of the terminal phase. 
Thus, the additional burden of sampling procedures would not be justified by the 
quality of the data which it would generate. 
Now reads: 
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, 
and PK data up to Day 7 will be reviewed for all groups receiving ≥ 12 µg 
OLP-1002. In Part B, safety, tolerability and PK data up to Day 22 will be 
reviewed for all dose groups. As the t1/2 of OLP-1002 is predicted to be 
approximately 180 hours (based on non-clinical data) review of safety data up 
to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma 
exposures are anticipated to be low, it is expected that it will only be possible 
to perform an assessment of peak concentrations (Cmax) and therefore PK data 
to Day 7 (Part A) and Day 22 (Part B) will be sufficient. Additionally, a 
cumulative safety review will occur such that additional emerging safety data 
from earlier groups will be considered when making a dose escalation decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower 
dose groups occurring in the event of PK data being quantifiable at doses ≥ 12 
µg and if supported by bioanalytical stability data. Dose escalation decisions 
for doses <12 µg in Part A will not require PK data. The rationale for this is 
that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical 
species has a lower limit of quantification (LLOQ) of 5 ng/mL. The increased 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
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sample volume possible from humans (compared to small animals) may afford an 
approximate 10-fold increase in sensitivity with possibly an additional 5-fold 
increase from the use of a more sensitive mass spectrometer. This could potentially 
deliver an LLOQ of around 0.1 ng/mL. Therefore, even with the increased assay 
sensitivity plasma levels from doses at or below 12 µg are not expected to be 
quantifiable. It is apparent from the predicted plasma concentrations (see Section 
3.5.2) that only a small number of samples around Cmax at the highest dose would 
be quantifiable and that a conventional approach to pharmacokinetic will not 
achieve a full definition of the plasma concentration vs time profile or enable an 
estimation of the terminal phase. In addition the planned dose levels have a high 
safety margin when comparing the predicted exposures to the exposures at the 
NOAEL (see Section 3.5.2), with the 12 µg dose level having an expected 312-
fold and 255-fold safety margin based on Cmax and AUC0-∞, respectively. 
Therefore if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
Section 3.4.1 
Previously read: 
In Part B, all subjects in a group will be dosed on the same day. Accumulation of 
OLP-1002 is expected following multiple doses, based on the preclinical data, and 
will be taken into account when determining the doses for Part B (see 
Section 3.5.3). 
Now reads: 
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 
at steady state is predicted to exceed exposures that have been shown to be safe 
and well tolerated in earlier groups in Parts A or B. When used, two subjects 
(1 active; 1 placebo), will be dosed 4 days prior to the remaining 6 subjects 
(5 active; 2 placebo). The 2 sentinel subjects will always be 2 doses ahead of the 
remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not 
predicted to exceed that tested in Part A will be dosed on the same day. 
Accumulation of OLP-1002 is expected following multiple doses, based on the 
preclinical data, and will be taken into account when determining the doses for Part 
B (see Section 3.5.3). If it is not possible to quantify exposure it will be assumed 
that multiple dosing results in a 4-fold accumulation based on the predicted t1/2 
of 180h. 
Section 3.5.3 
Text added: 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose 
administered will not exceed 20 µg and predicted systemic exposure will not 


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exceed that stated in the dose escalation stopping criteria [Section 3.7]) based 
on available PK data. 
Section 3.6 
Previously read: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety and tolerability data up to Day 18 (120 hours post-final dose) from 
groups that received lower doses of OLP-1002. Doses may be reduced and may be 
lower than the starting dose. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 5 subjects, who have received OLP-1002 will be used to make the dose-
escalation decision. Dose escalation in Part B will only occur if data from a 
minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
Now reads: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
For escalation to doses > 12 µg, PK data up to Day 7 (144 hours postdose) will 
also be reviewed. All available safety, tolerability, and PK data from previous 
groups will be reviewed prior to dose escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) 
from groups that received lower doses of OLP-1002. Doses may be reduced and 
may be lower than the starting dose. Available safety, tolerability, and PK data 
from all previous groups will be reviewed prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 3 or 4 subjects, respectively, who have received OLP-1002 will be used to make 
the dose-escalation decision. Dose escalation in Part B will only occur if data from 
a minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 


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Protocol Reference: OLP-1002-001 
Protocol Version 3, 29 January 2019 
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Section 3.7 
Previously read: 
In Parts A and B, following consultation with the Sponsor, dose escalation will be 
stopped if: 
•
Clinically relevant signs or symptoms of similar nature occur in 2 or more
subjects in a group that, in the opinion of the Investigator, warrant stopping
of dose escalation.
•
There is evidence of clinically significant increases in liver function tests
(aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase
and total bilirubin) defined as 3 times the upper limit of normal in 3 or more
subjects in a group (confirmed with repeat testing).
•
QT interval corrected for heart rate using Fridericia’s method (QTcF)
increases > 60 msec compared to baseline (predose for Part A or Day 1
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by
repeat measurement) in 2 or more subjects in a group.
•
Tachycardia (> 150 beats/min) in the resting supine position (confirmed by
2 repeat measurements) on at least 2 occasions within a 24-hour interval in
at least 2 subjects in a group.
•
Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic
blood pressure > 110 mmHg) in the resting supine position (confirmed by
2 repeat measurements) on at least 2 occasions within a 24-hour interval in
at least 2 subjects in a group.
Now reads: 
•
Clinically relevant signs or symptoms of similar nature occur in 2 or more
subjects in a group that, in the opinion of the Investigator, warrant stopping
of dose escalation.
•
One or more subjects experience an SAE that is considered to be
related to OLP-1002.
•
Two or more subjects in the same group experience severe non-serious
AEs (ie. severe non-serious AEs considered as, at least, possibly related
to OLP-1002 administration), independent of whether the AEs are
within or not within the same system organ class.
•
There is evidence of clinically significant increases in aspartate
aminotransferase, alanine aminotransferase or alkaline phosphatase (defined
as 3 times the upper limit of normal), or total bilirubin (defined as 2 times
the upper limit of normal) that are considered to be related to OLP-
1002 in 2 or more subjects in a group. Results will be confirmed with
repeat testing.


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Protocol Reference: OLP-1002-001 
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•
QT interval corrected for heart rate using Fridericia’s method (QTcF)
increases > 60 msec compared to baseline (predose for Part A or Day 1
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by
repeat measurement) in 2 or more subjects in a group.
•
Tachycardia (> 150 beats/min) in the resting supine position (confirmed by
2 repeat measurements) on at least 1 occasion within a 24-hour interval in
≥1 subject in a group.
•
Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic
blood pressure > 110 mmHg) in the resting supine position (confirmed by
2 repeat measurements) on at least 1 occasion within a 24-hour interval in
≥1 subject in a group.
•
The dose will not exceed 20 µg or the systemic exposure for any
individual subject is predicted to exceed a Cmax of 24.9 ng/mL (plasma)
and/or an AUC0-24 of 128 ng/mL; i.e., systemic exposure will be no
greater than the NOAEL in the most sensitive species (100,000 pmol/kg
in rat [462 µg/kg]).
Section 4.2 
Exclusion criteria added: 
4.
Female subjects who are pregnant or breastfeeding.
Section 4.4 
Previously read: 
•
any clinically relevant sign or symptom that, in the opinion of the
Investigator (or designee), warrants subject withdrawal
Now reads: 
•
any clinically relevant sign or symptom that, in the opinion of the
Investigator (or designee), warrants subject withdrawal, including:
o
a serious adverse reaction (i.e., a SAE considered at least
possibly related to OLP-1002 administration),
o
severe non-serious adverse reaction (i.e., severe non-serious AE
considered to at least possibly related to OLP-1002
administration),
o
elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN),
o
QTcF increases > 60 msec compared to baseline (predose for
Part A or Day 1 predose for Part B) and/or absolute QTcF
values > 500 msec (confirmed by repeat measurement),
o
Tachycardia (> 150 beats/min) in the resting supine position
(confirmed by 2 repeat measurements),


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o
Severe hypertension (systolic blood pressure > 180 mmHg
and/or diastolic blood pressure > 110 mmHg) in the resting
supine position (confirmed by 2 repeat measurements).
Section 7.1 
Section added: 
7.1  Pharmacokinetic Assessments 
7.1.1 Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times 
indicated in the Schedule of Assessments (Appendix 6). Furthermore, 
additional blood samples may be taken from each subject per treatment 
period, with the maximum volume of blood withdrawn per subject not 
exceeding the limit detailed in Appendix 3. Any changes to the scheduled times 
of PK assessments will be agreed with the Sponsor and documented in the 
TMF. Samples taken from subjects who received placebo will not be analyzed. 
In Part A, only samples collected from subjects that received >12 µg OLP-1002 
will be initially analyzed. If PK data is quantifiable at concentrations of OLP-
1002 >12 µg, samples from lower dose groups will be retrospectively analyzed. 
In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated 
analytical procedures. Specifics of the analytical methods will be provided in 
separate documents. 
Section 8.2 
Previously read: 
8.2.1 Pharmacodynamic population 
The PD population will include all subjects who received at least 1 dose of study 
treatment OLP-1002 or placebo and for whom PD can be evaluated. 
8.2.2 Safety Population 
The safety population will include all subjects who received at least 1 dose of study 
treatment or placebo and have at least 1 postdose safety assessment. 
Now reads: 


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8.2.1 Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of 
OLP-1002 that have evaluable PK data and have had no AEs or protocol 
deviations considered to impact PK. 
8.2.2 Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-
1002 or placebo and for whom PD can be evaluated. 
8.2.3 Safety Population 
The safety population will include all subjects who received at least 1 dose of 
OLP-1002 or placebo. 
8.3 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma and 
urine concentration data, using commercial software such as Phoenix® 
WinNonlin®. Plasma concentrations of OLP-1002 and PK parameters will be 
listed and summarized using descriptive statistics. Individual and arithmetic 
mean OLP-1002 concentration-time profiles will also be presented graphically. 
Appendix 3 
Table updated: 
Part A 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis* 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
33.5109.5 
Part B 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 


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Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
78.5194.5 
Appendix 6 
PK and Blood sampling rows added to the schedule of events for Part A and Part B. 
In the Schedule of events for Part A, footnote e was added. In the Schedule of 
events for Part B, footnote b was added. 
Clinical chemistry, hematology, and urinalysis was added to the Schedule of events 
for Part A on Day 14.  


TITLE PAGE 
Protocol 
OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single 
and Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, 
and Pharmacodynamic Study in Healthy Male and Female Subjects 
Protocol Status: Final 
Protocol Date: 12 December 2018 
Protocol Version: 2.2 
Investigational Product: OLP-1002 
 
Protocol Reference Number: OLP-1002-001 
Covance Study Number: 8379789 
EudraCT Number: 2018-003085-13 
 
 
Sponsor: 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung-gu, Yongin, Gyeonggi 17015 
Republic of Korea 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street  
Leeds, LS2 9LH 
United Kingdom 
 
 
Sponsor Signatory: 
 
 
Principal Investigator: 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP-1 002-001 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
 
 
Protocol Version 2.2, 12 December 2018 
Date 
Page 2 of79 


Protocol 
Co vance Study: 83 79789 
CONFIDENTIAL 
Protocol Reference: OLP-1002-001 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
 
Principal Investigator 
Protocol Version 2.2, 12 December 2018 
Date 
Page 3 of79 


Protocol 
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Protocol Version 2.2, 12 December 2018 
Page 4 of 79 
STUDY IDENTIFICATION 
Sponsor 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Study Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Medical Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Medical Monitor 
(24-hour emergency 
medical contact) 
 
 
 
 
 
Study Site 
Covance Clinical Research Unit Ltd. 
Springfield House, 
Hyde Street, 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
Project Physician 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 


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Protocol Version 2.2, 12 December 2018 
Page 5 of 79 
 
Clinical Laboratory 
 
 
 
Statistician 
 
Covance 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
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SYNOPSIS 
Title of study: OLP-1002 – A first-in-human, double-blind, placebo-controlled, single and multiple 
subcutaneous dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy 
male and female subjects 
Objectives:  
The primary objective of the study is to assess the safety and tolerability of single and multiple 
subcutaneous doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the pharmacodynamic effect of OLP-1002 
following single subcutaneous doses in healthy volunteers using a capsaicin pain model, and to 
monitor the effects of a single subcutaneous doses of OLP-1002 on cardiac QT interval. Where 
possible, single and/or multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy 
subjects will be determined. 
Study design: 
This will be a double-blind, randomized, placebo-controlled, single and multiple subcutaneous dose 
study conducted in 2 parts, including healthy male and female subjects. 
Number of subjects: 
Part A: 44 subjects will be studied in 8 groups (5 groups of 4 and 3 groups of 8). 
Part B: 24 subjects will be studied in 3 groups (Groups B1 to B3). 
Up to 24 additional subjects may be recruited into Part A and Part B of the study if required. 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged between 18 and 60 years (inclusive) with a body mass index 
between 18.0 and 28.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test product: OLP-1002 
Proposed dose levels for Part A: 30 ng, 120 ng, 400 ng, 1.2 µg, 3 µg, 6 µg, 12 µg, and 20 µg. 
Proposed dose levels for Part B: the doses for Part B will be decided in consultation with the 
Sponsor and on the basis of data from Part A of the study. The highest dose in Part B will be up to 
50% of the highest dose in Part A. 
Administration route: subcutaneous 
Reference product and mode of administration: 
Reference product: placebo 
Administration route: subcutaneous 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 8 weeks for Part A and 
approximately 12 weeks for Part B. 


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Endpoints: 
Pharmacodynamics: 
In Part A, the analgesic effect of OLP-1002 will be investigated in 3 groups consisting of 8 subjects 
(6 active: 2 placebo) using experimental capsaicin-evoked pain methods. Measurement of 
capsaicin-evoked pain will be performed at pre-screening, baseline and on Day 2, and secondary 
hyperalgesia at 5 and 30 minutes post-capsaicin injection. Continuous electrocardiogram (ECG) 
recording will be conducted to investigate the effect of OLP-1002 on cardiac function. 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 12-lead 
ECGs, vital signs measurements, injection site assessment, heat pain threshold and tolerance, and 
physical examinations. 
Pharmacokinetics: 
In Part A, the following PK parameters will be determined where possible: area under the plasma 
concentration-time curve (AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the 
time of the last quantifiable concentration (AUC0-tlast), maximum observed plasma concentration 
(Cmax), time of the maximum observed plasma concentration (tmax), and apparent plasma terminal 
elimination half-life (t1/2). PK analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups 
occurring in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by 
bioanalytical stability data. 
In Part B, the following PK parameters will be determined where possible: AUC over a dosing 
interval (AUC0-τ), AUC0-∞, Cmax, minimum observed plasma concentration (Cmin), tmax, t1/2, observed 
accumulation ratio based on AUC0-τ (RAAUC0-τ), observed accumulation ratio based on Cmax 
(RACmax), and Temporal change parameter (TCP). PK samples from all groups in Part B will be 
analyzed. 
Statistical methods: 
Pharmacodynamics: 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of pharmacodynamic data is planned. 
Safety: 
Safety parameters will be listed and summarized using descriptive statistics. No formal statistical 
analysis of safety data is planned. 
Pharmacokinetics: 
Individual plasma concentrations and PK parameters of OLP-1002 will be listed and summarized 
using descriptive statistics. Individual and mean OLP-1002 concentration-time profiles will be 
presented graphically. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................12 
1.1. 
Overview ................................................................................................................12 
1.2. 
Summary of Nonclinical Pharmacology ................................................................12 
1.2.1. 
In Vitro Pharmacology Studies ....................................................................12 
1.2.2. 
In Vivo Pharmacology Studies ....................................................................13 
1.2.3. 
Ex Vivo Pharmacology Studies ...................................................................14 
1.3. 
Summary of Safety Pharmacology ........................................................................15 
1.4. 
Summary of Toxicology ........................................................................................15 
1.5. 
Summary of Nonclinical Pharmacokinetics ...........................................................16 
1.6. 
Study Rationale ......................................................................................................17 
1.7. 
Benefit-risk Assessment .........................................................................................17 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................17 
2.1. 
Objectives ..............................................................................................................17 
2.2. 
Endpoints ...............................................................................................................17 
2.2.1. 
Primary Endpoints .......................................................................................17 
2.2.2. 
Exploratory Endpoints .................................................................................18 
3. 
INVESTIGATIONAL PLAN ..........................................................................................19 
3.1. 
Overall Study Design and Plan ..............................................................................19 
3.1.1. 
Part A ...........................................................................................................19 
3.1.2. 
Part B ...........................................................................................................21 
3.2. 
Start of Study and End of Study Definitions .........................................................22 
3.3. 
Additional Groups ..................................................................................................22 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................22 
3.4.1. 
Dose Interval ................................................................................................24 
3.4.2. 
Pharmacodynamic Assessment ....................................................................24 
3.5. 
Selection of Doses in the Study .............................................................................25 
3.5.1. 
Starting Dose ................................................................................................25 
3.5.2. 
Exposure ......................................................................................................26 
3.5.3. 
Proposed Doses ............................................................................................27 


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3.6. 
Dose Escalation ......................................................................................................28 
3.7. 
Dose Escalation Stopping Criteria .........................................................................29 
4. 
SELECTION OF STUDY POPULATION .....................................................................30 
4.1. 
Inclusion Criteria ...................................................................................................30 
4.2. 
Exclusion Criteria ..................................................................................................30 
4.3. 
Subject Number and Identification ........................................................................32 
4.4. 
Subject Withdrawal and Replacement ...................................................................32 
4.5. 
Study Termination .................................................................................................33 
5. 
STUDY TREATMENTS .................................................................................................33 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................33 
5.2. 
Study Treatment Administration ............................................................................33 
5.3. 
Randomization .......................................................................................................33 
5.4. 
Blinding..................................................................................................................34 
5.5. 
Treatment Compliance ...........................................................................................34 
5.6. 
Drug Accountability...............................................................................................34 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................35 
6.1. 
Concomitant Therapies ..........................................................................................35 
6.2. 
Diet .........................................................................................................................35 
6.3. 
Smoking .................................................................................................................35 
6.4. 
Exercise ..................................................................................................................35 
6.5. 
Blood Donation ......................................................................................................36 
6.6. 
Other Restrictions ..................................................................................................36 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................36 
7.1. 
Pharmacokinetic Assessments ...............................................................................36 
7.1.1. 
Sample Collection and Processing ...............................................................36 
7.1.2. 
Analytical Methodology ..............................................................................37 
7.2. 
Pharmacodynamic Assessments ............................................................................37 
7.2.1. 
Capsaicin-evoked Pain Model .....................................................................37 
7.2.2. 
Secondary Hyperalgesia ...............................................................................37 
7.3. 
Safety and Tolerability Assessments .....................................................................37 
7.3.1. 
Adverse Events ............................................................................................37 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................38 
7.3.3. 
Vital Signs ....................................................................................................38 
7.3.4. 
Electrocardiogram ........................................................................................39 
7.3.5. 
Heat Pain Threshold Test .............................................................................39 
7.3.6. 
Physical Examination...................................................................................40 
7.3.7. 
Body Weight and Height .............................................................................40 
7.3.8. 
Injection Site Assessments ...........................................................................40 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................42 


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8.1. 
Determination of Sample Size ...............................................................................42 
8.2. 
Analysis Populations ..............................................................................................42 
8.2.1. 
Pharmacokinetic Population ........................................................................42 
8.2.2. 
Pharmacodynamic Population .....................................................................42 
8.2.3. 
Safety Population .........................................................................................42 
8.3. 
Pharmacokinetic Analyses .....................................................................................42 
8.4. 
Pharmacodynamic Analyses ..................................................................................43 
8.5. 
Safety Analysis ......................................................................................................43 
9. 
REFERENCES ................................................................................................................43 
10. APPENDICES .................................................................................................................45 
Appendix 1: Adverse Event Reporting ..............................................................................46 
Appendix 2: Clinical Laboratory Evaluations ...................................................................50 
Appendix 3: Total Blood Volume ......................................................................................51 
Appendix 4: Contraception Guidance ................................................................................52 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................55 
Appendix 6: Schedule of Assessments ..............................................................................58 
Appendix 7: Protocol Amendment Summary of Changes .................................................65 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 ........................26 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 ....................27 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B ..........................................................................................................27 
 
Figure 1: 
Study Schematic (Part A)...........................................................................20 
Figure 2: 
Study Schematic (Part B) ...........................................................................22 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve extrapolated to infinity 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours postdose 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
DN 
Dose normalized 
DRG 
dorsal root ganglion 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Emax 
maximum pain intensity 
FCA 
Freund's Complete Adjuvant 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SNL 
spinal nerve ligation 
t1/2 
elimination half-life 
tEmax 
time of maximum pain intensity 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
VAS 
Visual Analogic Scale 
VGSC 
voltage-gated sodium channel 


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1. INTRODUCTION 
1.1. 
Overview 
OLP-1002 is a novel peptide nucleic acid (PNA) derivative which acts as a specific voltage-
gated sodium channel (VGSC) protein (Nav1.7) inhibitor, and is being developed by OliPass 
for the treatment of pain. 
The Nav1.7 protein is a subtype of VGSCs. Nav1.7 is particularly important in nociception 
and pain signaling, with congenital loss-of-function mutations in Nav1.7 resulting in the 
inability to experience pain. Selective Nav1.7 inhibitors are believed to have the potential to 
treat severe pain safely1. The active sites of VGSC subtypes are virtually indistinguishable by 
their 3-dimensional structure and thus the discovery of selective Nav1.7 small molecule 
inhibitors has been extremely challenging. Since inhibition of Nav1.5 subtype elicits long QT 
cardiotoxicity, inhibition of Nav1.5 subtype should be avoided at therapeutic doses. 
To date, there are several Nav1.7 inhibitors claimed to be selective that have been evaluated 
in human subjects: 
• Vixotrigine (formerly known as raxatrigine) inhibits Nav1.7 as well as other VGSC 
subtypes. Vixotrigine is in phase III clinical development for trigeminal neuralgia. 
Due to the limited Nav1.7 selectivity over Nav1.5, vixotrigine was evaluated primarily 
in patients with a low heart risk. 
• Funapide is a Nav1.7 inhibitor with limited Nav1.7 selectivity, and was in phase IIb 
clinical trials as of July 2014. Although funapide showed analgesic activity in a small 
number of erythromelalgia patients, dose-limiting adverse events (AEs), including 
dizziness and somnolence, were observed2. The central nervous system (CNS) AEs 
were due to its poor Nav1.7 selectivity. 
• PF-05089771 is a Nav1.7 selective inhibitor with a claimed Nav1.7 selectivity of 
> 2000-fold versus other subtypes of sodium channel and was evaluated in patients of 
erythromelalgia or dental pain. It is thought low drug concentrations achieved in the 
target tissue could be a possible explanation for its poor analgesic activity in human 
patients3. 
OLP-1002 is fully complementary to a 14-mer RNA sequence spanning the junction of 
intron 4 and exon 5 in the human SCN9A pre-mRNA which codes for the Nav1.7 channel. 
OLP-1002 yields SCN9A mRNA splice variant(s) encoding variant Nav1.7 protein(s) lacking 
the sodium channel activity (ie, a non-functional channel), thereby inhibiting Nav1.7 channel 
function. 
1.2. 
Summary of Nonclinical Pharmacology 
1.2.1. 
In Vitro Pharmacology Studies 
Overall, results from the in vitro pharmacology studies showed OLP-1002 elicits responses 
consistent with its designed function4. It inhibits SCN9A mRNA expression and yields the 


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Nav1.7 variant protein or proteins lacking sodium channel activity. Its effects are highly 
selective, which may provide for an improved margin of safety compared to other Nav1.7 
inhibitors. 
OLP-1002 at 1 to 100 zM in PC3 prostate carcinoma cells induced exon skipping and yielded 
SCN9A mRNA splice variant(s) encoding a Nav1.7 variant protein or proteins lacking 
sodium channel activity.  
In rat dorsal root ganglion (DRG) neuronal cells, OLP-1002 at 1000 zM inhibited Nav1.7 
protein expression by > 50%, while OLP-1002R at 100 and 1000 zM inhibited Nav1.7 
expression almost completely. As OLP-1002R is fully complementary to rat SCN9A pre-
mRNA, OLP-1002R would be predicted to be more potent than OLP-1002 in this cell type. 
SCN9A mRNA expression level was evaluated by quantitative polymerase chain reaction 
(qPCR). OLP-1002 inhibited the expression of the SCN9A mRNA in PC3 cells with sub-
attomolar potency.  
In SH-SY5Y human neuroblastoma cells stimulated with tumor necrosis factor (TNF)-1α to 
upregulate the expression of SCN9A mRNA, OLP-1002 decreased expression by 46% to 
49% at 1 fM to 10 pM. In rat DRG neuronal cells, OLP-1002 at 1 fM significantly decreased 
SCN9A mRNA expression by 54%. 
In rat DRG neuronal cells, OLP-1002 markedly and significantly inhibited the sodium current 
by 77% at 0.1 aM and 73% at 1 aM, while for OLP-1002R, the inhibition was 66% at 0.1 aM 
and 70% at 1 aM. Given that rat DRG neuronal cells express various subtypes of sodium 
channel, the observed inhibitions of 66% to 77% correspond to the complete knockout of the 
Nav1.7 sodium channel subtype with OLP-1002 or OLP-1002R. 
The Nav1.7 selectivity over Nav1.5 was evaluated in H9C2 rat cardiomyocytes which are 
known to abundantly express the rat Nav1.5 sodium channel subtype. Following incubation 
with OLP-1002 or OLP-1002R at 1 aM or 1 pM, there were no notable decreases in the 
sodium current. Considering that OLP-1002 and OLP-1002R inhibit the expression of Nav1.7 
protein at 1 aM or lower in rat DRG neuronal cells, the Nav1.7 selectivity of OLP-1002 and 
OLP-1002R over Nav1.5 is estimated to be in excess of one million-fold. Such a large Nav1.7 
selectivity over Nav1.5 has not been realized with small molecule Nav1.7 inhibitors, 
suggesting that OLP-1002 potentially offers pain management with much greater 
cardiovascular safety. 
1.2.2. 
In Vivo Pharmacology Studies 
Spinal nerve ligation (SNL) has been widely applied as a rat model for neuropathic pain. 
OLP-1002 and OLP-1002R were found to be very potent, but highly variable in potency, in 
reversing neuropathic allodynia in this model. Analyses of the therapeutic potency strongly 
suggested that a marked proportion of subcutaneously (SC) administered OLP-1002 or OLP-
1002R may have been topically delivered directly to the spinal nerves exposed in the dorsal 
cavity created during the SNL modelling. In addition, the variability of the therapeutic 
potency may be due to a variable degree of healing of the SNL surgery wound. If an animal 


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recovers slowly, the animal tends to be left with a dorsal cavity. Therefore, estimations of 
potency in these studies with this model should be treated with caution. 
In one study using the SNL model, allodynia in rats was slowly and gradually reversed by 
OLP-1002 SC administered at nominal doses of 1, 3, and 6 pmol/kg once every 2 days (due 
to adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). As the onset time for pain reduction was 4 days, 
the doses used were not sufficient for fast onset of activity. In this study, the animals should 
have reasonably recovered from the dorsal wound, and therefore less susceptible to topical 
delivery directly to the exposed spinal nerves. However, in another study in this model, when 
OLP-1002 was intraperitoneally (IP) administered once every 3 days to avoid the likelihood 
of local delivery to the spinal nerves, OLP-1002 surprisingly reversed the allodynia at 
5 fmol/kg, and was superior or comparable to pregabalin 30 mg/kg, a gold standard for 
neuropathic pain studies. The high potency shown at 5 fmol/kg IP strongly suggests the 
possibility that OLP-1002 is efficiently absorbed by the enteric nervous system, travels to the 
spinal cord, and then redistributes to the spinal nerves of the SNL ligation. This opens the 
possibility of efficient oral delivery of OLP-1002 to the spinal cord. 
When evaluated for their ability to reverse the inflammatory pain in rats inflicted with 
Freund's Complete Adjuvant (FCA)-induced severe paw inflammation, OLP-1002 at 
300 pmol/kg and OLP-1002R at 100 pmol/kg significantly reversed the thermal hyperalgesia, 
and both were more effective than pregabalin 30 mg/kg. 
Paw burn injury induces hyperalgesia in rats and is known to upregulate Nav1.7 expression in 
the L5 and L6 DRGs of the affected side. Burn injury induces a far weaker degree of paw 
inflammation than FCA-induced paw inflammation. OLP-1002 SC administered inhibited the 
thermal hyperalgesia in paw burn injury in a dose-dependent manner. At 25 fmol/kg, OLP-
1002 did not inhibit thermal hyperalgesia. Although OLP-1002 at 625 fmol/kg significantly 
inhibited the thermal hyperalgesia, the efficacy was moderate and weaker than pregabalin 
30 mg/kg. This suggests that SC dosing does not offer the local topical delivery to spinal 
nerves in this model as seen in rats without a dorsal cavity wound. In this study, the Nav1.7 
expression in the DRG of the burn injury side significantly decreased by 58% with 
625 fmol/kg OLP-1002, validating the target engagement for analgesic activity. 
An intraplantar injection of formalin induces severe acute pain. The contributors to acute pain 
are known to be complex and require further elucidation. However, acute peripheral 
inflammation is known to contribute much to Phase II Pain (pain from 10 to 40 min after the 
formalin injection). In this model, OLP-1002 significantly inhibited Phase II Pain at 
comparable or saturated efficacy when SC administered at 10 to 100 pmol/kg (due to 
adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). Thus peripheral acute inflammatory pain could be 
treated with 10 pmol/kg or less. 
1.2.3. 
Ex Vivo Pharmacology Studies 
One day post-SC injection, OLP-1002 and OLP-1002R at 100 pmol/kg significantly inhibited 
the expression of Nav1.7 protein by 39% and 57%, respectively, in the spinal cord of rats 
subjected to SNL.  


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In other rats subjected to SNL, OLP-1002R slowly and gradually reversed the allodynia in a 
dose-dependent manner. OLP-1002R at 30 fmol/kg (the highest dose administered) had the 
greatest effect, but the dose was not high enough to elicit full therapeutic efficacy. 
OLP-1002R inhibited expression of Nav1.7 protein in these animals, most notably at 1 
fmol/kg, and decreased SCN9A mRNA expression by approximately 40% at 1 to 30 fmol/kg. 
The observed inhibitions were largely consistent with the in vivo therapeutic activity 
findings. 
Taking all the in vivo and ex vivo findings together, OLP-1002R was concluded to inhibit 
neuropathic allodynia by inhibiting the expression of the SCN9A mRNA and the Nav1.7 
protein. 
1.3. 
Summary of Safety Pharmacology 
In vitro, OLP-1002 did not inhibit the human ether-à-go-go-related gene (hERG) channel 
current expressed in human embryonic kidney (HEK) cells at the highest concentration tested 
2 μM (the limit of the validated analytical method for OLP-1002). 
In the in vivo safety pharmacology studies, OLP-1002 SC administered at dose levels up to 
100 nmol/kg had no effect on body temperature, neurological function, or respiratory 
function in rats, and had no significant toxic effect on cardiovascular function in cynomolgus 
monkeys. 
1.4. 
Summary of Toxicology 
In rats, following twice-weekly SC dosing for 13 weeks, OLP-1002-related microscopic 
findings included pigment accumulation in the kidney of males administered 
100 nmol/kg/dose and females administered ≥ 10 nmol/kg/dose, foreign material and 
vacuolated macrophage infiltrates in males and/or females administered ≥ 1 nmol/kg/dose, 
and an increased incidence and/or severity of mononuclear cell infiltrates at the injection sites 
in males and/or females administered ≥ 10 nmol/kg/dose. These findings persisted through 
the recovery phase in animals administered 100 nmol/kg/dose. However, the effects were 
considered non-adverse due to their mild severity and lack of impact on animal health and 
wellbeing. The no-observed-adverse-effect level (NOAEL) was 100 nmol/kg/dose. This dose 
level corresponded to maximum observed plasma concentration (Cmax) and area under the 
plasma concentration-time curve (AUC) from 0 to 24 hours postdose (AUC0-24) values of 
27.6 ng/mL and 174 ng·hr/mL, respectively, in males and 24.9 ng/mL and 128 ng·hr/mL, 
respectively, in females on Day 88 of the dosing phase. 
In cynomolgus monkeys, following twice-weekly SC dosing for 13 weeks, OLP-1002-related 
microscopic findings included mononuclear cell infiltrates at the SC injection sites of animals 
administered ≥ 10 nmol/kg/dose. This finding was not resolved with the completion of the 
recovery phase. However, the effects of 100 nmol/kg/dose were considered non-adverse due 
to the mild severity of findings and the lack of impact on animal health and wellbeing. The 
NOAEL was 100 nmol/kg/dose (equivalent to 462.29 µg/kg/dose), which corresponded to 
Cmax and AUC from 0 to 72 hours postdose (AUC0-72) values of 121 ng/mL and 
2840 ng·hr/mL in males, respectively, and 216 ng/mL and 4840 ng·hr/mL in females, 
respectively, on Day 88 of the dosing phase. 


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The genotoxic and mutagenic potential of OLP-1002 was evaluated with standard Good 
Laboratory Practice (GLP) via in vitro bacterial mutagenicity and chromosomal aberration 
studies, and was found to be negative. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
In rats, following a single SC dose of 14C-OLP-1002, the time of maximum observed 
concentration (Tmax) was 0.5 to 1 hour for both radioactivity and parent compound. Plasma 
concentrations of total radioactivity were quantifiable through the last sampling time of 72 
hours postdose, but was variable for the parent compound. The elimination half-life (t1/2) of 
total radioactivity from plasma was 23 hours. Total radioactivity distributed into tissues, 
including those of the CNS protected by the blood-brain barrier. 14C-OLP-1002-derived total 
radioactivity was not rapidly excreted from rats, with minimal amounts present in urine and 
feces. The bulk of the total radioactivity remained in carcasses, primarily in kidneys (cortex 
and medulla) and liver. Parent 14C-OLP-1002 was present in plasma and tissues, but 
concentrations declined over time and were substantially lower than total radioactivity 
concentrations at the later sampling times.  
After a single SC administration of 14C-OLP-1002 to rats, the highest concentrations of total 
radioactivity were retained predominantly in the liver (10.4% to 13.3% of the dose), kidney 
cortex (3.47% to 4.96%), and kidney medulla (1.10% to 1.59% of the dose) through 168 
hours postdose. For all other tissues, the total amounts of total radioactivity were 
substantially less, ranging from 0.0000203% in the 5th DRG to 0.327% in the spleen. 
Radioactivity was excreted slowly via both the renal and fecal routes of elimination. Total 
average recoveries of radioactivity in urine and feces through 336 hours postdose accounted 
for 2.31% and 1.75% of the administered radioactivity, respectively. The bulk of the 
administered total radioactivity was retained in the rat carcasses through 168, 336, 504, and 
840 hours postdose. The kidney cortex, kidney medulla, and liver were the 3 tissues that 
retained the greatest amounts of the administered radioactivity. 
Following a 16.1-µg/kg dose in rats, the plasma concentrations were still quantifiable at 
72 hours postdose and the rate of elimination was slow, with t1/2 17.5 hours. It was not 
possible to accurately define the elimination phase for the 2.67- and 5.28-µg/kg dose levels. 
In cynomolgus monkeys, following a single SC dose of 14C-OLP-1002, Tmax ranged from 
0.25 to 1 hour for both total radioactivity and parent compound. Concentrations of total 
radioactivity were sustained in blood and plasma through the last sampling time of 144 hours 
postdose. Concentrations of parent compound were sustained in plasma through the last 
sampling time of 144 hours postdose in 2 of 3 monkeys, and were similar to plasma total 
radioactivity concentrations at 8 hours postdose. From 24 to 144 hours postdose, plasma 
concentrations of total radioactivity were substantially higher than for parent 14C-OLP-1002 
plasma concentrations.  
The mean Cmax of parent 14C-OLP-1002 in plasma was 1.96 ng/mL. The mean plasma Tmax 
was 0.833 hours. Plasma exposure of parent 14C-OLP-1002 based on AUC extrapolated to 
infinity (AUC0-∞), was 12.7 ng·h/mL. After reaching Cmax, plasma concentrations of parent 
14C-OLP-1002 declined with a mean t1/2 of 84 hours. 


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1.6. 
Study Rationale 
This is the first time OLP-1002 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when OLP-1002 is administered SC as single 
and multiple doses to healthy subjects. This information, together with the pharmacodynamic 
(PD) and pharmacokinetic (PK) data, will help establish the doses and dosing regimen 
suitable for future studies in patients. The analgesic effects of OLP-1002 on a capsaicin-
induced pain model will also be investigated. 
1.7. 
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 investigational medicinal product 
(IMP), although there may also be some discomfort from collection of blood samples and 
other study procedures. For subjects in the PD assessment groups in Part A there will be 
some additional discomfort from the capsaicin test. More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with OLP-1002 may be 
found in the Investigator’s Brochure4. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is to assess the safety and tolerability of single and 
multiple SC doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the PD effect of OLP-1002 following 
single SC doses in healthy volunteers using a capsaicin pain model, and to monitor the effects 
of single SC doses of OLP-1002 on cardiac QT interval. Where possible, single and/or 
multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy subjects will be 
determined. 
2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of AEs 
• vital signs measurements (blood pressure, pulse rate, respiratory rate) 
• 12-lead electrocardiogram (ECG) parameters 
• incidence of clinical laboratory abnormalities, based on clinical chemistry, 
hematology, and urinalysis test results 
• physical examinations 
• injection site assessment. 


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• demonstrate that exposure to OLP-1002 does not exceed pre-defined exposure limits 
from non-clinical studies. 
2.2.2. 
Exploratory Endpoints 
The following exploratory objectives will be assessed:  
• pain intensity and duration will be assessed by AUC, maximum pain intensity (Emax), 
and time of maximum pain intensity (tEmax), calculated using a capsaicin-evoked pain 
model. The exploratory endpoint of secondary hyperalgesia will be assessed by the 
area of secondary area of hyperalgesia (Part A only). 
• continuous (24-hour) ECG monitoring will be recorded in this study and archived for 
potential future analysis of OLP-1002 effects on the QT interval (Part A). 
• heat pain threshold measurements and heat pain tolerance measurements. 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from time zero to 
infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable concentration 
(AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK: 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 


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Other PK parameters may also be added if deemed necessary. 
3. INVESTIGATIONAL PLAN 
This will be a double-blind, randomized, placebo-controlled, single and multiple SC dose 
study conducted in 2 parts. 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy subjects will 
be studied in 8 groups. Up to 3 additional groups (24 subjects in total) may be included for 
further assessment of safety, tolerability, PK, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Potential subjects for Groups A2, A4, and A6 will 
attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will return 
for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 2 days), and for a 
poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential visits 
may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 10 (216 hours postdose) from the lower dose levels. For doses 
≥ 12 µg, PK data will also be reviewed up to Day 7 prior to dose escalation. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 3 subjects will receive 
OLP-1002 and 1 subject will receive placebo. To assess PD parameters, Groups A2, A4, and 
A6 will consist of 8 subjects; 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo.  
Sentinel dosing will be employed for all groups in Part A. To maintain the blind in a 
4-subject group, the first subject will be dosed 48 hours before the second subject, and the 
second subject will be dosed 48 hours prior to the third and fourth subjects. In PD assessment 
groups, 2 subjects (1 active: 1 placebo) will be dosed 48 hours before the remaining 6 
subjects (5 active: 1 placebo). 
An overview of the study design is shown in  
Figure 1.


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Figure 1: 
Study Schematic (Part A) 
Group A1 
(30 ng SC)
3 active:
1 placebo
Group A2
(120 ng SC)
6 active:
2 placebo
Group A3
(400 ng SC)
3 active:
1 placebo
Group A4
(1.2 µg SC)
6 active:
2 placebo
Group A5
(3 µg SC)
3 active:
1 placebo
Group A6
(6 µg SC)
6 active:
2 placebo
Group A7
(12 µg SC)
3 active:
1 placebo
Group A8
(20 µg SC)
3 active:
1 placebo
Group A9
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A10
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A11
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
Groups A9 to A11 may be included if required; dose levels will not exceed the maximum proposed dose of 20 µg. 
Three groups consist of 8 subjects (6 active: 2 placebo); all other groups will consist of 4 subjects (3 active: 1 placebo).


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The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 8 weeks. 
3.1.2. 
Part B 
Part B will comprise a multiple-dose, sequential-group study. Overall, 24 subjects will be 
studied in 3 groups (Groups B1 to B3), with each group consisting of 8 subjects. Up to 
3 additional groups (24 subjects in total) may be included for further assessment of safety and 
tolerability (Section 3.3).  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (± 2 days), 22 (± 2 days), 25 
(± 2 days), and 29 (± 2 days), and for a poststudy visit on Day 57 (± 2 days). 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo. For all subjects, a single subcutaneous dose will be administered on Days 1, 4, 7, 10, 
and 13. Prior to each dosing occasion a physician will review the available safety and 
tolerability data from each subject to confirm it is acceptable to continue dosing. The dosing 
frequency in Part B may be changed following review of data from groups in Part A 
(Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to OLP-1002 at 
steady state is predicted to exceed exposures that have been shown to be safe and well 
tolerated in earlier groups in Parts A or B. In the event of sentinel dosing, 2 subjects (1 active, 
1 placebo) will be dosed at least 4 days prior to the remaining 6 subjects (5 active: 1 placebo). 
Safety data for the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 1 and 2 will be 
reviewed prior to the remaining subjects receiving dose 1). In addition, safety data from each 
subject will be reviewed by a physician prior to each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of safety, 
tolerability, and PK data up to Day 22 (216 hours post-final dose) from the lower dose levels. 
Part B may start after a review of the safety, tolerability, and available PK for Groups A1 to 
A6. The total daily dose administered will not exceed the highest single dose given in Part A. 
An overview of the study design is shown in Figure 2. 


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Figure 2: 
Study Schematic (Part B) 
Group B1
(TBC SC)
6 active:
2 placebo
Group B2 
(TBC SC)
6 active:
2 placebo
Group B3
(TBC SC)
6 active:
2 placebo
Group B4
(TBC SC)
6 active:
2 placebo
Group B5 
(TBC SC)
6 active:
2 placebo
Group B6
(TBC SC)
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
All doses will be confirmed based on results of Part A; dose levels will not exceed the maximum proposed dose 
of 20 µg..  
Groups B4 to B6 will be included if required. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 12 weeks. 
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
 Start of Study and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, PK, and PD data (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]), 
additional dose groups may be added to the study. The maximum dose for any additional 
group will not exceed 20 µg. Up to 3 further groups of 8 subjects (6 active: 2 placebo) may 
be included in Part A, and up to 3 additional groups of 8 subjects (6 active: 2 placebo) may be 
included in Part B. The requirement for additional groups will be agreed with the Sponsor 
and documented in the Trial Master File (TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For both parts of the study, a sequential-group, ascending-dose design has been chosen for 
safety reasons as OLP-1002 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Subcutaneous doses have been 
chosen for both parts of the study, as this is the intended clinical route of administration. 
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, and PK data up 
to Day 7 will be reviewed for all groups receiving ≥ 12 µg OLP-1002. In Part B, safety, 


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tolerability and PK data up to Day 22 will be reviewed for all dose groups. As the t1/2 of 
OLP-1002 is predicted to be approximately 180 hours (based on non-clinical data) review of 
safety data up to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma exposures are 
anticipated to be low, it is expected that it will only be possible to perform an assessment of 
peak concentrations (Cmax) and therefore PK data to Day 7 (Part A) and Day 22 (Part B) will 
be sufficient. Additionally, a cumulative safety review will occur such that additional 
emerging safety data from earlier groups will be considered when making a dose escalation 
decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of females 
of childbearing potential is in accordance with International Council for Harmonisation (ICH) 
M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be sufficient in 
order to determine safety and tolerability. In order to assess the PD effects of OLP-1002, 
3 groups in Part A will include 8 subjects (6 active; 2 placebo). A full review of the safety 
and tolerability data from Part A will be performed to determine the dose regimen for Part B. 
Part B may start after a full review of all safety and tolerability data from Group A1 to A6. A 
review of PD data may also be performed, at the discretion of the Investigator. Details of the 
dosing regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 57-day 
follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups receiving 
≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring 
in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. Dose escalation decisions for doses <12 µg in Part A will not require PK data. 
The rationale for this is that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical species has a 
lower limit of quantification (LLOQ) of 5 ng/mL. The increased sample volume possible 
from humans (compared to small animals) may afford an approximate 10-fold increase in 
sensitivity with possibly an additional 5-fold increase from the use of a more sensitive mass 
spectrometer. This could potentially deliver an LLOQ of around 0.1 ng/mL. Therefore, even 
with the increased assay sensitivity plasma levels from doses at or below 12 µg are not 
expected to be quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose would be 
quantifiable and that a conventional approach to pharmacokinetic will not achieve a full 
definition of the plasma concentration vs time profile or enable an estimation of the terminal 
phase. In addition the planned dose levels have a high safety margin when comparing the 
predicted exposures to the exposures at the NOAEL (see Section 3.5.2), with the 12 µg dose 
level having an expected 312-fold and 255-fold safety margin based on Cmax and AUC0-∞, 
respectively. Therefore, if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
 


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This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
Continuous ECG monitoring will be recorded in this study and archived for potential future 
analysis of OLP-1002 effects on the QT interval, with a view of supporting a potential 
thorough QT study waiver. 
3.4.1. 
Dose Interval 
Following thorough review of all available nonclinical data (pharmacological and 
toxicological), dosing in Part A for groups consisting of 4 subjects will be such that there will 
be 48 hours between the first and second subjects, and 48 hours between the second and 
remaining 2 subjects in each group. For groups in Part A consisting of 8 subjects, 2 subjects 
(1 active: 1 placebo) will be dosed 48 hours prior to the remaining 6 subjects.  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 at steady state 
is predicted to exceed exposures that have been shown to be safe and well tolerated in earlier 
groups in Parts A or B. When used, two subjects (1 active; 1 placebo), will be dosed 4 days 
prior to the remaining 6 subjects (5 active; 2 placebo). The 2 sentinel subjects will always be 
2 doses ahead of the remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not predicted to 
exceed that tested in Part A will be dosed on the same day. Accumulation of OLP-1002 is 
expected following multiple doses, based on the preclinical data, and will be taken into 
account when determining the doses for Part B (see Section 3.5.3). If it is not possible to 
quantify exposure it will be assumed that multiple dosing results in a 4-fold accumulation 
based on the predicted t1/2 of 180h.  
In Parts A and B, there will be a minimum interval of a 10-minute gap between dosing 
subjects (when dosed on the same day). Continuation to dose the remaining subjects in a 
group will be at the Investigator’s discretion. 
3.4.2. 
Pharmacodynamic Assessment 
Pharmacodynamic assessments will be conducted for subjects in Groups A2, A4, and A6. 
Human experimental pain models using healthy volunteers can be used to assess the effect of 
a drug or treatment under controlled clinical conditions. Capsaicin is a vanilloid responsible 
for the pungent taste of hot peppers. In mammalian species, capsaicin-induced pain is 
mediated through Group C nerve fibers following activation of vanilloid 1 transient receptor 
potential (TRPV1) channels5. Nav1.7 has been implicated in controlling neuropeptide release 
from C-fibers, and suppression of capsaicin-induced neurogenic flair has been demonstrated 
by an NAv1.7 inhibitor6. 


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Several studies have used intradermal capsaicin for human experimental pain studies7,8. It has 
been possible to demonstrate dose-dependent responses, with intradermal injections of 
100 μg generally agreed to be the ideal dosage for these studies. Intradermal injection of 
capsaicin causes a brief stinging/burning pain at the injection site (spontaneous pain) 
followed by development of secondary hyperalgesia, which can be assessed using equipment 
such as Von Frey hairs. A study by Gazerani et al.5 found that the response was site-specific 
and while peak pain intensity and duration were greatest in the forehead it was found that 
areas of visible flare and secondary hyperalgesia were significantly larger in the forearm, 
making the forearm the most suitable site for experimentation. 
Covance CRU, Leeds, UK in 2009 performed a validation study using intradermal capsaicin 
(Covance CRU Study: 9999-004) with between-subject and within-subject variability 
demonstrating that the assessments can be reliably conducted to assess pharmacological 
response. 
For these reasons, it has been decided to: 
• Measure both capsaicin-evoked pain and secondary hyperalgesia. 
• Limit the number of capsaicin tests to 3 for each subject (pre-screening, baseline, and 
48 hours postdose) 
• Exclude subjects who have pain <3 or >9 (using a Visual Analogic Scale [VAS]) at 
the pre-screening visit from PD assessment groups. 
3.5. 
Selection of Doses in the Study 
3.5.1. 
Starting Dose 
The rat has been identified as the most sensitive species in a 13-week SC toxicity study with 
a 4-week recovery phase (Covance study no. 8355564). The NOAEL was the 
100 nmol/kg/dose (462.29 µg/kg/dose). This dose level resulted in Cmax of 27.6 ng/mL and 
24.9 ng/mL in males and females, respectively, and AUC0-24 of 174 ng.h/mL and 
128 ng.h/mL in males and females, respectively4. As the exposure was lower in the female 
rats these data have been used to calculate the safety margins. 
The dose of 462.29 µg/kg/dose corresponds to human equivalent doses (HEDs) of 
74.8 µg/kg/dose, which gives a maximum recommended starting dose (MRSD) of 444 µg for 
a 60-kg human and thus a 15000-fold safety margin to the proposed starting dose of 30 ng 
and 22-fold margin to the proposed maximum dose of 20 µg. Additionally the NOAEL dose 
in the cynomolgus monkey was identified as 100 nmol/kg/dose (462.29 µg/kg/dose), which 
gives a higher HED of 150 µg/kg/dose. 
In vivo, doses of 10 pmol/kg/dose (0.0462µg/kg/dose) or less were found to inhibit peripheral 
acute inflammatory pain. The equivalent human dose for a 60-kg human is 44 ng, thus a dose 
at which minimal biological effect is anticipated has been selected as the starting dose of 
30 ng. 


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3.5.2. 
Exposure 
Human exposures have been estimated from the pharmacokinetics in the cynomolgus 
monkey since a non-human primate represents the most closely related species. 
Approximately dose-proportional exposure was seen in the 13-week toxicity study (Covance 
study no. 8355565) and 14C pharmacokinetic study (Covance study no. 8355568) over a dose 
range of approximately 1.1 to 100 nmol/kg (5.06 to 462.29 µg/kg)4. However, the lowest 
dose (5.06 µg/kg) from the 14C study has been used to estimate the human exposures as it is 
closest to the proposed human dose range and has the sufficient quantifiable data. 
The assumptions made in the human exposure estimation were that human exposure would 
be similar to the cynomolgus monkey and that exposure would be linear with dose. Following 
a dose of 5.06 µg/kg in the cynomolgus monkey, the Cmax was 1.96 ng/mL and AUC0-∞ was 
12.7 ng.h/mL. The extrapolated exposures at the planned human doses are shown in Table 1 
with margins calculated to the exposures at the NOAEL in the female rat. 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 
Human dose 
Single dose to human 
Safety margins for single dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax 
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin  
to Cmax 
Margin  
to AUC0-∞ 
0.03 
0.000500 
0.000194 
0.00125 
129000 
102000 
0.12 
0.00200 
0.000775 
0.00502 
32100 
25500 
0.4 
0.00667 
0.00258 
0.0167 
9640 
7650 
1.2 
0.0200 
0.0077 
0.0502 
3210 
2550 
3 
0.0500 
0.0194 
0.125 
1290 
1020 
6 
0.100 
0.0387 
0.251 
643 
510 
12 
0.200 
0.0775 
0.502 
321 
255 
20 
0.333 
0.129 
0.837 
193 
153 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
The dosing interval currently anticipated for the multiple-ascending-dose part of this study is 
72 hours or 96 hours. Thus the average dosing interval (82 hours) is similar to the half-life 
determined in the monkey 14C study of 84 hours. Dosing at approximately once per half-life 
would be anticipated to result in accumulation of around 2-fold. However, higher levels of 
accumulation were observed (2.28-fold for Cmax and 3.76-fold for AUC0-24) on Day 88 at the 
top dose group (100 nmol/kg, 462.28 µg/kg) in the 13-week cynomologus monkey toxicity 
study following twice-weekly dosing (every 72 or 96 hours). Calculations were performed to 
estimate the likely human half-life using a standard 1-point allometric approach from the 14C 
cynomolgus monkey pharmacokinetic study data. The exponents used were 0.75 for apparent 
total plasma clearance (CL/F) and 1 for apparent volume of distribution (Vz/F) values 
combined with the average body weight of the animal (3.1 kg) and scaling to a 60 kg human 
9–11. This resulted in a human half-life estimate of 180 h which in turn gave an accumulation 
estimate of 3.7-fold based upon a dosing interval of 82 h. This further supports the use of the 
greater than 2-fold accumulation from the 13-week cynomolgus study to estimate exposure 
following multiple dosing. Multiplication of the exposure estimates for the single ascending 


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dose by 2.28 for Cmax and 3.76 for AUC resulted in exposure estimates for multiple dosing 
presented in Table 2. 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 
Human dose 
Multiple dose to human 
Safety margins for multiple dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax  
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin 
to Cmax 
Margin 
to AUC0-τ,ss 
0.03 
0.000500 
0.000442 
0.00472 
56000 
27000 
0.12 
0.00200 
0.00177 
0.0189 
14100 
6800 
0.4 
0.00667 
0.00589 
0.0629 
4230 
2030 
1.2 
0.0200 
0.017663 
0.189 
1410 
680 
3 
0.0500 
0.0442 
0.472 
560 
270 
6 
0.100 
0.0883 
0.944 
282 
136 
12 
0.200 
0.177 
1.89 
141 
68 
20 
0.333 
0.294 
3.15 
85 
41 
30 
0.500 
0.442 
4.72 
56 
27 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
3.5.3. 
Proposed Doses 
The proposed IMP dose levels for Parts A and B are shown in Table 3. 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
Study Part 
Group 
Dose (OLP-1002) 
Part A 
A1 
30 ng or placebo 
 
A2 
120 ng or placebo 
 
A3 
400 ng or placebo 
 
A4 
1.2 µg or placebo 
 
A5 
3 µg or placebo 
 
A6 
6 µg or placebo 
 
A7 
12 µg or placebo 
 
A8 
20 µg or placebo 
 
A9* 
TBC or placebo 
 
A10* 
TBC or placebo 
 
A11* 
TBC or placebo 
 
 
 
Part B 
B1 
TBC or placebo 
 
B2 
TBC or placebo 
 
B3 
TBC or placebo 
 
B4* 
TBC or placebo 
 
B5* 
TBC or placebo 
 
B6* 
TBC or placebo 
Abbreviations: TBC = to be confirmed 
* groups to be included if required. 


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In Parts A and B, there should not be an increase of > 3-fold between dose levels above 
120 ng. 
For Part B, dose levels, dosing frequency, and dosing duration will be decided, in 
consultation with the Sponsor, on the basis of data from Part A of the study. Since predictions 
of human exposure of OLP-1002 suggest that OLP-1002 concentrations may be not be 
quantifiable and human data have been estimated from a single species, it is proposed that the 
highest dose in the multiple-ascending-dose part will be up to 50% of the highest dose in the 
single-ascending-dose part (ie, if the highest dose in the single-ascending-dose part is 20 µg, 
the highest dose in the multiple-ascending-dose part will be 10 µg). Therefore, if the 
predicted accumulation of 3.7-fold occurs, the highest exposure in the multiple-ascending-
dose part will not exceed ~2-fold the maximum exposure in the single-ascending-dose part. 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose administered will 
not exceed 20 µg and predicted systemic exposure will not exceed that stated in the dose 
escalation stopping criteria [Section 3.7]) based on available PK data. 
Details of all doses administered in Parts A and B of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
In Part A, doses will be administered in an escalating manner following satisfactory review 
by the Sponsor and Investigator of the safety, and tolerability data up to Day 10 (216 hours 
postdose) from groups that received lower doses of OLP-1002. For escalation to doses 
> 12 µg, PK data up to Day 7 (144 hours postdose) will also be reviewed. All available 
safety, tolerability, and PK data from previous groups will be reviewed prior to dose 
escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and may be lower than the starting 
dose. Available safety, tolerability, and PK data from all previous groups will be reviewed 
prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups A1, 
A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have been reviewed from the 
previous lower dose group, such that data from a minimum of 3 or 4 subjects, respectively, 
who have received OLP-1002 will be used to make the dose-escalation decision. Dose 
escalation in Part B will only occur if data from a minimum of 6 subjects have been reviewed 
from the previous lower dose group, such that data from a minimum of 4 subjects who have 
received OLP-1002 will be used to make the dose-escalation decision. 
The justification for this is as follows: 
• The study drug is of a known pharmacological class for which the on-target effects in 
humans are well characterized. Based upon nonclinical data, no clinically important 
off-target effects are expected within the proposed dose range. 


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• A minimum of 3 subjects receiving the active drug is considered sufficient to 
characterize the safety profile for OLP-1002. 
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarizing 
results from all available safety assessments, will be sent to the Sponsor and a dose-escalation 
meeting will occur prior to the start of each successive group. Any clinically significant 
results will be discussed with the Sponsor before dose escalation continues. Interim PD data 
may also be reviewed on an ongoing basis. In the event of a disagreement between Sponsor 
and Investigator on the dose-escalation decision, the decision of the Investigator will be 
upheld. 
3.7. 
Dose Escalation Stopping Criteria 
In Parts A and B, following consultation with the Sponsor, dose escalation will be stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in 
a group that, in the opinion of the Investigator, warrant stopping of dose escalation. 
• One or more subjects experience an SAE that is considered to be related to OLP-1002. 
• Two or more subjects in the same group experience severe non-serious AEs (ie. 
severe non-serious AEs considered as, at least, possibly related to OLP-1002 
administration), independent of whether the AEs are within or not within the same 
system organ class.  
• There is evidence of clinically significant increases in aspartate aminotransferase, 
alanine aminotransferase or alkaline phosphatase (defined as 3 times the upper limit 
of normal), or total bilirubin (defined as 2 times the upper limit of normal) that are 
considered to be related to OLP-1002 in 2 or more subjects in a group. Results will be 
confirmed with repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose for 
Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat measurement) 
in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 110 mmHg) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• The dose will not exceed 20 µg or the systemic exposure for any individual subject is 
predicted to exceed a Cmax of 24.9 ng/mL (plasma) and/or an AUC0-24 of 128 ng/mL; 
i.e., systemic exposure will be no greater than the NOAEL in the most sensitive 
species (100,000 pmol/kg in rat [462 µg/kg]). 


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If the sponsor deems it appropriate to resume dosing after the internal safety review, it 
can be done after the approval of a substantial protocol amendment. 
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. Healthy male or females of any race, between 18 and 60 years of age, inclusive. 
2. Body mass index (BMI) between 18.0 and 28.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, single 12-lead ECG (resting heart rate > 45 bpm and 
< 90 bpm), vital signs measurements, and clinical laboratory evaluations (congenital 
nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome based on total 
and direct bilirubin] is not acceptable) at Screening as assessed by the Investigator (or 
designee).  
4. Willing to abide by the contraception requirements 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: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. Any of the following: 
• QTcF > 450 ms confirmed by repeat measurement. 
• QRS duration > 110 ms confirmed by repeat measurement. 
• PR interval > 220 ms confirmed by repeat measurement. 
• findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
• history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalemia, family history of long QT syndrome). 
4. Female subjects who are pregnant or breastfeeding. 
5. History of alcoholism or drug/chemical abuse within 1 year prior to Screening. 


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6. Alcohol consumption of > 21 units per week for males and >14 units per week for 
females. 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. 
7. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
8. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
9. Active skin conditions such as dermatitis, allergy, eczema, psoriasis, or abnormal 
healing. 
10. Tattoos, scars, or moles that in the opinion of the Investigator are likely to interfere 
with dosing or study assessments at any of the potential injection sites. 
11. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days or 5 half-lives of the investigational product, 
whichever is longer, prior to Check-in. 
12. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 
13. Use or intend to use any prescription medications/products other than hormone-
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptive concomitant medications within 14 days prior to Check-in, unless 
deemed acceptable by the Investigator (or designee). 
14. 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). 
15. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee) and/or 
Sponsor have given their prior consent. 
16. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.  
17. Receipt of blood products within 60 days prior to Check-in. 
18. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening.  
19. Poor peripheral venous access. 
20. Have previously completed or withdrawn from this study or any other study 
investigating OLP-1002, and have previously received the investigational product. 
21. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
22. Part A – PD assessment groups only 
• Subjects considered non-acceptable responders to the intradermal capsaicin 
test at screening, defined as maximum VAS score of < 3.0 or > 9.0. 


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4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomization. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, in Part A, Subjects 101, 102, 
etc., in Part B Subjects 201, 202, etc.). Replacement subjects (Section 4.4) will be assigned a 
subject number corresponding to the number of the subject he/she is replacing plus 1000 
(eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least possibly related to 
OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE considered to 
at least possibly related to OLP-1002 administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements). 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the 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 stabilized. 


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Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• 
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) 
• 
medical or ethical reasons affecting the continued performance of the study 
• 
difficulties in the recruitment of subjects 
• 
cancelation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Vials of OLP-1002 Injection Solution 100 µg/mL (1.5 mL in 5-mL vials) and the Diluent for 
OLP-1002 Injection Solution (5 mL in 10-mL vials) will be supplied by the Sponsor, along 
with the batch/lot number and Certificate of Analysis. The Diluent for OLP-1002 Injection 
Solution will also be used as the Placebo formulation. A certificate of batch certification and 
release, authorized by a Qualified Person in the European Union (EU) will also be issued, by 
a Covance CRU Qualified Person, for each batch of IMP imported into the EU. 
The IMPs will be stored according to the instructions on the label at the CRU in a location 
that is locked with restricted access. 
Dose solutions (OLP-1002 Injection Solution diluted with the Diluent for OLP-1002 
Injection Solution) will be prepared by Covance CRU Pharmacy staff in accordance with 
instructions provided in the Pharmacy Manual. The Placebo formulation will be the Diluent 
for OLP-1002 Injection Solution without further manipulation. 
5.2. 
Study Treatment Administration 
Subjects will be administered the IMP in numerical order. OLP-1002 will be administered by 
SC injection in the upper arm. If subcutaneous dosing of OLP-1002 in the upper arm is not 
possible, the subject may be dosed in the abdomen at the Investigator’s discretion. For 
subjects in Groups A2, A4, and A6, dosing will be on the opposite arm to the intradermal 
capsaicin test. 
5.3. 
Randomization 
The randomization code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. In Part A, 1 subject in groups 


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consisting of 4 subjects, and 2 subjects in groups consisting of 8 subjects, will be randomly 
assigned to receive placebo. In Part B, 2 subjects per group will be randomly assigned to 
receive placebo. All other subjects in a group will be randomized to receive OLP-1002. 
Prior to the start of the study, a copy of the master randomization code will be supplied into 
the Covance CRU pharmacy staff (in sealed envelopes). 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo solution will be identical in appearance to the OLP-1002. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 
To maintain the blind, the Investigator will be provided with sealed randomization 
code-break envelopes for each subject, containing details of their treatment. These individual 
sealed envelopes will be kept in a limited access area that is accessible 24 hours a day. In 
order to manage subject safety or to support dose-escalation decisions (in the event of 
possibly treatment-related SAEs or severe AEs), the decision to unblind resides solely with 
the Investigator. Whenever possible, and providing it does not interfere with or delay any 
decision in the best interest of the subject, the Investigator will discuss the intended code-
break with the Sponsor. If it becomes necessary to break the code during the study, the date, 
time, and reason will be recorded in the subject’s source data and on the individual envelope 
and will be witnessed by a second person. 
5.5. 
Treatment Compliance 
All doses of IMP will be administered by suitably qualified study site staff. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription medications/products from 14 days prior to 
dosing until the Follow-up visit, and non-prescription medications/products from 7 days prior 
to dosing until the Follow-up visit, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone-replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary 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 standardized 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 safety laboratory tests. On dosing days, 
subjects will receive a light breakfast approximately 2 hours prior to dosing. Meals will be 
provided as appropriate at other times and water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Check-in until the Follow-up visit. 
Xanthine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until Discharge from the site. Xanthine-containing foods and beverages will also not be 
allowed form 36 hours before non-residential site visits. 
Chili pepper/hot sauce will not be allowed for 48 hours prior to Check-in for all subjects. 
Subjects in Groups A2, A4, and A6 will not be allowed chili pepper/hot sauce for 48 hours 
prior to their pre-screening visit. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until 
Discharge. Following discharge, up to 2 units/day of alcohol are permitted until 36 hours 
before each non-residential visit and 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 3 days before Check-in until the 
Follow-up visit and will otherwise maintain their normal level of physical activity during this 


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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. Subjects should not be in receipt of blood products for 
60 days prior to check-in. 
6.6. 
Other Restrictions 
Subjects in Groups A2, A4, and A6 will not be allowed to shower within 1 hour prior to the 
capsaicin-evoked pain tests at prescreening, predose, and postdose. 
Subjects will not be allowed to apply moisturizing creams or oils to the dosing site within 
1 hour prior to dosing, or to the assessment site within 1 hour prior to the capsaicin-evoked 
pain test.  
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): 
• dosing 
• vital signs 
• blood samples 
• cardiac monitoring/ECG extractions 
• any other procedures. 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments (Appendix 6). Furthermore, additional blood samples may be taken 
from each subject per treatment period, with the maximum volume of blood withdrawn per 
subject not exceeding the limit detailed in Appendix 3. Any changes to the scheduled times of 
PK assessments will be agreed with the Sponsor and documented in the TMF. Samples taken 
from subjects who received placebo will not be analyzed. 
In Part A, PK analysis will initially only be conducted for groups receiving ≥ 12 µg 
OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the 


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event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 
7.2. 
Pharmacodynamic Assessments 
Capsaicin intradermal test will be performed for subjects in Groups A2, A4, and A6. Each 
subject will be tested at a pre-screening visit before being tested twice during the study (1 
predose and 1 postdose). 
7.2.1. 
Capsaicin-evoked Pain Model 
The capsaicin model will be conducted by intradermal injection of capsaicin (100 μg in 
100 μL of sterile saline containing 8% [w/w] Tween 80) into the skin of the anterior aspect of 
the forearm, midway between the elbow and the wrist. The bleb area (wheal) will be a sign of 
local plasma extravasation. An assessment of the pain intensity related to capsaicin injection 
will be estimated by repeated use of a VAS from injection to 5 minutes post-injection or until 
the pain intensity returned to zero. The AUC, Emax, and tEmax will be calculated and reported 
using dedicated software. 
7.2.2. 
Secondary Hyperalgesia 
The area of secondary hyperalgesia will be quantified with a 60-g weighted von Frey hair, by 
stimulating along 8 linear paths (4 vectors crossing at the location of the injection site) 
arranged vertically and horizontally around the stimulation site in 5-mm steps (starting 
approximately 6 cm away from the injection site). The area of secondary hyperalgesia will be 
evaluated at 5 and 30 minutes post-capsaicin injection. 
7.3. 
Safety and Tolerability Assessments 
Safety and tolerability assessments will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). Timepoints may be adjusted based on an ongoing review of the 
data, and additional assessments may be conducted if deemed necessary by the Investigator 
or designee. 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs 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 


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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. 
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 drug. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a follicle-stimulating hormone (FSH) test and 
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. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and 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. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. 
Subjects must be supine for at least 5 minutes before blood pressure, pulse rate, and 
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7.3.4. 
Electrocardiogram 
7.3.4.1. 
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: 
• QTcF value > 500 msec 
• QTcF change from the mean baseline (Day 1 predose) is > 60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.3.4.2. 
Continuous (24-hour) Electrocardiogram 
At the times indicated in the Schedule of Assessments (Appendix 6), continuous (24-hour) 
ECGs will be performed.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint. Each extraction will last for 5 minutes. 
Environmental distractions (eg, television, playing games, radio, conversation) should be 
avoided during the pre-ECG time window.  
Continuous 24-hour ECGs are not planned for Part B of the study but may be implemented if 
any clinically significant findings are identified in the data from Part A. 
7.3.5. 
Heat Pain Threshold Test 
Heat pain threshold tests will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). 
A computer-controlled thermal sensory analyzer device will be used to measure the heat pain 
threshold and tolerance level of the subjects. The heat pain assessments will be conducted on 
the subject’s thigh. 
Heat Pain Threshold: 
For heat pain threshold measurements, the thermode will be placed directly on the skin of the 
right thigh, within an area selected before the start of the experiment and defined by surgical 
marking. The thermode will have a baseline temperature of 32 °C, and will be programmed to 
gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 


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their dominant hand, to indicate when the heat pain threshold (first sensation of heat pain) is 
reached by pushing a button. At that time, the test will be stopped and the temperature 
returned to baseline within 1 second. This process will be repeated a further 2 times, with an 
interval of at least 1 minute between measurements (from start to start). The computer will 
record the average value of 3 experiments. 
Heat Pain Tolerance: 
For heat pain tolerance measurements, the thermode will be placed within the same surgically 
marked skin area of the anterior side of the right thigh, which was used to assess heat pain 
threshold. The thermode will have a baseline temperature of 32 °C, and will be programmed 
to gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 
their dominant hand, to indicate when the heat-evoked pain has reached an intensity that is no 
longer tolerable, by pushing a button. At that time, the test will be stopped and the 
temperature returned to baseline within 1 second. This process will be repeated a further 
2 times, with an interval of at least 1 minute between measurements (from start to start). The 
computer will record the average value of 3 experiments. 
Safety Precautions 
As there is a risk that OLP-1002 may affect the heat pain threshold, Covance CRU will put 
appropriate safety measures in place to ensure that subjects are not exposed to extremes of 
temperature when taking a shower or consuming hot drinks. During the heat pain safety 
assessments, the cut-off temperature for either test is 53 °C in order to prevent skin injury. 
7.3.6. 
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.  
7.3.7. 
Body Weight and Height 
Body weight (in underclothes) and height will be recorded at the times indicated in the 
Schedule of Assessments in Appendix 6. BMI will be calculated using the following formula: 
BMI = body weight (kg)      (kg/m2) 
                  (height [m])2 
7.3.8. 
Injection Site Assessments 
Injection site assessments will be made at the times indicated in the Study Plan (Appendix 6). 
Assessments will involve evaluation of the dosing site for the following criteria:  
• Pain will be evaluated according to the following scale: 


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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Does not 
interfere with 
activity 
Interferes with 
activity or 
repeated use of 
non-narcotic 
pain reliever 
Prevents daily 
activity or 
repeated use of 
narcotic pain 
reliever 
Requires 
medical 
intervention 
greater than 
analgesia  
 
• Redness will be assessed by estimating the size of the red patch at the injection site across 
its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm 
51-100 mm 
More than 100 
mm 
Requires 
medical 
intervention 
greater than 
analgesia  
• Swelling will be assessed by estimating the size of the raised area around the injection site 
across its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm and 
does not 
interfere with 
activity 
51-100 mm or 
interferes with 
activity 
More than 100 
mm and 
prevents daily 
activity 
Requires 
medical 
intervention 
greater than 
analgesia 
In addition, how the swelling affects the subject in their daily routing activities will be 
considered. 
• Tenderness will be evaluated using the following scale: 


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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Mild pain to 
touch 
Moderate Pain 
to touch 
Severe pain to 
touch 
Requires 
medical 
intervention 
greater than 
analgesia 
• Bruising and ulceration will be evaluated as being present or absent. 
Local tolerability ratings of ≥Grade 3 and the presence of ulceration will be recorded as an 
adverse event.  
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time OLP-1002 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. In order to achieve PD endpoints 
in Part A, additional subjects will be included in 3 groups (8 subjects in total; 6 active: 
2 placebo). Up to 3 additional groups may be added to Part A, consisting of either 4 subjects 
(3 active; 1 placebo) or 8 subjects (6 active; 2 placebo). Up to 3 additional groups of 
8 subjects may be added to Part B (6 active; 2 placebo). 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of OLP-1002 that 
have evaluable PK data and have had no AEs or protocol deviations considered to impact PK. 
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo and for whom PD can be evaluated. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo. 
8.3. 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma concentration data, 
using commercial software such as Phoenix® WinNonlin®. Plasma concentrations of 


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OLP-1002 and PK parameters will be listed and summarized using descriptive statistics. 
Individual and arithmetic mean OLP-1002 concentration-time profiles will also be presented 
graphically. 
8.4. 
Pharmacodynamic Analyses 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No 
formal statistical analysis of PD data is planned. 
8.5. 
Safety Analysis 
Safety parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 
9. REFERENCES 
1.  Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A 
channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 
14;444(7121):894–8.  
2.  Goldberg YP, Price N, Namdari R, Cohen CJ, Lamers MH, Winters C, et al. Treatment of 
Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel 
blocker. Pain. 2012 Jan;153(1):80–5.  
3.  Jones HM, Butt RP, Webster RW, Gurrell I, Dzygiel P, Flanagan N, et al. Clinical Micro-
Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of 
Human Nav1.7 Voltage-Dependent Sodium Channels. Clin Pharmacokinet. 
2016;55(7):875–87.  
4.  Investigator Brochure - OLP-1002. 2018.  
5.  Gazerani P, Andersen OK, Arendt-Nielsen L. Site-specific, dose-dependent, and sex-
related responses to the experimental pain model induced by intradermal injection of 
capsaicin to the foreheads and forearms of healthy humans. J Orofac Pain. 
2007;21(4):289–302.  
6.  Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, et al. 
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in 
Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE 
[Internet]. 2016 Apr 6 [cited 2018 Jun 15];11(4). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822888/ 
7.  Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-
dependent pain, allodynia, and hyperalgesia in humans. J Investig Med Off Publ Am Fed 
Clin Res. 2006 Jul;54(5):238–44.  


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8.  Anderson WS, Sheth RN, Bencherif B, Frost JJ, Campbell JN. Naloxone increases pain 
induced by topical capsaicin in healthy human volunteers. Pain. 2002 Sep;99(1–2):207–
16.  
9.  Pharmacokinetics and Metabolism in Drug Design, 3rd Edition [Internet]. Wiley.com. 
[cited 2018 Aug 21]. Available from: https://www.wiley.com/en-
us/Pharmacokinetics+and+Metabolism+in+Drug+Design%2C+3rd+Edition-p-
9783527329540 
10.  Mahmood I. Pharmacokinetic allometric scaling of antibodies: application to the first-in-
human dose estimation. J Pharm Sci. 2009 Oct;98(10):3850–61.  
11.  Offman E, Edginton AN. Pharmacokinetic Time Course Scaling of a Subcutaneously 
Administered Pegylated Peptide Conjugate for a First-in-Human Investigation. Eur J 
Drug Metab Pharmacokinet. 2017 Feb;42(1):69–78.  
 
 


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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 unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but posing no 
significant or permanent risk of harm to the subject. 
• 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 drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
• 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. 
• 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. 
• Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized 
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 
stabilized. 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: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize 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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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 48 of 79 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 
Definition of Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization 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 
Covance Drug Safety Services (DSS) Europe, Maidenhead, UK are 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 facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the Safety 
Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of the 
SAE within 2 working days of the initial notification to DSS. Drug Safety Services 
will delete any information from the SAE report forms that may identify the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined in 
the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions 
and forward to the Ethics Committee, Medicines and Healthcare Products Regulatory 
Agency, Principal 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. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfill regulatory requirements any pregnancy reported by female subjects or 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 49 of 79 
the female partners of male subjects should be reported following the SAE process to collect 
data on the outcome for both mother and fetus. 
 
 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Urea 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
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  
Serologya: 
Drug screenb: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
MDMA 
Alcohol breath test 
Follicle-stimulating hormonea  
Serum pregnancy test (human 
chorionic gonadotropin)a 
Urine pregnancy testc 
a Only analyzed at Screening. 
b Only analyzed at Screening and Check-in. 
c A positive urine pregnancy test will be confirmed with a serum pregnancy test. 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
Part A 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
6 
45 
Serology 
3.5 
1 
3.5 
Total: 
124.5  
Part B 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
194.5  
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
during the study will not exceed that donated during a standard blood donation 
(approximately 500 mL). 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 52 of 79 
Appendix 4: Contraception Guidance 
Definitions 
Females of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Females of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 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-estrogens, or selective estrogen 
receptor modulators.  
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. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary highly effective and 1 secondary method) of birth control from the time of signing 
the informed consent form until 90 days after the Follow-up visit. Primary highly effective 
methods of contraception include:  
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  
• hormonal or non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject). 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 53 of 79 
Secondary (barrier) methods of contraception include:  
• male condom with spermicide 
• female condom with spermicide  
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects can only choose a cervical cap or diaphragm if they have already had a 
prescription and fitting by their healthcare provider to ensure protocol requirements are met. 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in until 90 days after the Follow-up 
visit. Acceptable methods of contraception include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide 
• vasectomised male subject (sterilization 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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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
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Sexual Abstinence and Same-sex Relationships 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 55 of 79 
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: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with Clinical Research Unit personnel, subjects will sign 
2 copies of the ICF in the presence of a suitably trained member of staff to indicate that they 
are freely giving their informed consent. One copy will be given to the subject, and the other 
will be maintained in the subject’s records. 
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 


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Protocol Version 2.2, 12 December 2018 
Page 56 of 79 
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 Organization (CRO) auditors or other 
authorized personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All 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.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality tolerance 
thresholds, controls, and mitigation plans will be documented in a risk management 
register. Additional details of quality checking to be performed on the data may be 
included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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. 
• 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.  


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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
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Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 Code of Federal 
Regulations 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 the Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled and randomized subject, according to the 
eCRF completion instructions. The Sponsor, or CRO, will review the supporting source 
documentation against the data entered into the eCRFs to verify the accuracy of the electronic 
data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 
information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 58 of 79 
Appendix 6: Schedule of Assessments 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 59 of 79 
Study Plan – Part A (Single Dose) 
 
Pre- 
screeningd
Screening 
Day
-2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
 
X 
X
 
 
 
 
 
 
Alcohol breath test 
 
X 
X
 
 
 
 
 
 
Cotinine test 
 
X 
X 
 
 
 
 
 
 
Serology 
 
X 
 
 
 
 
 
 
 
 
Hormone panel 
 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
X 
X 
 
 
 
 
 
 
X 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
Day 3 (48 hours 
postdose) 
 
 
 
 
 
Non-residential visit 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Study drug administration: 
 
 
 
 
Day 1 (0 hours)  
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, pulse 
rate, respiratory rate, and 
body temperature 
 
X 
 
 
Predose, 1, 2, 4, 
8, 24 (± 1 hour), 
and 48 hours 
postdose 
X 
X 
X 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 60 of 79 
Pre- 
screeningd
Screening 
Day
-2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Supine 12-lead ECG 
X 
Predose, 4, 24 
(± 1 hour) and 48 
hours postdose 
X
X
X
Continuous ECG 
extractionb,c
-24,  
-23.5,  
-23,  
-22.5,  
-22,  
-21.5,  
-21,  
-20, 
-18,  
-16,  
-12 
hours 
Day 1: Predose, 
0.5, 1, 1.5, 2, 2.5, 
3, 4, 6, 8, 12 and 
24 hours 
Heat pain threshold test 
(heat pain threshold and heat 
pain tolerance) 
Day 1: predose, 2, 
4, 12, and 24 
hours postdose (± 
1 hour) 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
48 hours postdose 
X 
X 
X 
Height and BMI 
X 
Body weight  
X 
X 
X 
Physical examination 
X
Symptom-directed physical 
examination 
Prior to discharge 
X 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 61 of 79 
Abbreviations: BMI = body mass index; ECG = electrocardiogram. 
a A positive urine pregnancy test result will be confirmed with a serum pregnancy test. 
b All times are relative to dosing with OLP-1002. 
c Continuous ECG recording may begin at approximately 25 hours before dosing to allow for checks to be completed prior to the first extraction timepoint and will continue for 24 hours 
postdose, ie, until after the last timepoint for ECG extraction (24 hours postdose). At timepoints for ECG extractions, subjects will be supinely resting for a total of 15 minutes (10-minute supine 
rest period, 5-minute extraction). Data will be archived for potential future analysis and will not be available for review during the study. 
d Pharmacodynamic assessment groups only. 
e PK analysis in Part A will initially only be conducted for groups receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the event of PK data 
being quantifiable at doses ≥ 12 µg and if supported by bioanalytical stability data. 
Pre- 
screeningd 
Screening
Day 
-2
Day 
 -1
Days 1 to 3 
Day 
4
Day 7 
(± 2 days)
Day 10 
(± 2 days)
Day 14 
(± 2 days)
Poststudy 
(Day 28 
± 2 days) 
Injection site assessment 
Predose, 1, 2, 4, 
8, 24, 48 hours 
postdose 
X
X
X
Pharmacokineticse 
Blood sampling 
Predose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 
12, 16, 24, 36 and 
48 hours postdose 
X 
X 
X 
X 
X 
Pharmacodynamicsd:
Intradermal capsaicin test 
(capsaicin-evoked pain and 
secondary hyperalgesia 
measurement) 
X 
X 
Day 2 (The area 
of secondary area 
of hyperalgesia 
will be evaluated 
at 5 and 30 
minutes post-
capsaicin 
injection) 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 62 of 79 
Study Plan – Part B (Multiple Dose) 
 
Screening
Day -1 
Days 1-15 
Day 18 
(± 2 days) 
Day 22 
(± 2 days) 
Day 25 
(± 2 days) 
Day 29 
(± 2 days) 
Poststudy 
(Day 57 
± 2 days) 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
X 
X 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
Cotinine test 
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
Hormone panel 
X 
 
 
 
 
 
 
 
Urine pregnancy testa 
X 
X 
 
 
X 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
Check-out 
 
 
Day 15 (48 hours postdose) 
 
 
 
 
 
Non-residential visit 
X 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
Days 1, 4, 7, 10, and 13 
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording  
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, 
pulse rate, respiratory rate, 
and body temperature 
X 
 
Day 1: predose, 1, 2, 4 and 8 hours 
postdose 
Day 2, Day 4 (postdose), Day 5, Day 7 
(postdose), Day 9, Day 10 (postdose), 
Day 12, Day 13: predose, 1, 2, 4 and 8 
hours postdose, and Day 15 
 
X 
X 
X 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 63 of 79 
 
Screening
Day -1 
Days 1-15 
Day 18 
Day 22 
Day 25 
Day 29 
Poststudy 
(Day 57 
± 2 days) 
Heat pain threshold test 
(heat pain threshold and 
heat pain tolerance) 
X 
 
Day 1 and Day 13: predose, 1, 2, 4, 8, 
24 hours postdose 
 
 
 
 
 
Supine 12-lead ECG 
X 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Days 2, 5, 9, 12, 17 
 
X 
 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
Days 1, 4, 7, 10, 13 
 
X 
 
X 
X 
Injection site assessment  
 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Pharmacokinetics:
 
 
 
 
 
 
 
Blood samplingb 
 
 
Day 1 and Day 13: Pre dose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
X 
X 
X 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 64 of 79 
Abbreviations: BMI = body mass index; ECG = electrocardiogram. 
a Positive urine pregnancy test results will be confirmed with a serum pregnancy test. 
b  PK timepoints will be reviewed based on emerging data and may be updated.


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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
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Appendix 7: Protocol Amendment Summary of Changes 
Protocol Amendment 3 (Version 2.2; 12 December 2018) 
This non-substantial amendment has been issued to include a clinical laboratory assessment 
on Day -2 in Part A. 
Appendix 3 
Additional clinical laboratory sample added to Part A. Total blood volume 
withdrawn in Part A updated to 124.5 mL. 
Appendix 6 
Study Plan (Part A) 
Clinical chemistry, haematology, and urinalysis assessment added on Day -2. 
Protocol Amendment 2 (Version 2.1; 29 November 2018) 
This non-substantial amendment has been issued to correct minor inconsistencies in PK 
sampling timepoints, data cut off for dose escalation, clinical laboratory assessment 
timepoints, and the synopsis. Additionally, details of the injection site assessments have been 
added to the protocol. 
A detailed summary of changes is presented below. For each section, deleted text is shown in 
strikethrough, and new text is shown in bold: 
Synopsis: Endpoints 
Text added: 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 
12-lead ECGs, vital signs measurements, injection site assessment, heat pain threshold 
and tolerance, and physical examinations. 
 
Section 3.6 
Previously read: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
Now reads: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.2, 12 December 2018 
Page 66 of 79 
Day 10 (216 hours postdose) from groups that received lower doses of OLP-1002. 
Section 7.3.8 
Entire section added to describe injection site assessments. 
Appendix 3 
Total blood volume for PK analysis (76 mL) added. 
Appendix 6 - Schedule of assessments Part A 
24 hour postdose continuous ECG recording timepoint added. 
Appendix 6 - Schedule of assessments Part B 
Clinical chemistry, haematology, and urinalysis for Days 1-15 previously read: 
Days 2, 4, 7, 10,13 
Clinical chemistry, haematology, and urinalysis for Days 1-15 now reads: 
Days 2, 5, 9, 12, 17 
 
PK blood sampling for Days 1-15 previously read: 
Day 1 and Day 15: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 8, 11, 15 Predose 
PK blood sampling for Days 1-15 now reads: 
Day 1 and Day 13: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
Protocol Amendment 1 (Version 2; 02 October 2018) 
This amendment has been generated following the non-acceptance of the original protocol 
(version 1) by the Medicines and Healthcare products Regulatory Agency (MHRA) on 20 
September 2018. All changes made have been in response to comments provided by the 
MHRA. 
The primary changes in this amendment are: 
1. Inclusion of PK sampling in Parts A and B: 
• PK objective and exploratory endpoints added (Section 2). 


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• Discussion of PK included Section 3.4. 
• PK stopping criteria added to Section 3.7. 
• PK assessments included in Section 7.1. 
• PK population and analysis (Section 8.2.1). 
• Blood volumes updated to include samples for PK assessments (Appendix 3). 
2. Exclusion and stopping criteria updated 
• Women who are pregnant or breastfeeding have been excluded from the study 
(Section 4.2). 
• Liver function tests, tachycardia, and hypertension stopping criteria have been 
updated (Section 3.7 and Section 4.4). 
• Stopping criteria for SAEs and serious AEs have been added (Section 3.7 and 
Section 4.4). 
3. Safety, tolerability, and PK data up to Day 22 in Part B will be reviewed prior to dose 
escalation (Section 3.1.2). 
4. Sentinel dosing included in Part B (Section 3.1.2). 
5. It has been specified that the maximum dose for additional groups will not exceed 20 
µg (Section 3.5.3). 
Minor changes: 
1. Additional clinical laboratory evaluations have been included on Day 14 in Part A. 
2. The definition of the Safety population has been updated to include all subjects who 
receive OLP-1002. 
3. Typographical errors and formatting errors were corrected, as necessary. 
A detailed summary of changes is presented below. For each section, deleted text is shown in 
strikethrough, and new text is shown in bold: 
Section 1.6 
Previously read: 
This information, together with the pharmacodynamic (PD data, will help establish 
the doses and dosing regimen suitable for future studies in patients. 
Now reads: 
This information, together with the pharmacodynamic (PD) and pharmacokinetic 
(PK) data, will help establish the doses and dosing regimen suitable for future 
studies in patients. 
Section 2.1  


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Objective added: 
Where possible, single and/or multiple subcutaneous dose pharmacokinetics of 
OLP-1002 in healthy subjects will be determined. 
Section 2.2.1 
Endpoint added: 
• demonstrate that exposure to OLP-1002 does not exceed pre-defined 
exposure limits from non-clinical studies. 
Section 2.2.2 
Endpoints added: 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from 
time zero to infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable 
concentration (AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and 
DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 


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o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 
Other PK parameters may also be added if deemed necessary. 
Section 3.1.1 
Previously read: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 7 (144 hours postdose) from the lower dose 
levels. 
Now reads: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, PK, and PD 
(Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 


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Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 10 (216 hours postdose) from the lower dose 
levels. For doses ≥ 12 µg, PK data will also be reviewed up to Day 7 prior to 
dose escalation. 
Figure 1 – footnote 
Text added:  
Groups A9 to A11 may be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Figure 2 – footnote 
Text added: 
Groups B4 to B6 will be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Section 3.1.2 
Previously read: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. There will be no sentinel dosing in Part B. For all subjects, a single 
subcutaneous dose will be administered on Days 1, 4, 7, 10, and 13. The dosing 
frequency in Part B may be changed following review of data from groups in Part 
A (Section 3.4).  
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 18 (120 hours post-final dose) from the lower 
dose levels. Part B may start after a review of the safety and tolerability for Groups 
A1 to A6. The total daily dose administered will not exceed the highest single dose 
given in Part A. 
Now reads: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. For all subjects, a single subcutaneous dose will be administered 
on Days 1, 4, 7, 10, and 13. Prior to each dosing occasion a physician will review 
the available safety and tolerability data from each subject to confirm it is 
acceptable to continue dosing. The dosing frequency in Part B may be changed 


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following review of data from groups in Part A (Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to 
OLP-1002 at steady state is predicted to exceed exposures that have been 
shown to be safe and well tolerated in earlier groups in Parts A or B. In the 
event of sentinel dosing, 2 subjects (1 active, 1 placebo) will be dosed at least 
4 days prior to the remaining 6 subjects (5 active: 1 placebo). Safety data for 
the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 
1 and 2 will be reviewed prior to the remaining subjects receiving dose 1). In 
addition, safety data from each subject will be reviewed by a physician prior to 
each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from the 
lower dose levels. Part B may start after a review of the safety, tolerability, and 
available PK data for Groups A1 to A6. The total daily dose administered will not 
exceed the highest single dose given in Part A. 
Section 3.3 
Previously read: 
Following review of the safety, tolerability, and PD data, additional dose groups 
may be added to the study. 
Now reads: 
Following review of the safety, tolerability, PK, and PD data (where systemic 
exposure is not expected to exceed that stated in the dose escalation stopping 
criteria [Section 3.7]), additional dose groups may be added to the study. The 
maximum dose for any additional group will not exceed 20 µg. 
Section 3.4 
Previously read: 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 


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may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis will not be conducted in this study. The bioanalytical 
method used for preclinical species has a lower limit of quantification (LLOQ) of 
5 ng/mL. The increased sample volume possible from humans (compared to small 
animals) may afford an approximate 10-fold increase in sensitivity with possibly an 
additional 5-fold increase from the use of a more sensitive mass spectrometer. This 
could potentially deliver an LLOQ of around 0.1 ng/mL. It is apparent from the 
predicted plasma concentrations (see Section 3.5.2) that only a small number of 
samples around Cmax at the highest doses would be quantifiable and that a 
conventional approach to pharmacokinetic will not achieve a full definition of the 
plasma concentration vs time profile or enable an estimation of the terminal phase. 
Thus, the additional burden of sampling procedures would not be justified by the 
quality of the data which it would generate. 
Now reads:  
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, 
and PK data up to Day 7 will be reviewed for all groups receiving ≥ 12 µg 
OLP-1002. In Part B, safety, tolerability and PK data up to Day 22 will be 
reviewed for all dose groups. As the t1/2 of OLP-1002 is predicted to be 
approximately 180 hours (based on non-clinical data) review of safety data up 
to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma 
exposures are anticipated to be low, it is expected that it will only be possible 
to perform an assessment of peak concentrations (Cmax) and therefore PK data 
to Day 7 (Part A) and Day 22 (Part B) will be sufficient. Additionally, a 
cumulative safety review will occur such that additional emerging safety data 
from earlier groups will be considered when making a dose escalation decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 


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regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower 
dose groups occurring in the event of PK data being quantifiable at doses ≥ 12 
µg and if supported by bioanalytical stability data. Dose escalation decisions 
for doses <12 µg in Part A will not require PK data. The rationale for this is 
that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical 
species has a lower limit of quantification (LLOQ) of 5 ng/mL. The increased 
sample volume possible from humans (compared to small animals) may afford an 
approximate 10-fold increase in sensitivity with possibly an additional 5-fold 
increase from the use of a more sensitive mass spectrometer. This could potentially 
deliver an LLOQ of around 0.1 ng/mL. Therefore, even with the increased assay 
sensitivity plasma levels from doses at or below 12 µg are not expected to be 
quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose 
would be quantifiable and that a conventional approach to pharmacokinetic will not 
achieve a full definition of the plasma concentration vs time profile or enable an 
estimation of the terminal phase. In addition the planned dose levels have a high 
safety margin when comparing the predicted exposures to the exposures at the 
NOAEL (see Section 3.5.2), with the 12 µg dose level having an expected 312-
fold and 255-fold safety margin based on Cmax and AUC0-∞, respectively. 
Therefore if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
 
Section 3.4.1 
Previously read: 
In Part B, all subjects in a group will be dosed on the same day. Accumulation of 
OLP-1002 is expected following multiple doses, based on the preclinical data, and 
will be taken into account when determining the doses for Part B (see 
Section 3.5.3). 
Now reads:  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 
at steady state is predicted to exceed exposures that have been shown to be safe 
and well tolerated in earlier groups in Parts A or B. When used, two subjects 
(1 active; 1 placebo), will be dosed 4 days prior to the remaining 6 subjects 
(5 active; 2 placebo). The 2 sentinel subjects will always be 2 doses ahead of the 
remaining subjects (ie. sentinel subjects will receive dose 2 before the 


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remaining subjects receive dose 1). Subjects in groups where exposure is not 
predicted to exceed that tested in Part A will be dosed on the same day. 
Accumulation of OLP-1002 is expected following multiple doses, based on the 
preclinical data, and will be taken into account when determining the doses for Part 
B (see Section 3.5.3). If it is not possible to quantify exposure it will be assumed 
that multiple dosing results in a 4-fold accumulation based on the predicted t1/2 
of 180h. 
Section 3.5.3 
Text added: 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose 
administered will not exceed 20 µg and predicted systemic exposure will not 
exceed that stated in the dose escalation stopping criteria [Section 3.7]) based 
on available PK data. 
Section 3.6 
Previously read:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety and tolerability data up to Day 18 (120 hours post-final dose) from 
groups that received lower doses of OLP-1002. Doses may be reduced and may be 
lower than the starting dose. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 5 subjects, who have received OLP-1002 will be used to make the dose-
escalation decision. Dose escalation in Part B will only occur if data from a 
minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
Now reads:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
For escalation to doses > 12 µg, PK data up to Day 7 (144 hours postdose) will 
also be reviewed. All available safety, tolerability, and PK data from previous 


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groups will be reviewed prior to dose escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) 
from groups that received lower doses of OLP-1002. Doses may be reduced and 
may be lower than the starting dose. Available safety, tolerability, and PK data 
from all previous groups will be reviewed prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 3 or 4 subjects, respectively, who have received OLP-1002 will be used to make 
the dose-escalation decision. Dose escalation in Part B will only occur if data from 
a minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
 
Section 3.7 
Previously read: 
In Parts A and B, following consultation with the Sponsor, dose escalation will be 
stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping 
of dose escalation. 
• There is evidence of clinically significant increases in liver function tests 
(aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase 
and total bilirubin) defined as 3 times the upper limit of normal in 3 or more 
subjects in a group (confirmed with repeat testing). 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in 
at least 2 subjects in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in 
at least 2 subjects in a group. 


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Now reads: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping 
of dose escalation. 
• One or more subjects experience an SAE that is considered to be 
related to OLP-1002. 
• Two or more subjects in the same group experience severe non-serious 
AEs (ie. severe non-serious AEs considered as, at least, possibly related 
to OLP-1002 administration), independent of whether the AEs are 
within or not within the same system organ class.  
• There is evidence of clinically significant increases in aspartate 
aminotransferase, alanine aminotransferase or alkaline phosphatase (defined 
as 3 times the upper limit of normal), or total bilirubin (defined as 2 times 
the upper limit of normal) that are considered to be related to OLP-
1002 in 2 or more subjects in a group. Results will be confirmed with 
repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in 
≥1 subject in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in 
≥1 subject in a group. 
• The dose will not exceed 20 µg or the systemic exposure for any 
individual subject is predicted to exceed a Cmax of 24.9 ng/mL (plasma) 
and/or an AUC0-24 of 128 ng/mL; i.e., systemic exposure will be no 
greater than the NOAEL in the most sensitive species (100,000 pmol/kg 
in rat [462 µg/kg]). 
 
Section 4.2 
Exclusion criteria added: 
4. 
Female subjects who are pregnant or breastfeeding. 
Section 4.4 


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Previously read: 
• any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal 
Now reads: 
• any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least 
possibly related to OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE 
considered to at least possibly related to OLP-1002 
administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for 
Part A or Day 1 predose for Part B) and/or absolute QTcF 
values > 500 msec (confirmed by repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position 
(confirmed by 2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg 
and/or diastolic blood pressure > 110 mmHg) in the resting 
supine position (confirmed by 2 repeat measurements). 
Section 7.1 
Section added: 
7.1  Pharmacokinetic Assessments 
7.1.1 Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times 
indicated in the Schedule of Assessments (Appendix 6). Furthermore, 
additional blood samples may be taken from each subject per treatment 
period, with the maximum volume of blood withdrawn per subject not 
exceeding the limit detailed in Appendix 3. Any changes to the scheduled times 
of PK assessments will be agreed with the Sponsor and documented in the 
TMF. Samples taken from subjects who received placebo will not be analyzed. 
In Part A, only samples collected from subjects that received >12 µg OLP-1002 
will be initially analyzed. If PK data is quantifiable at concentrations of OLP-
1002 >12 µg, samples from lower dose groups will be retrospectively analyzed. 
In Part B, PK samples will be analyzed for all groups. 
Procedures for collection, processing, and shipping of PK blood samples will 


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be detailed in a separate document. 
7.1.2 Analytical Methodology 
Plasma concentrations of OLP-1002 will be determined using validated 
analytical procedures. Specifics of the analytical methods will be provided in 
separate documents. 
Section 8.2 
Previously read: 
8.2.1 Pharmacodynamic population 
The PD population will include all subjects who received at least 1 dose of study 
treatment OLP-1002 or placebo and for whom PD can be evaluated. 
8.2.2 Safety Population 
The safety population will include all subjects who received at least 1 dose of study 
treatment or placebo and have at least 1 postdose safety assessment. 
Now reads: 
8.2.1 Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of 
OLP-1002 that have evaluable PK data and have had no AEs or protocol 
deviations considered to impact PK. 
8.2.2 Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-
1002 or placebo and for whom PD can be evaluated. 
8.2.3 Safety Population 
The safety population will include all subjects who received at least 1 dose of 
OLP-1002 or placebo. 
8.3 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma and 
urine concentration data, using commercial software such as Phoenix® 
WinNonlin®. Plasma concentrations of OLP-1002 and PK parameters will be 
listed and summarized using descriptive statistics. Individual and arithmetic 
mean OLP-1002 concentration-time profiles will also be presented graphically. 
Appendix 3 


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Table updated: 
Part A 
 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis* 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
33.5109.5  
Part B 
 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
78.5194.5  
 
Appendix 6 
PK and Blood sampling rows added to the schedule of events for Part A and Part B. 
In the Schedule of events for Part A, footnote e was added. In the Schedule of 
events for Part B, footnote b was added. 
Clinical chemistry, hematology, and urinalysis was added to the Schedule of events 
for Part A on Day 14.  
 
 


TITLE PAGE 
Protocol 
OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single 
and Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, 
and Pharmacodynamic Study in Healthy Male and Female Subjects 
Protocol Status: Final 
Protocol Date: 29 November 2018 
Protocol Version: 2.1 
Investigational Product: OLP-1002 
 
Protocol Reference Number: OLP-1002-001 
Covance Study Number: 8379789 
EudraCT Number: 2018-003085-13 
 
 
Sponsor: 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung-gu, Yongin, Gyeonggi 17015 
Republic of Korea 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street  
Leeds, LS2 9LH 
United Kingdom 
 
 
Sponsor Signatory: 
 
 
Principal Investigator: 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP-1 002-00 I 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
  
 
Protocol Version 2.1, 29 November 2018 
Date 
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Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP-1 002-001 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
 
Principal Investigator 
Protocol Version 2.1, 29 November 2018 
Date 
Page 3 of79 


Protocol 
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STUDY IDENTIFICATION 
Sponsor 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Study Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Medical Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Medical Monitor 
(24-hour emergency 
medical contact) 
 
 
 
 
 
Study Site 
Covance Clinical Research Unit Ltd. 
Springfield House, 
Hyde Street, 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
Project Physician 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 


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Clinical Laboratory 
 
 
 
Statistician 
 
Covance 


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Protocol Version 2.1, 29 November 2018 
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SYNOPSIS 
Title of study: OLP-1002 – A first-in-human, double-blind, placebo-controlled, single and multiple 
subcutaneous dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy 
male and female subjects 
Objectives:  
The primary objective of the study is to assess the safety and tolerability of single and multiple 
subcutaneous doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the pharmacodynamic effect of OLP-1002 
following single subcutaneous doses in healthy volunteers using a capsaicin pain model, and to 
monitor the effects of a single subcutaneous doses of OLP-1002 on cardiac QT interval. Where 
possible, single and/or multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy 
subjects will be determined. 
Study design: 
This will be a double-blind, randomized, placebo-controlled, single and multiple subcutaneous dose 
study conducted in 2 parts, including healthy male and female subjects. 
Number of subjects: 
Part A: 44 subjects will be studied in 8 groups (5 groups of 4 and 3 groups of 8). 
Part B: 24 subjects will be studied in 3 groups (Groups B1 to B3). 
Up to 24 additional subjects may be recruited into Part A and Part B of the study if required. 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged between 18 and 60 years (inclusive) with a body mass index 
between 18.0 and 28.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test product: OLP-1002 
Proposed dose levels for Part A: 30 ng, 120 ng, 400 ng, 1.2 µg, 3 µg, 6 µg, 12 µg, and 20 µg. 
Proposed dose levels for Part B: the doses for Part B will be decided in consultation with the 
Sponsor and on the basis of data from Part A of the study. The highest dose in Part B will be up to 
50% of the highest dose in Part A. 
Administration route: subcutaneous 
Reference product and mode of administration: 
Reference product: placebo 
Administration route: subcutaneous 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 8 weeks for Part A and 
approximately 12 weeks for Part B. 


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Endpoints: 
Pharmacodynamics: 
In Part A, the analgesic effect of OLP-1002 will be investigated in 3 groups consisting of 8 subjects 
(6 active: 2 placebo) using experimental capsaicin-evoked pain methods. Measurement of 
capsaicin-evoked pain will be performed at pre-screening, baseline and on Day 2, and secondary 
hyperalgesia at 5 and 30 minutes post-capsaicin injection. Continuous electrocardiogram (ECG) 
recording will be conducted to investigate the effect of OLP-1002 on cardiac function. 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 12-lead 
ECGs, vital signs measurements, injection site assessment, heat pain threshold and tolerance, and 
physical examinations. 
Pharmacokinetics: 
In Part A, the following PK parameters will be determined where possible: area under the plasma 
concentration-time curve (AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the 
time of the last quantifiable concentration (AUC0-tlast), maximum observed plasma concentration 
(Cmax), time of the maximum observed plasma concentration (tmax), and apparent plasma terminal 
elimination half-life (t1/2). PK analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups 
occurring in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by 
bioanalytical stability data. 
In Part B, the following PK parameters will be determined where possible: AUC over a dosing 
interval (AUC0-τ), AUC0-∞, Cmax, minimum observed plasma concentration (Cmin), tmax, t1/2, observed 
accumulation ratio based on AUC0-τ (RAAUC0-τ), observed accumulation ratio based on Cmax 
(RACmax), and Temporal change parameter (TCP). PK samples from all groups in Part B will be 
analyzed. 
Statistical methods: 
Pharmacodynamics: 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of pharmacodynamic data is planned. 
Safety: 
Safety parameters will be listed and summarized using descriptive statistics. No formal statistical 
analysis of safety data is planned. 
Pharmacokinetics: 
Individual plasma concentrations and PK parameters of OLP-1002 will be listed and summarized 
using descriptive statistics. Individual and mean OLP-1002 concentration-time profiles will be 
presented graphically. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................12 
1.1. 
Overview ................................................................................................................12 
1.2. 
Summary of Nonclinical Pharmacology ................................................................12 
1.2.1. 
In Vitro Pharmacology Studies ....................................................................12 
1.2.2. 
In Vivo Pharmacology Studies ....................................................................13 
1.2.3. 
Ex Vivo Pharmacology Studies ...................................................................14 
1.3. 
Summary of Safety Pharmacology ........................................................................15 
1.4. 
Summary of Toxicology ........................................................................................15 
1.5. 
Summary of Nonclinical Pharmacokinetics...........................................................16 
1.6. 
Study Rationale ......................................................................................................17 
1.7. 
Benefit-risk Assessment.........................................................................................17 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................17 
2.1. 
Objectives ..............................................................................................................17 
2.2. 
Endpoints ...............................................................................................................17 
2.2.1. 
Primary Endpoints .......................................................................................17 
2.2.2. 
Exploratory Endpoints .................................................................................18 
3. 
INVESTIGATIONAL PLAN ..........................................................................................19 
3.1. 
Overall Study Design and Plan ..............................................................................19 
3.1.1. 
Part A ...........................................................................................................19 
3.1.2. 
Part B ...........................................................................................................21 
3.2. 
Start of Study and End of Study Definitions .........................................................22 
3.3. 
Additional Groups ..................................................................................................22 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................22 
3.4.1. 
Dose Interval ................................................................................................24 
3.4.2. 
Pharmacodynamic Assessment ....................................................................24 
3.5. 
Selection of Doses in the Study .............................................................................25 
3.5.1. 
Starting Dose ................................................................................................25 
3.5.2. 
Exposure ......................................................................................................26 
3.5.3. 
Proposed Doses ............................................................................................27 


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3.6. 
Dose Escalation ......................................................................................................28 
3.7. 
Dose Escalation Stopping Criteria .........................................................................29 
4. 
SELECTION OF STUDY POPULATION .....................................................................30 
4.1. 
Inclusion Criteria ...................................................................................................30 
4.2. 
Exclusion Criteria ..................................................................................................30 
4.3. 
Subject Number and Identification ........................................................................32 
4.4. 
Subject Withdrawal and Replacement ...................................................................32 
4.5. 
Study Termination .................................................................................................33 
5. 
STUDY TREATMENTS .................................................................................................33 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................33 
5.2. 
Study Treatment Administration............................................................................33 
5.3. 
Randomization .......................................................................................................33 
5.4. 
Blinding..................................................................................................................34 
5.5. 
Treatment Compliance ...........................................................................................34 
5.6. 
Drug Accountability...............................................................................................34 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................35 
6.1. 
Concomitant Therapies ..........................................................................................35 
6.2. 
Diet .........................................................................................................................35 
6.3. 
Smoking .................................................................................................................35 
6.4. 
Exercise ..................................................................................................................35 
6.5. 
Blood Donation ......................................................................................................36 
6.6. 
Other Restrictions ..................................................................................................36 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................36 
7.1. 
Pharmacokinetic Assessments ...............................................................................36 
7.1.1. 
Sample Collection and Processing ...............................................................36 
7.1.2. 
Analytical Methodology ..............................................................................37 
7.2. 
Pharmacodynamic Assessments ............................................................................37 
7.2.1. 
Capsaicin-evoked Pain Model .....................................................................37 
7.2.2. 
Secondary Hyperalgesia...............................................................................37 
7.3. 
Safety and Tolerability Assessments .....................................................................37 
7.3.1. 
Adverse Events ............................................................................................37 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................38 
7.3.3. 
Vital Signs ....................................................................................................38 
7.3.4. 
Electrocardiogram ........................................................................................39 
7.3.5. 
Heat Pain Threshold Test .............................................................................39 
7.3.6. 
Physical Examination...................................................................................40 
7.3.7. 
Body Weight and Height .............................................................................40 
7.3.8. 
Injection Site Assessments ...........................................................................40 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................42 


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8.1. 
Determination of Sample Size ...............................................................................42 
8.2. 
Analysis Populations ..............................................................................................42 
8.2.1. 
Pharmacokinetic Population ........................................................................42 
8.2.2. 
Pharmacodynamic Population .....................................................................42 
8.2.3. 
Safety Population .........................................................................................42 
8.3. 
Pharmacokinetic Analyses .....................................................................................42 
8.4. 
Pharmacodynamic Analyses ..................................................................................43 
8.5. 
Safety Analysis ......................................................................................................43 
9.
REFERENCES ................................................................................................................43
10. APPENDICES .................................................................................................................45
Appendix 1: Adverse Event Reporting ..............................................................................46 
Appendix 2: Clinical Laboratory Evaluations ...................................................................50 
Appendix 3: Total Blood Volume......................................................................................51 
Appendix 4: Contraception Guidance ................................................................................52 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................55 
Appendix 6: Schedule of Assessments ..............................................................................58 
Appendix 7: Protocol Amendment Summary of Changes .................................................65 
LIST OF TABLES AND FIGURES 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 ........................26 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 ....................27 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B ..........................................................................................................27 
Figure 1: 
Study Schematic (Part A)...........................................................................20 
Figure 2: 
Study Schematic (Part B) ...........................................................................22 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve extrapolated to infinity 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours postdose 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
DN 
Dose normalized 
DRG 
dorsal root ganglion 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Emax 
maximum pain intensity 
FCA 
Freund's Complete Adjuvant 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SNL 
spinal nerve ligation 
t1/2 
elimination half-life 
tEmax 
time of maximum pain intensity 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
VAS 
Visual Analogic Scale 
VGSC 
voltage-gated sodium channel 


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1. INTRODUCTION 
1.1. 
Overview 
OLP-1002 is a novel peptide nucleic acid (PNA) derivative which acts as a specific voltage-
gated sodium channel (VGSC) protein (Nav1.7) inhibitor, and is being developed by OliPass 
for the treatment of pain. 
The Nav1.7 protein is a subtype of VGSCs. Nav1.7 is particularly important in nociception 
and pain signaling, with congenital loss-of-function mutations in Nav1.7 resulting in the 
inability to experience pain. Selective Nav1.7 inhibitors are believed to have the potential to 
treat severe pain safely1. The active sites of VGSC subtypes are virtually indistinguishable by 
their 3-dimensional structure and thus the discovery of selective Nav1.7 small molecule 
inhibitors has been extremely challenging. Since inhibition of Nav1.5 subtype elicits long QT 
cardiotoxicity, inhibition of Nav1.5 subtype should be avoided at therapeutic doses. 
To date, there are several Nav1.7 inhibitors claimed to be selective that have been evaluated 
in human subjects: 
• Vixotrigine (formerly known as raxatrigine) inhibits Nav1.7 as well as other VGSC 
subtypes. Vixotrigine is in phase III clinical development for trigeminal neuralgia. 
Due to the limited Nav1.7 selectivity over Nav1.5, vixotrigine was evaluated primarily 
in patients with a low heart risk. 
• Funapide is a Nav1.7 inhibitor with limited Nav1.7 selectivity, and was in phase IIb 
clinical trials as of July 2014. Although funapide showed analgesic activity in a small 
number of erythromelalgia patients, dose-limiting adverse events (AEs), including 
dizziness and somnolence, were observed2. The central nervous system (CNS) AEs 
were due to its poor Nav1.7 selectivity. 
• PF-05089771 is a Nav1.7 selective inhibitor with a claimed Nav1.7 selectivity of 
> 2000-fold versus other subtypes of sodium channel and was evaluated in patients of 
erythromelalgia or dental pain. It is thought low drug concentrations achieved in the 
target tissue could be a possible explanation for its poor analgesic activity in human 
patients3. 
OLP-1002 is fully complementary to a 14-mer RNA sequence spanning the junction of 
intron 4 and exon 5 in the human SCN9A pre-mRNA which codes for the Nav1.7 channel. 
OLP-1002 yields SCN9A mRNA splice variant(s) encoding variant Nav1.7 protein(s) lacking 
the sodium channel activity (ie, a non-functional channel), thereby inhibiting Nav1.7 channel 
function. 
1.2. 
Summary of Nonclinical Pharmacology 
1.2.1. 
In Vitro Pharmacology Studies 
Overall, results from the in vitro pharmacology studies showed OLP-1002 elicits responses 
consistent with its designed function4. It inhibits SCN9A mRNA expression and yields the 


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Nav1.7 variant protein or proteins lacking sodium channel activity. Its effects are highly 
selective, which may provide for an improved margin of safety compared to other Nav1.7 
inhibitors. 
OLP-1002 at 1 to 100 zM in PC3 prostate carcinoma cells induced exon skipping and yielded 
SCN9A mRNA splice variant(s) encoding a Nav1.7 variant protein or proteins lacking 
sodium channel activity.  
In rat dorsal root ganglion (DRG) neuronal cells, OLP-1002 at 1000 zM inhibited Nav1.7 
protein expression by > 50%, while OLP-1002R at 100 and 1000 zM inhibited Nav1.7 
expression almost completely. As OLP-1002R is fully complementary to rat SCN9A pre-
mRNA, OLP-1002R would be predicted to be more potent than OLP-1002 in this cell type. 
SCN9A mRNA expression level was evaluated by quantitative polymerase chain reaction 
(qPCR). OLP-1002 inhibited the expression of the SCN9A mRNA in PC3 cells with sub-
attomolar potency.  
In SH-SY5Y human neuroblastoma cells stimulated with tumor necrosis factor (TNF)-1α to 
upregulate the expression of SCN9A mRNA, OLP-1002 decreased expression by 46% to 
49% at 1 fM to 10 pM. In rat DRG neuronal cells, OLP-1002 at 1 fM significantly decreased 
SCN9A mRNA expression by 54%. 
In rat DRG neuronal cells, OLP-1002 markedly and significantly inhibited the sodium current 
by 77% at 0.1 aM and 73% at 1 aM, while for OLP-1002R, the inhibition was 66% at 0.1 aM 
and 70% at 1 aM. Given that rat DRG neuronal cells express various subtypes of sodium 
channel, the observed inhibitions of 66% to 77% correspond to the complete knockout of the 
Nav1.7 sodium channel subtype with OLP-1002 or OLP-1002R. 
The Nav1.7 selectivity over Nav1.5 was evaluated in H9C2 rat cardiomyocytes which are 
known to abundantly express the rat Nav1.5 sodium channel subtype. Following incubation 
with OLP-1002 or OLP-1002R at 1 aM or 1 pM, there were no notable decreases in the 
sodium current. Considering that OLP-1002 and OLP-1002R inhibit the expression of Nav1.7 
protein at 1 aM or lower in rat DRG neuronal cells, the Nav1.7 selectivity of OLP-1002 and 
OLP-1002R over Nav1.5 is estimated to be in excess of one million-fold. Such a large Nav1.7 
selectivity over Nav1.5 has not been realized with small molecule Nav1.7 inhibitors, 
suggesting that OLP-1002 potentially offers pain management with much greater 
cardiovascular safety. 
1.2.2. 
In Vivo Pharmacology Studies 
Spinal nerve ligation (SNL) has been widely applied as a rat model for neuropathic pain. 
OLP-1002 and OLP-1002R were found to be very potent, but highly variable in potency, in 
reversing neuropathic allodynia in this model. Analyses of the therapeutic potency strongly 
suggested that a marked proportion of subcutaneously (SC) administered OLP-1002 or OLP-
1002R may have been topically delivered directly to the spinal nerves exposed in the dorsal 
cavity created during the SNL modelling. In addition, the variability of the therapeutic 
potency may be due to a variable degree of healing of the SNL surgery wound. If an animal 


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recovers slowly, the animal tends to be left with a dorsal cavity. Therefore, estimations of 
potency in these studies with this model should be treated with caution. 
In one study using the SNL model, allodynia in rats was slowly and gradually reversed by 
OLP-1002 SC administered at nominal doses of 1, 3, and 6 pmol/kg once every 2 days (due 
to adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). As the onset time for pain reduction was 4 days, 
the doses used were not sufficient for fast onset of activity. In this study, the animals should 
have reasonably recovered from the dorsal wound, and therefore less susceptible to topical 
delivery directly to the exposed spinal nerves. However, in another study in this model, when 
OLP-1002 was intraperitoneally (IP) administered once every 3 days to avoid the likelihood 
of local delivery to the spinal nerves, OLP-1002 surprisingly reversed the allodynia at 
5 fmol/kg, and was superior or comparable to pregabalin 30 mg/kg, a gold standard for 
neuropathic pain studies. The high potency shown at 5 fmol/kg IP strongly suggests the 
possibility that OLP-1002 is efficiently absorbed by the enteric nervous system, travels to the 
spinal cord, and then redistributes to the spinal nerves of the SNL ligation. This opens the 
possibility of efficient oral delivery of OLP-1002 to the spinal cord. 
When evaluated for their ability to reverse the inflammatory pain in rats inflicted with 
Freund's Complete Adjuvant (FCA)-induced severe paw inflammation, OLP-1002 at 
300 pmol/kg and OLP-1002R at 100 pmol/kg significantly reversed the thermal hyperalgesia, 
and both were more effective than pregabalin 30 mg/kg. 
Paw burn injury induces hyperalgesia in rats and is known to upregulate Nav1.7 expression in 
the L5 and L6 DRGs of the affected side. Burn injury induces a far weaker degree of paw 
inflammation than FCA-induced paw inflammation. OLP-1002 SC administered inhibited the 
thermal hyperalgesia in paw burn injury in a dose-dependent manner. At 25 fmol/kg, OLP-
1002 did not inhibit thermal hyperalgesia. Although OLP-1002 at 625 fmol/kg significantly 
inhibited the thermal hyperalgesia, the efficacy was moderate and weaker than pregabalin 
30 mg/kg. This suggests that SC dosing does not offer the local topical delivery to spinal 
nerves in this model as seen in rats without a dorsal cavity wound. In this study, the Nav1.7 
expression in the DRG of the burn injury side significantly decreased by 58% with 
625 fmol/kg OLP-1002, validating the target engagement for analgesic activity. 
An intraplantar injection of formalin induces severe acute pain. The contributors to acute pain 
are known to be complex and require further elucidation. However, acute peripheral 
inflammation is known to contribute much to Phase II Pain (pain from 10 to 40 min after the 
formalin injection). In this model, OLP-1002 significantly inhibited Phase II Pain at 
comparable or saturated efficacy when SC administered at 10 to 100 pmol/kg (due to 
adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). Thus peripheral acute inflammatory pain could be 
treated with 10 pmol/kg or less. 
1.2.3. 
Ex Vivo Pharmacology Studies 
One day post-SC injection, OLP-1002 and OLP-1002R at 100 pmol/kg significantly inhibited 
the expression of Nav1.7 protein by 39% and 57%, respectively, in the spinal cord of rats 
subjected to SNL.  


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In other rats subjected to SNL, OLP-1002R slowly and gradually reversed the allodynia in a 
dose-dependent manner. OLP-1002R at 30 fmol/kg (the highest dose administered) had the 
greatest effect, but the dose was not high enough to elicit full therapeutic efficacy. 
OLP-1002R inhibited expression of Nav1.7 protein in these animals, most notably at 1 
fmol/kg, and decreased SCN9A mRNA expression by approximately 40% at 1 to 30 fmol/kg. 
The observed inhibitions were largely consistent with the in vivo therapeutic activity 
findings. 
Taking all the in vivo and ex vivo findings together, OLP-1002R was concluded to inhibit 
neuropathic allodynia by inhibiting the expression of the SCN9A mRNA and the Nav1.7 
protein. 
1.3. 
Summary of Safety Pharmacology 
In vitro, OLP-1002 did not inhibit the human ether-à-go-go-related gene (hERG) channel 
current expressed in human embryonic kidney (HEK) cells at the highest concentration tested 
2 μM (the limit of the validated analytical method for OLP-1002). 
In the in vivo safety pharmacology studies, OLP-1002 SC administered at dose levels up to 
100 nmol/kg had no effect on body temperature, neurological function, or respiratory 
function in rats, and had no significant toxic effect on cardiovascular function in cynomolgus 
monkeys. 
1.4. 
Summary of Toxicology 
In rats, following twice-weekly SC dosing for 13 weeks, OLP-1002-related microscopic 
findings included pigment accumulation in the kidney of males administered 
100 nmol/kg/dose and females administered ≥ 10 nmol/kg/dose, foreign material and 
vacuolated macrophage infiltrates in males and/or females administered ≥ 1 nmol/kg/dose, 
and an increased incidence and/or severity of mononuclear cell infiltrates at the injection sites 
in males and/or females administered ≥ 10 nmol/kg/dose. These findings persisted through 
the recovery phase in animals administered 100 nmol/kg/dose. However, the effects were 
considered non-adverse due to their mild severity and lack of impact on animal health and 
wellbeing. The no-observed-adverse-effect level (NOAEL) was 100 nmol/kg/dose. This dose 
level corresponded to maximum observed plasma concentration (Cmax) and area under the 
plasma concentration-time curve (AUC) from 0 to 24 hours postdose (AUC0-24) values of 
27.6 ng/mL and 174 ng·hr/mL, respectively, in males and 24.9 ng/mL and 128 ng·hr/mL, 
respectively, in females on Day 88 of the dosing phase. 
In cynomolgus monkeys, following twice-weekly SC dosing for 13 weeks, OLP-1002-related 
microscopic findings included mononuclear cell infiltrates at the SC injection sites of animals 
administered ≥ 10 nmol/kg/dose. This finding was not resolved with the completion of the 
recovery phase. However, the effects of 100 nmol/kg/dose were considered non-adverse due 
to the mild severity of findings and the lack of impact on animal health and wellbeing. The 
NOAEL was 100 nmol/kg/dose (equivalent to 462.29 µg/kg/dose), which corresponded to 
Cmax and AUC from 0 to 72 hours postdose (AUC0-72) values of 121 ng/mL and 
2840 ng·hr/mL in males, respectively, and 216 ng/mL and 4840 ng·hr/mL in females, 
respectively, on Day 88 of the dosing phase. 


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The genotoxic and mutagenic potential of OLP-1002 was evaluated with standard Good 
Laboratory Practice (GLP) via in vitro bacterial mutagenicity and chromosomal aberration 
studies, and was found to be negative. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
In rats, following a single SC dose of 14C-OLP-1002, the time of maximum observed 
concentration (Tmax) was 0.5 to 1 hour for both radioactivity and parent compound. Plasma 
concentrations of total radioactivity were quantifiable through the last sampling time of 72 
hours postdose, but was variable for the parent compound. The elimination half-life (t1/2) of 
total radioactivity from plasma was 23 hours. Total radioactivity distributed into tissues, 
including those of the CNS protected by the blood-brain barrier. 14C-OLP-1002-derived total 
radioactivity was not rapidly excreted from rats, with minimal amounts present in urine and 
feces. The bulk of the total radioactivity remained in carcasses, primarily in kidneys (cortex 
and medulla) and liver. Parent 14C-OLP-1002 was present in plasma and tissues, but 
concentrations declined over time and were substantially lower than total radioactivity 
concentrations at the later sampling times.  
After a single SC administration of 14C-OLP-1002 to rats, the highest concentrations of total 
radioactivity were retained predominantly in the liver (10.4% to 13.3% of the dose), kidney 
cortex (3.47% to 4.96%), and kidney medulla (1.10% to 1.59% of the dose) through 168 
hours postdose. For all other tissues, the total amounts of total radioactivity were 
substantially less, ranging from 0.0000203% in the 5th DRG to 0.327% in the spleen. 
Radioactivity was excreted slowly via both the renal and fecal routes of elimination. Total 
average recoveries of radioactivity in urine and feces through 336 hours postdose accounted 
for 2.31% and 1.75% of the administered radioactivity, respectively. The bulk of the 
administered total radioactivity was retained in the rat carcasses through 168, 336, 504, and 
840 hours postdose. The kidney cortex, kidney medulla, and liver were the 3 tissues that 
retained the greatest amounts of the administered radioactivity. 
Following a 16.1-µg/kg dose in rats, the plasma concentrations were still quantifiable at 
72 hours postdose and the rate of elimination was slow, with t1/2 17.5 hours. It was not 
possible to accurately define the elimination phase for the 2.67- and 5.28-µg/kg dose levels. 
In cynomolgus monkeys, following a single SC dose of 14C-OLP-1002, Tmax ranged from 
0.25 to 1 hour for both total radioactivity and parent compound. Concentrations of total 
radioactivity were sustained in blood and plasma through the last sampling time of 144 hours 
postdose. Concentrations of parent compound were sustained in plasma through the last 
sampling time of 144 hours postdose in 2 of 3 monkeys, and were similar to plasma total 
radioactivity concentrations at 8 hours postdose. From 24 to 144 hours postdose, plasma 
concentrations of total radioactivity were substantially higher than for parent 14C-OLP-1002 
plasma concentrations.  
The mean Cmax of parent 14C-OLP-1002 in plasma was 1.96 ng/mL. The mean plasma Tmax 
was 0.833 hours. Plasma exposure of parent 14C-OLP-1002 based on AUC extrapolated to 
infinity (AUC0-∞), was 12.7 ng·h/mL. After reaching Cmax, plasma concentrations of parent 
14C-OLP-1002 declined with a mean t1/2 of 84 hours. 


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1.6. 
Study Rationale 
This is the first time OLP-1002 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when OLP-1002 is administered SC as single 
and multiple doses to healthy subjects. This information, together with the pharmacodynamic 
(PD) and pharmacokinetic (PK) data, will help establish the doses and dosing regimen 
suitable for future studies in patients. The analgesic effects of OLP-1002 on a capsaicin-
induced pain model will also be investigated. 
1.7. 
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 investigational medicinal product 
(IMP), although there may also be some discomfort from collection of blood samples and 
other study procedures. For subjects in the PD assessment groups in Part A there will be 
some additional discomfort from the capsaicin test. More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with OLP-1002 may be 
found in the Investigator’s Brochure4. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is to assess the safety and tolerability of single and 
multiple SC doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the PD effect of OLP-1002 following 
single SC doses in healthy volunteers using a capsaicin pain model, and to monitor the effects 
of single SC doses of OLP-1002 on cardiac QT interval. Where possible, single and/or 
multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy subjects will be 
determined. 
2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of AEs 
• vital signs measurements (blood pressure, pulse rate, respiratory rate) 
• 12-lead electrocardiogram (ECG) parameters 
• incidence of clinical laboratory abnormalities, based on clinical chemistry, 
hematology, and urinalysis test results 
• physical examinations 
• injection site assessment. 


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• demonstrate that exposure to OLP-1002 does not exceed pre-defined exposure limits 
from non-clinical studies. 
2.2.2. 
Exploratory Endpoints 
The following exploratory objectives will be assessed:  
• pain intensity and duration will be assessed by AUC, maximum pain intensity (Emax), 
and time of maximum pain intensity (tEmax), calculated using a capsaicin-evoked pain 
model. The exploratory endpoint of secondary hyperalgesia will be assessed by the 
area of secondary area of hyperalgesia (Part A only). 
• continuous (24-hour) ECG monitoring will be recorded in this study and archived for 
potential future analysis of OLP-1002 effects on the QT interval (Part A). 
• heat pain threshold measurements and heat pain tolerance measurements. 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from time zero to 
infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable concentration 
(AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK: 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 


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Other PK parameters may also be added if deemed necessary. 
3. INVESTIGATIONAL PLAN 
This will be a double-blind, randomized, placebo-controlled, single and multiple SC dose 
study conducted in 2 parts. 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy subjects will 
be studied in 8 groups. Up to 3 additional groups (24 subjects in total) may be included for 
further assessment of safety, tolerability, PK, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Potential subjects for Groups A2, A4, and A6 will 
attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will return 
for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 2 days), and for a 
poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential visits 
may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 10 (216 hours postdose) from the lower dose levels. For doses 
≥ 12 µg, PK data will also be reviewed up to Day 7 prior to dose escalation. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 3 subjects will receive 
OLP-1002 and 1 subject will receive placebo. To assess PD parameters, Groups A2, A4, and 
A6 will consist of 8 subjects; 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo.  
Sentinel dosing will be employed for all groups in Part A. To maintain the blind in a 
4-subject group, the first subject will be dosed 48 hours before the second subject, and the 
second subject will be dosed 48 hours prior to the third and fourth subjects. In PD assessment 
groups, 2 subjects (1 active: 1 placebo) will be dosed 48 hours before the remaining 6 
subjects (5 active: 1 placebo). 
An overview of the study design is shown in Figure 1.


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Figure 1: 
Study Schematic (Part A) 
Group A1 
(30 ng SC)
3 active:
1 placebo
Group A2
(120 ng SC)
6 active:
2 placebo
Group A3
(400 ng SC)
3 active:
1 placebo
Group A4
(1.2 µg SC)
6 active:
2 placebo
Group A5
(3 µg SC)
3 active:
1 placebo
Group A6
(6 µg SC)
6 active:
2 placebo
Group A7
(12 µg SC)
3 active:
1 placebo
Group A8
(20 µg SC)
3 active:
1 placebo
Group A9
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A10
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A11
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
Groups A9 to A11 may be included if required; dose levels will not exceed the maximum proposed dose of 20 µg. 
Three groups consist of 8 subjects (6 active: 2 placebo); all other groups will consist of 4 subjects (3 active: 1 placebo).


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The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 8 weeks. 
3.1.2. 
Part B 
Part B will comprise a multiple-dose, sequential-group study. Overall, 24 subjects will be 
studied in 3 groups (Groups B1 to B3), with each group consisting of 8 subjects. Up to 
3 additional groups (24 subjects in total) may be included for further assessment of safety and 
tolerability (Section 3.3).  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (± 2 days), 22 (± 2 days), 25 
(± 2 days), and 29 (± 2 days), and for a poststudy visit on Day 57 (± 2 days). 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo. For all subjects, a single subcutaneous dose will be administered on Days 1, 4, 7, 10, 
and 13. Prior to each dosing occasion a physician will review the available safety and 
tolerability data from each subject to confirm it is acceptable to continue dosing. The dosing 
frequency in Part B may be changed following review of data from groups in Part A 
(Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to OLP-1002 at 
steady state is predicted to exceed exposures that have been shown to be safe and well 
tolerated in earlier groups in Parts A or B. In the event of sentinel dosing, 2 subjects (1 active, 
1 placebo) will be dosed at least 4 days prior to the remaining 6 subjects (5 active: 1 placebo). 
Safety data for the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 1 and 2 will be 
reviewed prior to the remaining subjects receiving dose 1). In addition, safety data from each 
subject will be reviewed by a physician prior to each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of safety, 
tolerability, and PK data up to Day 22 (216 hours post-final dose) from the lower dose levels. 
Part B may start after a review of the safety, tolerability, and available PK for Groups A1 to 
A6. The total daily dose administered will not exceed the highest single dose given in Part A. 
An overview of the study design is shown in Figure 2. 


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Figure 2: 
Study Schematic (Part B) 
Group B1
(TBC SC)
6 active:
2 placebo
Group B2 
(TBC SC)
6 active:
2 placebo
Group B3
(TBC SC)
6 active:
2 placebo
Group B4
(TBC SC)
6 active:
2 placebo
Group B5 
(TBC SC)
6 active:
2 placebo
Group B6
(TBC SC)
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
All doses will be confirmed based on results of Part A; dose levels will not exceed the maximum proposed dose 
of 20 µg..  
Groups B4 to B6 will be included if required. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 12 weeks. 
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
 Start of Study and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, PK, and PD data (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]), 
additional dose groups may be added to the study. The maximum dose for any additional 
group will not exceed 20 µg. Up to 3 further groups of 8 subjects (6 active: 2 placebo) may 
be included in Part A, and up to 3 additional groups of 8 subjects (6 active: 2 placebo) may be 
included in Part B. The requirement for additional groups will be agreed with the Sponsor 
and documented in the Trial Master File (TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For both parts of the study, a sequential-group, ascending-dose design has been chosen for 
safety reasons as OLP-1002 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Subcutaneous doses have been 
chosen for both parts of the study, as this is the intended clinical route of administration. 
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, and PK data up 
to Day 7 will be reviewed for all groups receiving ≥ 12 µg OLP-1002. In Part B, safety, 


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tolerability and PK data up to Day 22 will be reviewed for all dose groups. As the t1/2 of 
OLP-1002 is predicted to be approximately 180 hours (based on non-clinical data) review of 
safety data up to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma exposures are 
anticipated to be low, it is expected that it will only be possible to perform an assessment of 
peak concentrations (Cmax) and therefore PK data to Day 7 (Part A) and Day 22 (Part B) will 
be sufficient. Additionally, a cumulative safety review will occur such that additional 
emerging safety data from earlier groups will be considered when making a dose escalation 
decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of females 
of childbearing potential is in accordance with International Council for Harmonisation (ICH) 
M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be sufficient in 
order to determine safety and tolerability. In order to assess the PD effects of OLP-1002, 
3 groups in Part A will include 8 subjects (6 active; 2 placebo). A full review of the safety 
and tolerability data from Part A will be performed to determine the dose regimen for Part B. 
Part B may start after a full review of all safety and tolerability data from Group A1 to A6. A 
review of PD data may also be performed, at the discretion of the Investigator. Details of the 
dosing regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 57-day 
follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups receiving 
≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring 
in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. Dose escalation decisions for doses <12 µg in Part A will not require PK data. 
The rationale for this is that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical species has a 
lower limit of quantification (LLOQ) of 5 ng/mL. The increased sample volume possible 
from humans (compared to small animals) may afford an approximate 10-fold increase in 
sensitivity with possibly an additional 5-fold increase from the use of a more sensitive mass 
spectrometer. This could potentially deliver an LLOQ of around 0.1 ng/mL. Therefore, even 
with the increased assay sensitivity plasma levels from doses at or below 12 µg are not 
expected to be quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose would be 
quantifiable and that a conventional approach to pharmacokinetic will not achieve a full 
definition of the plasma concentration vs time profile or enable an estimation of the terminal 
phase. In addition the planned dose levels have a high safety margin when comparing the 
predicted exposures to the exposures at the NOAEL (see Section 3.5.2), with the 12 µg dose 
level having an expected 312-fold and 255-fold safety margin based on Cmax and AUC0-∞, 
respectively. Therefore if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
 


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This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
Continuous ECG monitoring will be recorded in this study and archived for potential future 
analysis of OLP-1002 effects on the QT interval, with a view of supporting a potential 
thorough QT study waiver. 
3.4.1. 
Dose Interval 
Following thorough review of all available nonclinical data (pharmacological and 
toxicological), dosing in Part A for groups consisting of 4 subjects will be such that there will 
be 48 hours between the first and second subjects, and 48 hours between the second and 
remaining 2 subjects in each group. For groups in Part A consisting of 8 subjects, 2 subjects 
(1 active: 1 placebo) will be dosed 48 hours prior to the remaining 6 subjects.  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 at steady state 
is predicted to exceed exposures that have been shown to be safe and well tolerated in earlier 
groups in Parts A or B. When used, two subjects (1 active; 1 placebo), will be dosed 4 days 
prior to the remaining 6 subjects (5 active; 2 placebo). The 2 sentinel subjects will always be 
2 doses ahead of the remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not predicted to 
exceed that tested in Part A will be dosed on the same day. Accumulation of OLP-1002 is 
expected following multiple doses, based on the preclinical data, and will be taken into 
account when determining the doses for Part B (see Section 3.5.3). If it is not possible to 
quantify exposure it will be assumed that multiple dosing results in a 4-fold accumulation 
based on the predicted t1/2 of 180h.  
In Parts A and B, there will be a minimum interval of a 10-minute gap between dosing 
subjects (when dosed on the same day). Continuation to dose the remaining subjects in a 
group will be at the Investigator’s discretion. 
3.4.2. 
Pharmacodynamic Assessment 
Pharmacodynamic assessments will be conducted for subjects in Groups A2, A4, and A6. 
Human experimental pain models using healthy volunteers can be used to assess the effect of 
a drug or treatment under controlled clinical conditions. Capsaicin is a vanilloid responsible 
for the pungent taste of hot peppers. In mammalian species, capsaicin-induced pain is 
mediated through Group C nerve fibers following activation of vanilloid 1 transient receptor 
potential (TRPV1) channels5. Nav1.7 has been implicated in controlling neuropeptide release 
from C-fibers, and suppression of capsaicin-induced neurogenic flair has been demonstrated 
by an NAv1.7 inhibitor6. 


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Several studies have used intradermal capsaicin for human experimental pain studies7,8. It has 
been possible to demonstrate dose-dependent responses, with intradermal injections of 
100 μg generally agreed to be the ideal dosage for these studies. Intradermal injection of 
capsaicin causes a brief stinging/burning pain at the injection site (spontaneous pain) 
followed by development of secondary hyperalgesia, which can be assessed using equipment 
such as Von Frey hairs. A study by Gazerani et al.5 found that the response was site-specific 
and while peak pain intensity and duration were greatest in the forehead it was found that 
areas of visible flare and secondary hyperalgesia were significantly larger in the forearm, 
making the forearm the most suitable site for experimentation. 
Covance CRU, Leeds, UK in 2009 performed a validation study using intradermal capsaicin 
(Covance CRU Study: 9999-004) with between-subject and within-subject variability 
demonstrating that the assessments can be reliably conducted to assess pharmacological 
response. 
For these reasons, it has been decided to: 
• Measure both capsaicin-evoked pain and secondary hyperalgesia. 
• Limit the number of capsaicin tests to 3 for each subject (pre-screening, baseline, and 
48 hours postdose) 
• Exclude subjects who have pain <3 or >9 (using a Visual Analogic Scale [VAS]) at 
the pre-screening visit from PD assessment groups. 
3.5. 
Selection of Doses in the Study 
3.5.1. 
Starting Dose 
The rat has been identified as the most sensitive species in a 13-week SC toxicity study with 
a 4-week recovery phase (Covance study no. 8355564). The NOAEL was the 
100 nmol/kg/dose (462.29 µg/kg/dose). This dose level resulted in Cmax of 27.6 ng/mL and 
24.9 ng/mL in males and females, respectively, and AUC0-24 of 174 ng.h/mL and 
128 ng.h/mL in males and females, respectively4. As the exposure was lower in the female 
rats these data have been used to calculate the safety margins. 
The dose of 462.29 µg/kg/dose corresponds to human equivalent doses (HEDs) of 
74.8 µg/kg/dose, which gives a maximum recommended starting dose (MRSD) of 444 µg for 
a 60-kg human and thus a 15000-fold safety margin to the proposed starting dose of 30 ng 
and 22-fold margin to the proposed maximum dose of 20 µg. Additionally the NOAEL dose 
in the cynomolgus monkey was identified as 100 nmol/kg/dose (462.29 µg/kg/dose), which 
gives a higher HED of 150 µg/kg/dose. 
In vivo, doses of 10 pmol/kg/dose (0.0462µg/kg/dose) or less were found to inhibit peripheral 
acute inflammatory pain. The equivalent human dose for a 60-kg human is 44 ng, thus a dose 
at which minimal biological effect is anticipated has been selected as the starting dose of 
30 ng. 


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3.5.2. 
Exposure 
Human exposures have been estimated from the pharmacokinetics in the cynomolgus 
monkey since a non-human primate represents the most closely related species. 
Approximately dose-proportional exposure was seen in the 13-week toxicity study (Covance 
study no. 8355565) and 14C pharmacokinetic study (Covance study no. 8355568) over a dose 
range of approximately 1.1 to 100 nmol/kg (5.06 to 462.29 µg/kg)4. However, the lowest 
dose (5.06 µg/kg) from the 14C study has been used to estimate the human exposures as it is 
closest to the proposed human dose range and has the sufficient quantifiable data. 
The assumptions made in the human exposure estimation were that human exposure would 
be similar to the cynomolgus monkey and that exposure would be linear with dose. Following 
a dose of 5.06 µg/kg in the cynomolgus monkey, the Cmax was 1.96 ng/mL and AUC0-∞ was 
12.7 ng.h/mL. The extrapolated exposures at the planned human doses are shown in Table 1 
with margins calculated to the exposures at the NOAEL in the female rat. 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 
Human dose 
Single dose to human 
Safety margins for single dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax 
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin  
to Cmax 
Margin  
to AUC0-∞ 
0.03 
0.000500 
0.000194 
0.00125 
129000 
102000 
0.12 
0.00200 
0.000775 
0.00502 
32100 
25500 
0.4 
0.00667 
0.00258 
0.0167 
9640 
7650 
1.2 
0.0200 
0.0077 
0.0502 
3210 
2550 
3 
0.0500 
0.0194 
0.125 
1290 
1020 
6 
0.100 
0.0387 
0.251 
643 
510 
12 
0.200 
0.0775 
0.502 
321 
255 
20 
0.333 
0.129 
0.837 
193 
153 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
The dosing interval currently anticipated for the multiple-ascending-dose part of this study is 
72 hours or 96 hours. Thus the average dosing interval (82 hours) is similar to the half-life 
determined in the monkey 14C study of 84 hours. Dosing at approximately once per half-life 
would be anticipated to result in accumulation of around 2-fold. However, higher levels of 
accumulation were observed (2.28-fold for Cmax and 3.76-fold for AUC0-24) on Day 88 at the 
top dose group (100 nmol/kg, 462.28 µg/kg) in the 13-week cynomologus monkey toxicity 
study following twice-weekly dosing (every 72 or 96 hours). Calculations were performed to 
estimate the likely human half-life using a standard 1-point allometric approach from the 14C 
cynomolgus monkey pharmacokinetic study data. The exponents used were 0.75 for apparent 
total plasma clearance (CL/F) and 1 for apparent volume of distribution (Vz/F) values 
combined with the average body weight of the animal (3.1 kg) and scaling to a 60 kg human 
9–11. This resulted in a human half-life estimate of 180 h which in turn gave an accumulation 
estimate of 3.7-fold based upon a dosing interval of 82 h. This further supports the use of the 
greater than 2-fold accumulation from the 13-week cynomolgus study to estimate exposure 
following multiple dosing. Multiplication of the exposure estimates for the single ascending 


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dose by 2.28 for Cmax and 3.76 for AUC resulted in exposure estimates for multiple dosing 
presented in Table 2. 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 
Human dose 
Multiple dose to human 
Safety margins for multiple dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax  
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin 
to Cmax 
Margin 
to AUC0-τ,ss 
0.03 
0.000500 
0.000442 
0.00472 
56000 
27000 
0.12 
0.00200 
0.00177 
0.0189 
14100 
6800 
0.4 
0.00667 
0.00589 
0.0629 
4230 
2030 
1.2 
0.0200 
0.017663 
0.189 
1410 
680 
3 
0.0500 
0.0442 
0.472 
560 
270 
6 
0.100 
0.0883 
0.944 
282 
136 
12 
0.200 
0.177 
1.89 
141 
68 
20 
0.333 
0.294 
3.15 
85 
41 
30 
0.500 
0.442 
4.72 
56 
27 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
3.5.3. 
Proposed Doses 
The proposed IMP dose levels for Parts A and B are shown in Table 3. 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
Study Part 
Group 
Dose (OLP-1002) 
Part A 
A1 
30 ng or placebo 
 
A2 
120 ng or placebo 
 
A3 
400 ng or placebo 
 
A4 
1.2 µg or placebo 
 
A5 
3 µg or placebo 
 
A6 
6 µg or placebo 
 
A7 
12 µg or placebo 
 
A8 
20 µg or placebo 
 
A9* 
TBC or placebo 
 
A10* 
TBC or placebo 
 
A11* 
TBC or placebo 
 
 
 
Part B 
B1 
TBC or placebo 
 
B2 
TBC or placebo 
 
B3 
TBC or placebo 
 
B4* 
TBC or placebo 
 
B5* 
TBC or placebo 
 
B6* 
TBC or placebo 
Abbreviations: TBC = to be confirmed 
* groups to be included if required. 


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In Parts A and B, there should not be an increase of > 3-fold between dose levels above 
120 ng. 
For Part B, dose levels, dosing frequency, and dosing duration will be decided, in 
consultation with the Sponsor, on the basis of data from Part A of the study. Since predictions 
of human exposure of OLP-1002 suggest that OLP-1002 concentrations may be not be 
quantifiable and human data have been estimated from a single species, it is proposed that the 
highest dose in the multiple-ascending-dose part will be up to 50% of the highest dose in the 
single-ascending-dose part (ie, if the highest dose in the single-ascending-dose part is 20 µg, 
the highest dose in the multiple-ascending-dose part will be 10 µg). Therefore, if the 
predicted accumulation of 3.7-fold occurs, the highest exposure in the multiple-ascending-
dose part will not exceed ~2-fold the maximum exposure in the single-ascending-dose part. 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose administered will 
not exceed 20 µg and predicted systemic exposure will not exceed that stated in the dose 
escalation stopping criteria [Section 3.7]) based on available PK data. 
Details of all doses administered in Parts A and B of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
In Part A, doses will be administered in an escalating manner following satisfactory review 
by the Sponsor and Investigator of the safety, and tolerability data up to Day 10 (216 hours 
postdose) from groups that received lower doses of OLP-1002. For escalation to doses 
> 12 µg, PK data up to Day 7 (144 hours postdose) will also be reviewed. All available 
safety, tolerability, and PK data from previous groups will be reviewed prior to dose 
escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and may be lower than the starting 
dose. Available safety, tolerability, and PK data from all previous groups will be reviewed 
prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups A1, 
A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have been reviewed from the 
previous lower dose group, such that data from a minimum of 3 or 4 subjects, respectively, 
who have received OLP-1002 will be used to make the dose-escalation decision. Dose 
escalation in Part B will only occur if data from a minimum of 6 subjects have been reviewed 
from the previous lower dose group, such that data from a minimum of 4 subjects who have 
received OLP-1002 will be used to make the dose-escalation decision. 
The justification for this is as follows: 
• The study drug is of a known pharmacological class for which the on-target effects in 
humans are well characterized. Based upon nonclinical data, no clinically important 
off-target effects are expected within the proposed dose range. 


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• A minimum of 3 subjects receiving the active drug is considered sufficient to 
characterize the safety profile for OLP-1002. 
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarizing 
results from all available safety assessments, will be sent to the Sponsor and a dose-escalation 
meeting will occur prior to the start of each successive group. Any clinically significant 
results will be discussed with the Sponsor before dose escalation continues. Interim PD data 
may also be reviewed on an ongoing basis. In the event of a disagreement between Sponsor 
and Investigator on the dose-escalation decision, the decision of the Investigator will be 
upheld. 
3.7. 
Dose Escalation Stopping Criteria 
In Parts A and B, following consultation with the Sponsor, dose escalation will be stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in 
a group that, in the opinion of the Investigator, warrant stopping of dose escalation. 
• One or more subjects experience an SAE that is considered to be related to OLP-1002. 
• Two or more subjects in the same group experience severe non-serious AEs (ie. 
severe non-serious AEs considered as, at least, possibly related to OLP-1002 
administration), independent of whether the AEs are within or not within the same 
system organ class.  
• There is evidence of clinically significant increases in aspartate aminotransferase, 
alanine aminotransferase or alkaline phosphatase (defined as 3 times the upper limit 
of normal), or total bilirubin (defined as 2 times the upper limit of normal) that are 
considered to be related to OLP-1002 in 2 or more subjects in a group. Results will be 
confirmed with repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose for 
Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat measurement) 
in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 110 mmHg) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• The dose will not exceed 20 µg or the systemic exposure for any individual subject is 
predicted to exceed a Cmax of 24.9 ng/mL (plasma) and/or an AUC0-24 of 128 ng/mL; 
i.e., systemic exposure will be no greater than the NOAEL in the most sensitive 
species (100,000 pmol/kg in rat [462 µg/kg]). 


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If the sponsor deems it appropriate to resume dosing after the internal safety review, it 
can be done after the approval of a substantial protocol amendment. 
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. Healthy male or females of any race, between 18 and 60 years of age, inclusive. 
2. Body mass index (BMI) between 18.0 and 28.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, single 12-lead ECG (resting heart rate > 45 bpm and 
< 90 bpm), vital signs measurements, and clinical laboratory evaluations (congenital 
nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome based on total 
and direct bilirubin] is not acceptable) at Screening as assessed by the Investigator (or 
designee).  
4. Willing to abide by the contraception requirements 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: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. Any of the following: 
• QTcF > 450 ms confirmed by repeat measurement. 
• QRS duration > 110 ms confirmed by repeat measurement. 
• PR interval > 220 ms confirmed by repeat measurement. 
• findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
• history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalemia, family history of long QT syndrome). 
4. Female subjects who are pregnant or breastfeeding. 
5. History of alcoholism or drug/chemical abuse within 1 year prior to Screening. 


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6. Alcohol consumption of > 21 units per week for males and >14 units per week for 
females. 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. 
7. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
8. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
9. Active skin conditions such as dermatitis, allergy, eczema, psoriasis, or abnormal 
healing. 
10. Tattoos, scars, or moles that in the opinion of the Investigator are likely to interfere 
with dosing or study assessments at any of the potential injection sites. 
11. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days or 5 half-lives of the investigational product, 
whichever is longer, prior to Check-in. 
12. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 
13. Use or intend to use any prescription medications/products other than hormone-
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptive concomitant medications within 14 days prior to Check-in, unless 
deemed acceptable by the Investigator (or designee). 
14. 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). 
15. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee) and/or 
Sponsor have given their prior consent. 
16. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.  
17. Receipt of blood products within 60 days prior to Check-in. 
18. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening.  
19. Poor peripheral venous access. 
20. Have previously completed or withdrawn from this study or any other study 
investigating OLP-1002, and have previously received the investigational product. 
21. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
22. Part A – PD assessment groups only 
• Subjects considered non-acceptable responders to the intradermal capsaicin 
test at screening, defined as maximum VAS score of < 3.0 or > 9.0. 


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4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomization. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, in Part A, Subjects 101, 102, 
etc., in Part B Subjects 201, 202, etc.). Replacement subjects (Section 4.4) will be assigned a 
subject number corresponding to the number of the subject he/she is replacing plus 1000 
(eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least possibly related to 
OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE considered to 
at least possibly related to OLP-1002 administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements). 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the 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 
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Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• 
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) 
• 
medical or ethical reasons affecting the continued performance of the study 
• 
difficulties in the recruitment of subjects 
• 
cancelation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Vials of OLP-1002 Injection Solution 100 µg/mL (1.5 mL in 5-mL vials) and the Diluent for 
OLP-1002 Injection Solution (5 mL in 10-mL vials) will be supplied by the Sponsor, along 
with the batch/lot number and Certificate of Analysis. The Diluent for OLP-1002 Injection 
Solution will also be used as the Placebo formulation. A certificate of batch certification and 
release, authorized by a Qualified Person in the European Union (EU) will also be issued, by 
a Covance CRU Qualified Person, for each batch of IMP imported into the EU. 
The IMPs will be stored according to the instructions on the label at the CRU in a location 
that is locked with restricted access. 
Dose solutions (OLP-1002 Injection Solution diluted with the Diluent for OLP-1002 
Injection Solution) will be prepared by Covance CRU Pharmacy staff in accordance with 
instructions provided in the Pharmacy Manual. The Placebo formulation will be the Diluent 
for OLP-1002 Injection Solution without further manipulation. 
5.2. 
Study Treatment Administration 
Subjects will be administered the IMP in numerical order. OLP-1002 will be administered by 
SC injection in the upper arm. If subcutaneous dosing of OLP-1002 in the upper arm is not 
possible, the subject may be dosed in the abdomen at the Investigator’s discretion. For 
subjects in Groups A2, A4, and A6, dosing will be on the opposite arm to the intradermal 
capsaicin test. 
5.3. 
Randomization 
The randomization code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. In Part A, 1 subject in groups 


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consisting of 4 subjects, and 2 subjects in groups consisting of 8 subjects, will be randomly 
assigned to receive placebo. In Part B, 2 subjects per group will be randomly assigned to 
receive placebo. All other subjects in a group will be randomized to receive OLP-1002. 
Prior to the start of the study, a copy of the master randomization code will be supplied into 
the Covance CRU pharmacy staff (in sealed envelopes). 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo solution will be identical in appearance to the OLP-1002. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 
To maintain the blind, the Investigator will be provided with sealed randomization 
code-break envelopes for each subject, containing details of their treatment. These individual 
sealed envelopes will be kept in a limited access area that is accessible 24 hours a day. In 
order to manage subject safety or to support dose-escalation decisions (in the event of 
possibly treatment-related SAEs or severe AEs), the decision to unblind resides solely with 
the Investigator. Whenever possible, and providing it does not interfere with or delay any 
decision in the best interest of the subject, the Investigator will discuss the intended code-
break with the Sponsor. If it becomes necessary to break the code during the study, the date, 
time, and reason will be recorded in the subject’s source data and on the individual envelope 
and will be witnessed by a second person. 
5.5. 
Treatment Compliance 
All doses of IMP will be administered by suitably qualified study site staff. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription medications/products from 14 days prior to 
dosing until the Follow-up visit, and non-prescription medications/products from 7 days prior 
to dosing until the Follow-up visit, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone-replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary 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 standardized 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 safety laboratory tests. On dosing days, 
subjects will receive a light breakfast approximately 2 hours prior to dosing. Meals will be 
provided as appropriate at other times and water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Check-in until the Follow-up visit. 
Xanthine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until Discharge from the site. Xanthine-containing foods and beverages will also not be 
allowed form 36 hours before non-residential site visits. 
Chili pepper/hot sauce will not be allowed for 48 hours prior to Check-in for all subjects. 
Subjects in Groups A2, A4, and A6 will not be allowed chili pepper/hot sauce for 48 hours 
prior to their pre-screening visit. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until 
Discharge. Following discharge, up to 2 units/day of alcohol are permitted until 36 hours 
before each non-residential visit and 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 3 days before Check-in until the 
Follow-up visit and will otherwise maintain their normal level of physical activity during this 


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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. Subjects should not be in receipt of blood products for 
60 days prior to check-in. 
6.6. 
Other Restrictions 
Subjects in Groups A2, A4, and A6 will not be allowed to shower within 1 hour prior to the 
capsaicin-evoked pain tests at prescreening, predose, and postdose. 
Subjects will not be allowed to apply moisturizing creams or oils to the dosing site within 
1 hour prior to dosing, or to the assessment site within 1 hour prior to the capsaicin-evoked 
pain test.  
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): 
• dosing 
• vital signs 
• blood samples 
• cardiac monitoring/ECG extractions 
• any other procedures. 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments (Appendix 6). Furthermore, additional blood samples may be taken 
from each subject per treatment period, with the maximum volume of blood withdrawn per 
subject not exceeding the limit detailed in Appendix 3. Any changes to the scheduled times of 
PK assessments will be agreed with the Sponsor and documented in the TMF. Samples taken 
from subjects who received placebo will not be analyzed. 
In Part A, PK analysis will initially only be conducted for groups receiving ≥ 12 µg 
OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the 


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event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 
7.2. 
Pharmacodynamic Assessments 
Capsaicin intradermal test will be performed for subjects in Groups A2, A4, and A6. Each 
subject will be tested at a pre-screening visit before being tested twice during the study (1 
predose and 1 postdose). 
7.2.1. 
Capsaicin-evoked Pain Model 
The capsaicin model will be conducted by intradermal injection of capsaicin (100 μg in 
100 μL of sterile saline containing 8% [w/w] Tween 80) into the skin of the anterior aspect of 
the forearm, midway between the elbow and the wrist. The bleb area (wheal) will be a sign of 
local plasma extravasation. An assessment of the pain intensity related to capsaicin injection 
will be estimated by repeated use of a VAS from injection to 5 minutes post-injection or until 
the pain intensity returned to zero. The AUC, Emax, and tEmax will be calculated and reported 
using dedicated software. 
7.2.2. 
Secondary Hyperalgesia 
The area of secondary hyperalgesia will be quantified with a 60-g weighted von Frey hair, by 
stimulating along 8 linear paths (4 vectors crossing at the location of the injection site) 
arranged vertically and horizontally around the stimulation site in 5-mm steps (starting 
approximately 6 cm away from the injection site). The area of secondary hyperalgesia will be 
evaluated at 5 and 30 minutes post-capsaicin injection. 
7.3. 
Safety and Tolerability Assessments 
Safety and tolerability assessments will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). Timepoints may be adjusted based on an ongoing review of the 
data, and additional assessments may be conducted if deemed necessary by the Investigator 
or designee. 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs 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 


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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. 
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 drug. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a follicle-stimulating hormone (FSH) test and 
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. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and 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. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. 
Subjects must be supine for at least 5 minutes before blood pressure, pulse rate, and 
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7.3.4. 
Electrocardiogram 
7.3.4.1. 
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: 
• QTcF value > 500 msec 
• QTcF change from the mean baseline (Day 1 predose) is > 60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.3.4.2. 
Continuous (24-hour) Electrocardiogram 
At the times indicated in the Schedule of Assessments (Appendix 6), continuous (24-hour) 
ECGs will be performed.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint. Each extraction will last for 5 minutes. 
Environmental distractions (eg, television, playing games, radio, conversation) should be 
avoided during the pre-ECG time window.  
Continuous 24-hour ECGs are not planned for Part B of the study but may be implemented if 
any clinically significant findings are identified in the data from Part A. 
7.3.5. 
Heat Pain Threshold Test 
Heat pain threshold tests will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). 
A computer-controlled thermal sensory analyzer device will be used to measure the heat pain 
threshold and tolerance level of the subjects. The heat pain assessments will be conducted on 
the subject’s thigh. 
Heat Pain Threshold: 
For heat pain threshold measurements, the thermode will be placed directly on the skin of the 
right thigh, within an area selected before the start of the experiment and defined by surgical 
marking. The thermode will have a baseline temperature of 32 °C, and will be programmed to 
gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 


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their dominant hand, to indicate when the heat pain threshold (first sensation of heat pain) is 
reached by pushing a button. At that time, the test will be stopped and the temperature 
returned to baseline within 1 second. This process will be repeated a further 2 times, with an 
interval of at least 1 minute between measurements (from start to start). The computer will 
record the average value of 3 experiments. 
Heat Pain Tolerance: 
For heat pain tolerance measurements, the thermode will be placed within the same surgically 
marked skin area of the anterior side of the right thigh, which was used to assess heat pain 
threshold. The thermode will have a baseline temperature of 32 °C, and will be programmed 
to gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 
their dominant hand, to indicate when the heat-evoked pain has reached an intensity that is no 
longer tolerable, by pushing a button. At that time, the test will be stopped and the 
temperature returned to baseline within 1 second. This process will be repeated a further 
2 times, with an interval of at least 1 minute between measurements (from start to start). The 
computer will record the average value of 3 experiments. 
Safety Precautions 
As there is a risk that OLP-1002 may affect the heat pain threshold, Covance CRU will put 
appropriate safety measures in place to ensure that subjects are not exposed to extremes of 
temperature when taking a shower or consuming hot drinks. During the heat pain safety 
assessments, the cut-off temperature for either test is 53 °C in order to prevent skin injury. 
7.3.6. 
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.  
7.3.7. 
Body Weight and Height 
Body weight (in underclothes) and height will be recorded at the times indicated in the 
Schedule of Assessments in Appendix 6. BMI will be calculated using the following formula: 
BMI = body weight (kg)      (kg/m2) 
                  (height [m])2 
7.3.8. 
Injection Site Assessments 
Injection site assessments will be made at the times indicated in the Study Plan (Appendix 6). 
Assessments will involve evaluation of the dosing site for the following criteria:  
• Pain will be evaluated according to the following scale: 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 


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None 
Does not 
interfere with 
activity 
Interferes with 
activity or 
repeated use of 
non-narcotic 
pain reliever 
Prevents daily 
activity or 
repeated use of 
narcotic pain 
reliever 
Requires 
medical 
intervention 
greater than 
analgesia  
 
• Redness will be assessed by estimating the size of the red patch at the injection site across 
its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm 
51-100 mm 
More than 100 
mm 
Requires 
medical 
intervention 
greater than 
analgesia  
• Swelling will be assessed by estimating the size of the raised area around the injection site 
across its widest point, and will be evaluated according to the following scale:  
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm 
25-50 mm and 
does not 
interfere with 
activity 
51-100 mm or 
interferes with 
activity 
More than 100 
mm and 
prevents daily 
activity 
Requires 
medical 
intervention 
greater than 
analgesia 
In addition, how the swelling affects the subject in their daily routing activities will be 
considered. 
• Tenderness will be evaluated using the following scale: 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Mild pain to 
touch 
Moderate Pain 
to touch 
Severe pain to 
touch 
Requires 
medical 
intervention 


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greater than 
analgesia 
• Bruising and ulceration will be evaluated as being present or absent. 
Local tolerability ratings of ≥Grade 3 and the presence of ulceration will be recorded as an 
adverse event.  
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time OLP-1002 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. In order to achieve PD endpoints 
in Part A, additional subjects will be included in 3 groups (8 subjects in total; 6 active: 
2 placebo). Up to 3 additional groups may be added to Part A, consisting of either 4 subjects 
(3 active; 1 placebo) or 8 subjects (6 active; 2 placebo). Up to 3 additional groups of 
8 subjects may be added to Part B (6 active; 2 placebo). 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of OLP-1002 that 
have evaluable PK data and have had no AEs or protocol deviations considered to impact PK. 
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo and for whom PD can be evaluated. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo. 
8.3. 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma concentration data, 
using commercial software such as Phoenix® WinNonlin®. Plasma concentrations of 
OLP-1002 and PK parameters will be listed and summarized using descriptive statistics. 
Individual and arithmetic mean OLP-1002 concentration-time profiles will also be presented 
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8.4. 
Pharmacodynamic Analyses 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No 
formal statistical analysis of PD data is planned. 
8.5. 
Safety Analysis 
Safety parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 
9. REFERENCES 
1.  Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A 
channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 
14;444(7121):894–8.  
2.  Goldberg YP, Price N, Namdari R, Cohen CJ, Lamers MH, Winters C, et al. Treatment of 
Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel 
blocker. Pain. 2012 Jan;153(1):80–5.  
3.  Jones HM, Butt RP, Webster RW, Gurrell I, Dzygiel P, Flanagan N, et al. Clinical Micro-
Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of 
Human Nav1.7 Voltage-Dependent Sodium Channels. Clin Pharmacokinet. 
2016;55(7):875–87.  
4.  Investigator Brochure - OLP-1002. 2018.  
5.  Gazerani P, Andersen OK, Arendt-Nielsen L. Site-specific, dose-dependent, and sex-
related responses to the experimental pain model induced by intradermal injection of 
capsaicin to the foreheads and forearms of healthy humans. J Orofac Pain. 
2007;21(4):289–302.  
6.  Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, et al. 
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in 
Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE 
[Internet]. 2016 Apr 6 [cited 2018 Jun 15];11(4). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822888/ 
7.  Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-
dependent pain, allodynia, and hyperalgesia in humans. J Investig Med Off Publ Am Fed 
Clin Res. 2006 Jul;54(5):238–44.  
8.  Anderson WS, Sheth RN, Bencherif B, Frost JJ, Campbell JN. Naloxone increases pain 
induced by topical capsaicin in healthy human volunteers. Pain. 2002 Sep;99(1–2):207–
16.  
9.  Pharmacokinetics and Metabolism in Drug Design, 3rd Edition [Internet]. Wiley.com. 
[cited 2018 Aug 21]. Available from: https://www.wiley.com/en-


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us/Pharmacokinetics+and+Metabolism+in+Drug+Design%2C+3rd+Edition-p-
9783527329540 
10.  Mahmood I. Pharmacokinetic allometric scaling of antibodies: application to the first-in-
human dose estimation. J Pharm Sci. 2009 Oct;98(10):3850–61.  
11.  Offman E, Edginton AN. Pharmacokinetic Time Course Scaling of a Subcutaneously 
Administered Pegylated Peptide Conjugate for a First-in-Human Investigation. Eur J 
Drug Metab Pharmacokinet. 2017 Feb;42(1):69–78.  
 
 


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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 unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but posing no 
significant or permanent risk of harm to the subject. 
• 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 drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
• 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. 
• 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. 
• Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized 
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 
stabilized. 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: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize 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 Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization 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 
Covance Drug Safety Services (DSS) Europe, Maidenhead, UK are 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 facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the Safety 
Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of the 
SAE within 2 working days of the initial notification to DSS. Drug Safety Services 
will delete any information from the SAE report forms that may identify the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined in 
the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions 
and forward to the Ethics Committee, Medicines and Healthcare Products Regulatory 
Agency, Principal 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. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfill regulatory requirements any pregnancy reported by female subjects or 


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the female partners of male subjects should be reported following the SAE process to collect 
data on the outcome for both mother and fetus. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Urea 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
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  
Serologya: 
Drug screenb: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
MDMA 
Alcohol breath test 
Follicle-stimulating hormonea  
Serum pregnancy test (human 
chorionic gonadotropin)a 
Urine pregnancy testc 
a Only analyzed at Screening. 
b Only analyzed at Screening and Check-in. 
c 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. 
Part A 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
109.5  
Part B 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
194.5  
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
during the study will not exceed that donated during a standard blood donation 
(approximately 500 mL). 


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Appendix 4: Contraception Guidance 
Definitions 
Females of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Females of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 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-estrogens, or selective estrogen 
receptor modulators.  
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. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary highly effective and 1 secondary method) of birth control from the time of signing 
the informed consent form until 90 days after the Follow-up visit. Primary highly effective 
methods of contraception include:  
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  
• hormonal or non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject). 


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Secondary (barrier) methods of contraception include:  
• male condom with spermicide 
• female condom with spermicide  
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects can only choose a cervical cap or diaphragm if they have already had a 
prescription and fitting by their healthcare provider to ensure protocol requirements are met. 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in until 90 days after the Follow-up 
visit. Acceptable methods of contraception include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide 
• vasectomised male subject (sterilization 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 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 


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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: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with Clinical Research Unit personnel, subjects will sign 
2 copies of the ICF in the presence of a suitably trained member of staff to indicate that they 
are freely giving their informed consent. One copy will be given to the subject, and the other 
will be maintained in the subject’s records. 
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 


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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 Organization (CRO) auditors or other 
authorized personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All 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.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality tolerance 
thresholds, controls, and mitigation plans will be documented in a risk management 
register. Additional details of quality checking to be performed on the data may be 
included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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. 
• 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.  


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Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 Code of Federal 
Regulations 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 the Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled and randomized subject, according to the 
eCRF completion instructions. The Sponsor, or CRO, will review the supporting source 
documentation against the data entered into the eCRFs to verify the accuracy of the electronic 
data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 
information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 58 of 79 
Appendix 6: Schedule of Assessments 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 59 of 79 
Study Plan – Part A (Single Dose) 
 
Pre- 
screeningd 
Screening 
Day -
2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
 
X 
X 
 
 
 
 
 
 
 
Alcohol breath test 
 
X 
X 
 
 
 
 
 
 
 
Cotinine test 
 
X 
X 
 
 
 
 
 
 
 
Serology 
 
X 
 
 
 
 
 
 
 
 
Hormone panel 
 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
X 
X 
 
 
 
 
 
 
X 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
Day 3 (48 hours 
postdose) 
 
 
 
 
 
Non-residential visit 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Study drug administration: 
 
 
 
 
Day 1 (0 hours)  
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, pulse 
rate, respiratory rate, and 
body temperature 
 
X 
 
 
Predose, 1, 2, 4, 
8, 24 (± 1 hour), 
and 48 hours 
postdose 
X 
X 
X 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 60 of 79 
 
 
Pre- 
screeningd 
Screening 
Day -
2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Supine 12-lead ECG 
 
X 
 
 
Predose, 4, 24 
(± 1 hour) and 48 
hours postdose 
 
X 
 
X 
X 
Continuous ECG 
extractionb,c 
 
 
 
-24,  
-23.5,  
-23,   
-22.5,  
-22,  
-21.5,  
-21,  
-20, 
-18,  
-16,   
-12 
hours 
Day 1: Predose, 
0.5, 1, 1.5, 2, 2.5, 
3, 4, 6, 8, 12 and 
24 hours 
 
 
 
 
 
 
Heat pain threshold test 
(heat pain threshold and heat 
pain tolerance) 
 
 
 
 
Day 1: predose, 2, 
4, 12, and 24 
hours postdose (± 
1 hour) 
 
 
 
 
 
Clinical chemistry, 
haematology, and urinalysis 
 
X 
 
 
48 hours postdose 
 
X 
 
X 
X 
Height and BMI 
 
X 
 
 
 
 
 
 
 
 
Body weight  
 
X 
X 
 
 
 
 
 
 
X 
Physical examination 
 
X 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
 
 
Prior to discharge 
 
X 
 
X 
X 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 61 of 79 
Abbreviations: BMI = body mass index; ECG = electrocardiogram. 
a A positive urine pregnancy test result will be confirmed with a serum pregnancy test. 
b All times are relative to dosing with OLP-1002. 
c Continuous ECG recording may begin at approximately 25 hours before dosing to allow for checks to be completed prior to the first extraction timepoint and will continue for 24 hours 
postdose, ie, until after the last timepoint for ECG extraction (24 hours postdose). At timepoints for ECG extractions, subjects will be supinely resting for a total of 15 minutes (10-minute supine 
rest period, 5-minute extraction). Data will be archived for potential future analysis and will not be available for review during the study. 
d Pharmacodynamic assessment groups only. 
e PK analysis in Part A will initially only be conducted for groups receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the event of PK data 
being quantifiable at doses ≥ 12 µg and if supported by bioanalytical stability data. 
 
 
 
Pre- 
screeningd 
Screening 
Day -
2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Injection site assessment  
 
 
 
 
Predose, 1, 2, 4, 
8, 24, 48 hours 
postdose 
 
X 
 
X 
X 
Pharmacokineticse 
 
 
 
 
 
 
 
 
 
 
Blood sampling 
 
 
 
 
Predose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 
12, 16, 24, 36 and 
48 hours postdose 
X 
X 
X 
X 
X 
Pharmacodynamicsd: 
 
 
 
 
 
 
 
 
 
 
Intradermal capsaicin test 
(capsaicin-evoked pain and 
secondary hyperalgesia 
measurement) 
X 
 
X 
 
Day 2 (The area 
of secondary area 
of hyperalgesia 
will be evaluated 
at 5 and 30 
minutes post-
capsaicin 
injection) 
 
 
 
 
 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 62 of 79 
Study Plan – Part B (Multiple Dose) 
 
Screening 
Day -1 
Days 1-15 
Day 18 
(± 2 days) 
Day 22 
(± 2 days) 
Day 25 
(± 2 days) 
Day 29 
(± 2 days) 
Poststudy 
(Day 57 
± 2 days) 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
X 
X 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
Cotinine test 
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
Hormone panel 
X 
 
 
 
 
 
 
 
Urine pregnancy testa 
X 
X 
 
 
X 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
Check-out 
 
 
Day 15 (48 hours postdose) 
 
 
 
 
 
Non-residential visit 
X 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
Days 1, 4, 7, 10, and 13 
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording  
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, 
pulse rate, respiratory rate, 
and body temperature 
X 
 
Day 1: predose, 1, 2, 4 and 8 hours 
postdose 
Day 2, Day 4 (postdose), Day 5, Day 7 
(postdose), Day 9, Day 10 (postdose), 
Day 12, Day 13: predose, 1, 2, 4 and 8 
hours postdose, and Day 15 
 
X 
X 
X 
X 
X 


Protocol 
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Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 63 of 79 
 
Screening 
Day -1 
Days 1-15 
Day 18 
Day 22 
Day 25 
Day 29 
Poststudy 
(Day 57 
± 2 days) 
Heat pain threshold test 
(heat pain threshold and 
heat pain tolerance) 
X 
 
Day 1 and Day 13: predose, 1, 2, 4, 8, 
24 hours postdose 
 
 
 
 
 
Supine 12-lead ECG 
X 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Days 2, 5, 9, 12, 17 
 
X 
 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
Days 1, 4, 7, 10, 13 
 
X 
 
X 
X 
Injection site assessment  
 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Pharmacokinetics: 
 
 
 
 
 
 
 
 
Blood samplingb 
 
 
Day 1 and Day 13: Pre dose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
X 
X 
X 
X 
X 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 64 of 79 
Abbreviations: BMI = body mass index; ECG = electrocardiogram. 
a Positive urine pregnancy test results will be confirmed with a serum pregnancy test. 
b  PK timepoints will be reviewed based on emerging data and may be updated.


Protocol 
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Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 65 of 79 
Appendix 7: Protocol Amendment Summary of Changes 
Protocol Amendment 2 (Version 2.1; 21 November 2018) 
This non-substantial amendment has been issued to correct minor inconsistencies in 
PK sampling timepoints, data cut off for dose escalation, clinical laboratory 
assessment timepoints, and the synopsis. Additionally, details of the injection site 
assessments have been added to the protocol. 
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Synopsis: Endpoints 
Text added: 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 
12-lead ECGs, vital signs measurements, injection site assessment, heat pain threshold 
and tolerance, and physical examinations. 
 
Section 3.6 
Previously read: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
Now reads: 
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 10 (216 hours postdose) from groups that received lower doses of OLP-1002. 
Section 7.3.8 
Entire section added to describe injection site assessments. 
Appendix 3 
Total blood volume for PK analysis (76 mL) added. 
Appendix 6 - Schedule of assessments Part A 
24 hour postdose continuous ECG recording timepoint added. 
Appendix 6 - Schedule of assessments Part B 
Clinical chemistry, haematology, and urinalysis for Days 1-15 previously read: 


Protocol 
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Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 66 of 79 
Days 2, 4, 7, 10,13 
Clinical chemistry, haematology, and urinalysis for Days 1-15 now reads: 
Days 2, 5, 9, 12, 17 
 
PK blood sampling for Days 1-15 previously read: 
Day 1 and Day 15: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 8, 11, 15 Predose 
PK blood sampling for Days 1-15 now reads: 
Day 1 and Day 13: Pre dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 7, 10 Predose 
Day 15 
Protocol Amendment 1 (Version 2; 02 October 2018) 
This amendment has been generated following the non-acceptance of the original 
protocol (version 1) by the Medicines and Healthcare products Regulatory Agency 
(MHRA) on 20 September 2018. All changes made have been in response to 
comments provided by the MHRA. 
The primary changes in this amendment are: 
1. Inclusion of PK sampling in Parts A and B: 
• PK objective and exploratory endpoints added (Section 2). 
• Discussion of PK included Section 3.4. 
• PK stopping criteria added to Section 3.7. 
• PK assessments included in Section 7.1. 
• PK population and analysis (Section 8.2.1). 
• Blood volumes updated to include samples for PK assessments 
(Appendix 3). 
2. Exclusion and stopping criteria updated 
• Women who are pregnant or breastfeeding have been excluded from 
the study (Section 4.2). 
• Liver function tests, tachycardia, and hypertension stopping criteria 
have been updated (Section 3.7 and Section 4.4). 
• Stopping criteria for SAEs and serious AEs have been added 
(Section 3.7 and Section 4.4). 
3. Safety, tolerability, and PK data up to Day 22 in Part B will be reviewed prior 
to dose escalation (Section 3.1.2). 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
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4. Sentinel dosing included in Part B (Section 3.1.2). 
5. It has been specified that the maximum dose for additional groups will not 
exceed 20 µg (Section 3.5.3). 
Minor changes: 
1. Additional clinical laboratory evaluations have been included on Day 14 in 
Part A. 
2. The definition of the Safety population has been updated to include all 
subjects who receive OLP-1002. 
3. Typographical errors and formatting errors were corrected, as necessary. 
A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Section 1.6 
Previously read: 
This information, together with the pharmacodynamic (PD data, will help establish 
the doses and dosing regimen suitable for future studies in patients. 
Now reads: 
This information, together with the pharmacodynamic (PD) and pharmacokinetic 
(PK) data, will help establish the doses and dosing regimen suitable for future 
studies in patients. 
Section 2.1  
Objective added: 
Where possible, single and/or multiple subcutaneous dose pharmacokinetics of 
OLP-1002 in healthy subjects will be determined. 
Section 2.2.1 
Endpoint added: 
• demonstrate that exposure to OLP-1002 does not exceed pre-defined 
exposure limits from non-clinical studies. 
Section 2.2.2 
Endpoints added: 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-
1002 are as follows: 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 68 of 79 
Primary PK 
o area under the plasma concentration-time curve (AUC) from 
time zero to infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable 
concentration (AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and 
DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 
Other PK parameters may also be added if deemed necessary. 
Section 3.1.1 
Previously read: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 


Protocol 
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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 69 of 79 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 7 (144 hours postdose) from the lower dose 
levels. 
Now reads: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, PK, and PD 
(Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 10 (216 hours postdose) from the lower dose 
levels. For doses ≥ 12 µg, PK data will also be reviewed up to Day 7 prior to 
dose escalation. 
Figure 1 – footnote 
Text added:  
Groups A9 to A11 may be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Figure 2 – footnote 
Text added: 
Groups B4 to B6 will be included if required; dose levels will not exceed the 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
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maximum proposed dose of 20 µg. 
Section 3.1.2 
Previously read: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. There will be no sentinel dosing in Part B. For all subjects, a single 
subcutaneous dose will be administered on Days 1, 4, 7, 10, and 13. The dosing 
frequency in Part B may be changed following review of data from groups in Part 
A (Section 3.4).  
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 18 (120 hours post-final dose) from the lower 
dose levels. Part B may start after a review of the safety and tolerability for Groups 
A1 to A6. The total daily dose administered will not exceed the highest single dose 
given in Part A. 
Now reads: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. For all subjects, a single subcutaneous dose will be administered 
on Days 1, 4, 7, 10, and 13. Prior to each dosing occasion a physician will review 
the available safety and tolerability data from each subject to confirm it is 
acceptable to continue dosing. The dosing frequency in Part B may be changed 
following review of data from groups in Part A (Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to 
OLP-1002 at steady state is predicted to exceed exposures that have been 
shown to be safe and well tolerated in earlier groups in Parts A or B. In the 
event of sentinel dosing, 2 subjects (1 active, 1 placebo) will be dosed at least 
4 days prior to the remaining 6 subjects (5 active: 1 placebo). Safety data for 
the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 
1 and 2 will be reviewed prior to the remaining subjects receiving dose 1). In 
addition, safety data from each subject will be reviewed by a physician prior to 
each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from the 
lower dose levels. Part B may start after a review of the safety, tolerability, and 
available PK data for Groups A1 to A6. The total daily dose administered will not 
exceed the highest single dose given in Part A. 
Section 3.3 
Previously read: 
Following review of the safety, tolerability, and PD data, additional dose groups 


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Protocol Reference: OLP-1002-001 
Protocol Version 2.1, 29 November 2018 
Page 71 of 79 
may be added to the study. 
Now reads: 
Following review of the safety, tolerability, PK, and PD data (where systemic 
exposure is not expected to exceed that stated in the dose escalation stopping 
criteria [Section 3.7]), additional dose groups may be added to the study. The 
maximum dose for any additional group will not exceed 20 µg. 
Section 3.4 
Previously read: 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis will not be conducted in this study. The bioanalytical 
method used for preclinical species has a lower limit of quantification (LLOQ) of 
5 ng/mL. The increased sample volume possible from humans (compared to small 
animals) may afford an approximate 10-fold increase in sensitivity with possibly an 
additional 5-fold increase from the use of a more sensitive mass spectrometer. This 
could potentially deliver an LLOQ of around 0.1 ng/mL. It is apparent from the 
predicted plasma concentrations (see Section 3.5.2) that only a small number of 
samples around Cmax at the highest doses would be quantifiable and that a 
conventional approach to pharmacokinetic will not achieve a full definition of the 
plasma concentration vs time profile or enable an estimation of the terminal phase. 
Thus, the additional burden of sampling procedures would not be justified by the 
quality of the data which it would generate. 
Now reads:  
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, 
and PK data up to Day 7 will be reviewed for all groups receiving ≥ 12 µg 
OLP-1002. In Part B, safety, tolerability and PK data up to Day 22 will be 


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Protocol Version 2.1, 29 November 2018 
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reviewed for all dose groups. As the t1/2 of OLP-1002 is predicted to be 
approximately 180 hours (based on non-clinical data) review of safety data up 
to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma 
exposures are anticipated to be low, it is expected that it will only be possible 
to perform an assessment of peak concentrations (Cmax) and therefore PK data 
to Day 7 (Part A) and Day 22 (Part B) will be sufficient. Additionally, a 
cumulative safety review will occur such that additional emerging safety data 
from earlier groups will be considered when making a dose escalation decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower 
dose groups occurring in the event of PK data being quantifiable at doses ≥ 12 
µg and if supported by bioanalytical stability data. Dose escalation decisions 
for doses <12 µg in Part A will not require PK data. The rationale for this is 
that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical 
species has a lower limit of quantification (LLOQ) of 5 ng/mL. The increased 
sample volume possible from humans (compared to small animals) may afford an 
approximate 10-fold increase in sensitivity with possibly an additional 5-fold 
increase from the use of a more sensitive mass spectrometer. This could potentially 
deliver an LLOQ of around 0.1 ng/mL. Therefore, even with the increased assay 
sensitivity plasma levels from doses at or below 12 µg are not expected to be 
quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose 
would be quantifiable and that a conventional approach to pharmacokinetic will not 
achieve a full definition of the plasma concentration vs time profile or enable an 
estimation of the terminal phase. In addition the planned dose levels have a high 
safety margin when comparing the predicted exposures to the exposures at the 
NOAEL (see Section 3.5.2), with the 12 µg dose level having an expected 312-
fold and 255-fold safety margin based on Cmax and AUC0-∞, respectively. 
Therefore if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  


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Section 3.4.1 
Previously read: 
In Part B, all subjects in a group will be dosed on the same day. Accumulation of 
OLP-1002 is expected following multiple doses, based on the preclinical data, and 
will be taken into account when determining the doses for Part B (see 
Section 3.5.3). 
Now reads:  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 
at steady state is predicted to exceed exposures that have been shown to be safe 
and well tolerated in earlier groups in Parts A or B. When used, two subjects 
(1 active; 1 placebo), will be dosed 4 days prior to the remaining 6 subjects 
(5 active; 2 placebo). The 2 sentinel subjects will always be 2 doses ahead of the 
remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not 
predicted to exceed that tested in Part A will be dosed on the same day. 
Accumulation of OLP-1002 is expected following multiple doses, based on the 
preclinical data, and will be taken into account when determining the doses for Part 
B (see Section 3.5.3). If it is not possible to quantify exposure it will be assumed 
that multiple dosing results in a 4-fold accumulation based on the predicted t1/2 
of 180h. 
Section 3.5.3 
Text added: 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose 
administered will not exceed 20 µg and predicted systemic exposure will not 
exceed that stated in the dose escalation stopping criteria [Section 3.7]) based 
on available PK data. 
Section 3.6 
Previously read:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety and tolerability data up to Day 18 (120 hours post-final dose) from 
groups that received lower doses of OLP-1002. Doses may be reduced and may be 


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lower than the starting dose. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 5 subjects, who have received OLP-1002 will be used to make the dose-
escalation decision. Dose escalation in Part B will only occur if data from a 
minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
Now reads:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
For escalation to doses > 12 µg, PK data up to Day 7 (144 hours postdose) will 
also be reviewed. All available safety, tolerability, and PK data from previous 
groups will be reviewed prior to dose escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) 
from groups that received lower doses of OLP-1002. Doses may be reduced and 
may be lower than the starting dose. Available safety, tolerability, and PK data 
from all previous groups will be reviewed prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 3 or 4 subjects, respectively, who have received OLP-1002 will be used to make 
the dose-escalation decision. Dose escalation in Part B will only occur if data from 
a minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
 
Section 3.7 
Previously read: 
In Parts A and B, following consultation with the Sponsor, dose escalation will be 
stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping 
of dose escalation. 
• There is evidence of clinically significant increases in liver function tests 
(aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase 


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and total bilirubin) defined as 3 times the upper limit of normal in 3 or more 
subjects in a group (confirmed with repeat testing). 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in 
at least 2 subjects in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in 
at least 2 subjects in a group. 
Now reads: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping 
of dose escalation. 
• One or more subjects experience an SAE that is considered to be 
related to OLP-1002. 
• Two or more subjects in the same group experience severe non-serious 
AEs (ie. severe non-serious AEs considered as, at least, possibly related 
to OLP-1002 administration), independent of whether the AEs are 
within or not within the same system organ class.  
• There is evidence of clinically significant increases in aspartate 
aminotransferase, alanine aminotransferase or alkaline phosphatase (defined 
as 3 times the upper limit of normal), or total bilirubin (defined as 2 times 
the upper limit of normal) that are considered to be related to OLP-
1002 in 2 or more subjects in a group. Results will be confirmed with 
repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in 
≥1 subject in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in 
≥1 subject in a group. 
• The dose will not exceed 20 µg or the systemic exposure for any 
individual subject is predicted to exceed a Cmax of 24.9 ng/mL (plasma) 
and/or an AUC0-24 of 128 ng/mL; i.e., systemic exposure will be no 


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greater than the NOAEL in the most sensitive species (100,000 pmol/kg 
in rat [462 µg/kg]). 
 
Section 4.2 
Exclusion criteria added: 
4. 
Female subjects who are pregnant or breastfeeding. 
Section 4.4 
Previously read: 
• any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal 
Now reads: 
• any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least 
possibly related to OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE 
considered to at least possibly related to OLP-1002 
administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for 
Part A or Day 1 predose for Part B) and/or absolute QTcF 
values > 500 msec (confirmed by repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position 
(confirmed by 2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg 
and/or diastolic blood pressure > 110 mmHg) in the resting 
supine position (confirmed by 2 repeat measurements). 
Section 7.1 
Section added: 
7.1 Pharmacokinetic Assessments 
7.1.1 Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times 
indicated in the Schedule of Assessments (Appendix 6). Furthermore, 
additional blood samples may be taken from each subject per treatment 


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period, with the maximum volume of blood withdrawn per subject not 
exceeding the limit detailed in Appendix 3. Any changes to the scheduled times 
of PK assessments will be agreed with the Sponsor and documented in the 
TMF. Samples taken from subjects who received placebo will not be analyzed. 
In Part A, only samples collected from subjects that received >12 µg OLP-1002 
will be initially analyzed. If PK data is quantifiable at concentrations of OLP-
1002 >12 µg, samples from lower dose groups will be retrospectively analyzed. 
In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated 
analytical procedures. Specifics of the analytical methods will be provided in 
separate documents. 
Section 8.2 
Previously read: 
8.2.1 Pharmacodynamic population 
The PD population will include all subjects who received at least 1 dose of study 
treatment OLP-1002 or placebo and for whom PD can be evaluated. 
8.2.2 Safety Population 
The safety population will include all subjects who received at least 1 dose of study 
treatment or placebo and have at least 1 postdose safety assessment. 
Now reads: 
8.2.1 Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of 
OLP-1002 that have evaluable PK data and have had no AEs or protocol 
deviations considered to impact PK. 
8.2.2 Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-
1002 or placebo and for whom PD can be evaluated. 
8.2.3 Safety Population 
The safety population will include all subjects who received at least 1 dose of 
OLP-1002 or placebo. 


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8.3 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma and 
urine concentration data, using commercial software such as Phoenix® 
WinNonlin®. Plasma concentrations of OLP-1002 and PK parameters will be 
listed and summarized using descriptive statistics. Individual and arithmetic 
mean OLP-1002 concentration-time profiles will also be presented graphically. 
Appendix 3 
Table updated: 
Part A 
 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis* 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
33.5109.5  
Part B 
 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
78.5194.5  
Appendix 6 
PK and Blood sampling rows added to the schedule of events for Part A and Part B. 
In the Schedule of events for Part A, footnote e was added. In the Schedule of 
events for Part B, footnote b was added. 
Clinical chemistry, hematology, and urinalysis was added to the Schedule of events 


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for Part A on Day 14.  
 
 


TITLE PAGE 
Protocol 
OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single 
and Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, 
and Pharmacodynamic Study in Healthy Male and Female Subjects 
Protocol Status: Final 
Protocol Date: 02 October 2018 
Protocol Version: 2 
Investigational Product: OLP-1002 
 
Protocol Reference Number: OLP-1002-001 
Covance Study Number: 8379789 
EudraCT Number: 2018-003085-13 
 
 
Sponsor: 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung-gu, Yongin, Gyeonggi 17015 
Republic of Korea 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street  
Leeds, LS2 9LH 
United Kingdom 
 
 
Sponsor Signatory: 
 
 
Principal Investigator: 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP- I 002-001 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
 
Protocol Version 2, 02 October 2018 
Date 
Page 2of75 


Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP-1002-001 
INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
 
Principal Investigator 
Protocol Version 2, 02 October 2018 
Q3 0 LJ'2-{j) I y; 
Date 
Page 3 of75 


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STUDY IDENTIFICATION 
Sponsor 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Study Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Medical Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Medical Monitor 
(24-hour emergency 
medical contact) 
 
 
 
 
 
Study Site 
Covance Clinical Research Unit Ltd. 
Springfield House, 
Hyde Street, 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
Project Physician 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 


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United Kingdom 
 
Clinical Laboratory 
 
 
 
Statistician 
 
Covance 


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SYNOPSIS 
Title of study: OLP-1002 – A first-in-human, double-blind, placebo-controlled, single and multiple 
subcutaneous dose, safety, tolerability, pharmacokinetic, and pharmacodynamic study in healthy 
male and female subjects 
Objectives:  
The primary objective of the study is to assess the safety and tolerability of single and multiple 
subcutaneous doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the pharmacodynamic effect of OLP-1002 
following single subcutaneous doses in healthy volunteers using a capsaicin pain model, and to 
monitor the effects of a single subcutaneous doses of OLP-1002 on cardiac QT interval. Where 
possible, single and/or multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy 
subjects will be determined. 
Study design: 
This will be a double-blind, randomized, placebo-controlled, single and multiple subcutaneous dose 
study conducted in 2 parts, including healthy male and female subjects. 
Number of subjects: 
Part A: 44 subjects will be studied in 8 groups (5 groups of 4 and 3 groups of 8). 
Part B: 24 subjects will be studied in 3 groups (Groups B1 to B3). 
Up to 24 additional subjects may be recruited into Part A and Part B of the study if required. 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged between 18 and 60 years (inclusive) with a body mass index 
between 18.0 and 28.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test product: OLP-1002 
Proposed dose levels for Part A: 30 ng, 120 ng, 400 ng, 1.2 µg, 3 µg, 6 µg, 12 µg, and 20 µg. 
Proposed dose levels for Part B: the doses for Part B will be decided in consultation with the 
Sponsor and on the basis of data from Part A of the study. The highest dose in Part B will be up to 
50% of the highest dose in Part A. 
Administration route: subcutaneous 
Reference product and mode of administration: 
Reference product: placebo 
Administration route: subcutaneous 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 8 weeks for Part A and 
approximately 12 weeks for Part B. 


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Endpoints: 
Pharmacodynamics: 
In Part A, the analgesic effect of OLP-1002 will be investigated in 3 groups consisting of 8 subjects 
(6 active: 2 placebo) using experimental capsaicin-evoked pain methods. Measurement of 
capsaicin-evoked pain will be performed at pre-screening, baseline and on Day 2, and secondary 
hyperalgesia at 5 and 30 minutes post-capsaicin injection. Continuous electrocardiogram (ECG) 
recording will be conducted to investigate the effect of OLP-1002 on cardiac function. 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 12-lead 
ECGs, vital signs measurements, injection site assessment, and physical examinations. 
Pharmacokinetics: 
In Part A, the following PK parameters will be determined where possible: area under the plasma 
concentration-time curve (AUC) from time zero to infinity (AUC0-∞), AUC from time zero to the 
time of the last quantifiable concentration (AUC0-tlast), maximum observed plasma concentration 
(Cmax), time of the maximum observed plasma concentration (tmax), and apparent plasma terminal 
elimination half-life (t1/2). PK analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups 
occurring in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by 
bioanalytical stability data. 
In Part B, the following PK parameters will be determined where possible: AUC over a dosing 
interval (AUC0-τ), AUC0-∞, Cmax, minimum observed plasma concentration (Cmin), tmax, t1/2, observed 
accumulation ratio based on AUC0-τ (RAAUC0-τ), observed accumulation ratio based on Cmax 
(RACmax), and Temporal change parameter (TCP). PK samples from all groups in Part B will be 
analyzed. 
Statistical methods: 
Pharmacodynamics: 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of pharmacodynamic data is planned. 
Safety: 
Safety parameters will be listed and summarized using descriptive statistics. No formal statistical 
analysis of safety data is planned. 
Pharmacokinetics: 
Individual plasma concentrations and PK parameters of OLP-1002 will be listed and summarized 
using descriptive statistics. Individual and mean OLP-1002 concentration-time profiles will be 
presented graphically. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................13 
1.1. 
Overview ................................................................................................................13 
1.2. 
Summary of Nonclinical Pharmacology ................................................................13 
1.2.1. 
In Vitro Pharmacology Studies ....................................................................13 
1.2.2. 
In Vivo Pharmacology Studies ....................................................................14 
1.2.3. 
Ex Vivo Pharmacology Studies ...................................................................15 
1.3. 
Summary of Safety Pharmacology ........................................................................16 
1.4. 
Summary of Toxicology ........................................................................................16 
1.5. 
Summary of Nonclinical Pharmacokinetics ...........................................................17 
1.6. 
Study Rationale ......................................................................................................18 
1.7. 
Benefit-risk Assessment .........................................................................................18 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................18 
2.1. 
Objectives ..............................................................................................................18 
2.2. 
Endpoints ...............................................................................................................18 
2.2.1. 
Primary Endpoints .......................................................................................18 
2.2.2. 
Exploratory Endpoints .................................................................................19 
3. 
INVESTIGATIONAL PLAN ..........................................................................................20 
3.1. 
Overall Study Design and Plan ..............................................................................20 
3.1.1. 
Part A ...........................................................................................................20 
3.1.2. 
Part B ...........................................................................................................22 
3.2. 
Start of Study and End of Study Definitions .........................................................23 
3.3. 
Additional Groups ..................................................................................................23 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................23 
3.4.1. 
Dose Interval ................................................................................................25 
3.4.2. 
Pharmacodynamic Assessment ....................................................................25 
3.5. 
Selection of Doses in the Study .............................................................................26 
3.5.1. 
Starting Dose ................................................................................................26 
3.5.2. 
Exposure ......................................................................................................27 
3.5.3. 
Proposed Doses ............................................................................................28 
3.6. 
Dose Escalation ......................................................................................................29 


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3.7. 
Dose Escalation Stopping Criteria .........................................................................30 
4. 
SELECTION OF STUDY POPULATION .....................................................................31 
4.1. 
Inclusion Criteria ...................................................................................................31 
4.2. 
Exclusion Criteria ..................................................................................................31 
4.3. 
Subject Number and Identification ........................................................................33 
4.4. 
Subject Withdrawal and Replacement ...................................................................33 
4.5. 
Study Termination .................................................................................................34 
5. 
STUDY TREATMENTS .................................................................................................34 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................34 
5.2. 
Study Treatment Administration ............................................................................34 
5.3. 
Randomization .......................................................................................................34 
5.4. 
Blinding..................................................................................................................35 
5.5. 
Treatment Compliance ...........................................................................................35 
5.6. 
Drug Accountability...............................................................................................35 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................36 
6.1. 
Concomitant Therapies ..........................................................................................36 
6.2. 
Diet .........................................................................................................................36 
6.3. 
Smoking .................................................................................................................36 
6.4. 
Exercise ..................................................................................................................36 
6.5. 
Blood Donation ......................................................................................................37 
6.6. 
Other Restrictions ..................................................................................................37 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................37 
7.1. 
Pharmacokinetic Assessments ...............................................................................37 
7.1.1. 
Sample Collection and Processing ...............................................................37 
7.1.2. 
Analytical Methodology ..............................................................................38 
7.2. 
Pharmacodynamic Assessments ............................................................................38 
7.2.1. 
Capsaicin-evoked Pain Model .....................................................................38 
7.2.2. 
Secondary Hyperalgesia ...............................................................................38 
7.3. 
Safety and Tolerability Assessments .....................................................................38 
7.3.1. 
Adverse Events ............................................................................................38 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................39 
7.3.3. 
Vital Signs ....................................................................................................39 
7.3.4. 
Electrocardiogram ........................................................................................40 
7.3.5. 
Heat Pain Threshold Test .............................................................................40 
7.3.6. 
Physical Examination...................................................................................41 
7.3.7. 
Body Weight and Height .............................................................................41 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................41 
8.1. 
Determination of Sample Size ...............................................................................41 
8.2. 
Analysis Populations ..............................................................................................42 


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8.2.1. 
Pharmacokinetic Population ........................................................................42 
8.2.2. 
Pharmacodynamic Population .....................................................................42 
8.2.3. 
Safety Population .........................................................................................42 
8.3. 
Pharmacokinetic Analyses .....................................................................................42 
8.4. 
Pharmacodynamic Analyses ..................................................................................42 
8.5. 
Safety Analysis ......................................................................................................42 
9. 
REFERENCES ................................................................................................................42 
10.  APPENDICES .................................................................................................................44 
Appendix 1: Adverse Event Reporting ..............................................................................45 
Appendix 2: Clinical Laboratory Evaluations ...................................................................49 
Appendix 3: Total Blood Volume ......................................................................................50 
Appendix 4: Contraception Guidance ................................................................................51 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................54 
Appendix 6: Schedule of Assessments ..............................................................................57 
Appendix 7: Protocol Amendment Summary of Changes .................................................63 
7.1 
Pharmacokinetic Assessments ...............................................................................73 
7.1.1 
Sample Collection and Processing ...............................................................73 
7.1.2 
Analytical Methodology ..............................................................................73 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 ..........................................27 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 ......................................28 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
....................................................................................................................28 
 
Figure 1: 
Study Schematic (Part A)...........................................................................21 
Figure 2: 
Study Schematic (Part B) ...........................................................................23 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve extrapolated to infinity 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours 
postdose 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
DN 
Dose normalized 
DRG 
dorsal root ganglion 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Emax 
maximum pain intensity 
FCA 
Freund's Complete Adjuvant 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SNL 
spinal nerve ligation 
t1/2 
elimination half-life 
tEmax 
time of maximum pain intensity 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
VAS 
Visual Analogic Scale 


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VGSC 
voltage-gated sodium channel 


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1. INTRODUCTION 
1.1. 
Overview 
OLP-1002 is a novel peptide nucleic acid (PNA) derivative which acts as a specific voltage-
gated sodium channel (VGSC) protein (Nav1.7) inhibitor, and is being developed by OliPass 
for the treatment of pain. 
The Nav1.7 protein is a subtype of VGSCs. Nav1.7 is particularly important in nociception 
and pain signaling, with congenital loss-of-function mutations in Nav1.7 resulting in the 
inability to experience pain. Selective Nav1.7 inhibitors are believed to have the potential to 
treat severe pain safely1. The active sites of VGSC subtypes are virtually indistinguishable by 
their 3-dimensional structure and thus the discovery of selective Nav1.7 small molecule 
inhibitors has been extremely challenging. Since inhibition of Nav1.5 subtype elicits long QT 
cardiotoxicity, inhibition of Nav1.5 subtype should be avoided at therapeutic doses. 
To date, there are several Nav1.7 inhibitors claimed to be selective that have been evaluated 
in human subjects: 
• Vixotrigine (formerly known as raxatrigine) inhibits Nav1.7 as well as other VGSC 
subtypes. Vixotrigine is in phase III clinical development for trigeminal neuralgia. 
Due to the limited Nav1.7 selectivity over Nav1.5, vixotrigine was evaluated primarily 
in patients with a low heart risk. 
• Funapide is a Nav1.7 inhibitor with limited Nav1.7 selectivity, and was in phase IIb 
clinical trials as of July 2014. Although funapide showed analgesic activity in a small 
number of erythromelalgia patients, dose-limiting adverse events (AEs), including 
dizziness and somnolence, were observed2. The central nervous system (CNS) AEs 
were due to its poor Nav1.7 selectivity. 
• PF-05089771 is a Nav1.7 selective inhibitor with a claimed Nav1.7 selectivity of 
> 2000-fold versus other subtypes of sodium channel and was evaluated in patients of 
erythromelalgia or dental pain. It is thought low drug concentrations achieved in the 
target tissue could be a possible explanation for its poor analgesic activity in human 
patients3. 
OLP-1002 is fully complementary to a 14-mer RNA sequence spanning the junction of 
intron 4 and exon 5 in the human SCN9A pre-mRNA which codes for the Nav1.7 channel. 
OLP-1002 yields SCN9A mRNA splice variant(s) encoding variant Nav1.7 protein(s) lacking 
the sodium channel activity (ie, a non-functional channel), thereby inhibiting Nav1.7 channel 
function. 
1.2. 
Summary of Nonclinical Pharmacology 
1.2.1. 
In Vitro Pharmacology Studies 
Overall, results from the in vitro pharmacology studies showed OLP-1002 elicits responses 
consistent with its designed function4. It inhibits SCN9A mRNA expression and yields the 


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Nav1.7 variant protein or proteins lacking sodium channel activity. Its effects are highly 
selective, which may provide for an improved margin of safety compared to other Nav1.7 
inhibitors. 
OLP-1002 at 1 to 100 zM in PC3 prostate carcinoma cells induced exon skipping and yielded 
SCN9A mRNA splice variant(s) encoding a Nav1.7 variant protein or proteins lacking 
sodium channel activity.  
In rat dorsal root ganglion (DRG) neuronal cells, OLP-1002 at 1000 zM inhibited Nav1.7 
protein expression by > 50%, while OLP-1002R at 100 and 1000 zM inhibited Nav1.7 
expression almost completely. As OLP-1002R is fully complementary to rat SCN9A pre-
mRNA, OLP-1002R would be predicted to be more potent than OLP-1002 in this cell type. 
SCN9A mRNA expression level was evaluated by quantitative polymerase chain reaction 
(qPCR). OLP-1002 inhibited the expression of the SCN9A mRNA in PC3 cells with sub-
attomolar potency.  
In SH-SY5Y human neuroblastoma cells stimulated with tumor necrosis factor (TNF)-1α to 
upregulate the expression of SCN9A mRNA, OLP-1002 decreased expression by 46% to 
49% at 1 fM to 10 pM. In rat DRG neuronal cells, OLP-1002 at 1 fM significantly decreased 
SCN9A mRNA expression by 54%. 
In rat DRG neuronal cells, OLP-1002 markedly and significantly inhibited the sodium current 
by 77% at 0.1 aM and 73% at 1 aM, while for OLP-1002R, the inhibition was 66% at 0.1 aM 
and 70% at 1 aM. Given that rat DRG neuronal cells express various subtypes of sodium 
channel, the observed inhibitions of 66% to 77% correspond to the complete knockout of the 
Nav1.7 sodium channel subtype with OLP-1002 or OLP-1002R. 
The Nav1.7 selectivity over Nav1.5 was evaluated in H9C2 rat cardiomyocytes which are 
known to abundantly express the rat Nav1.5 sodium channel subtype. Following incubation 
with OLP-1002 or OLP-1002R at 1 aM or 1 pM, there were no notable decreases in the 
sodium current. Considering that OLP-1002 and OLP-1002R inhibit the expression of Nav1.7 
protein at 1 aM or lower in rat DRG neuronal cells, the Nav1.7 selectivity of OLP-1002 and 
OLP-1002R over Nav1.5 is estimated to be in excess of one million-fold. Such a large Nav1.7 
selectivity over Nav1.5 has not been realized with small molecule Nav1.7 inhibitors, 
suggesting that OLP-1002 potentially offers pain management with much greater 
cardiovascular safety. 
1.2.2. 
In Vivo Pharmacology Studies 
Spinal nerve ligation (SNL) has been widely applied as a rat model for neuropathic pain. 
OLP-1002 and OLP-1002R were found to be very potent, but highly variable in potency, in 
reversing neuropathic allodynia in this model. Analyses of the therapeutic potency strongly 
suggested that a marked proportion of subcutaneously (SC) administered OLP-1002 or OLP-
1002R may have been topically delivered directly to the spinal nerves exposed in the dorsal 
cavity created during the SNL modelling. In addition, the variability of the therapeutic 
potency may be due to a variable degree of healing of the SNL surgery wound. If an animal 


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recovers slowly, the animal tends to be left with a dorsal cavity. Therefore, estimations of 
potency in these studies with this model should be treated with caution. 
In one study using the SNL model, allodynia in rats was slowly and gradually reversed by 
OLP-1002 SC administered at nominal doses of 1, 3, and 6 pmol/kg once every 2 days (due 
to adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). As the onset time for pain reduction was 4 days, 
the doses used were not sufficient for fast onset of activity. In this study, the animals should 
have reasonably recovered from the dorsal wound, and therefore less susceptible to topical 
delivery directly to the exposed spinal nerves. However, in another study in this model, when 
OLP-1002 was intraperitoneally (IP) administered once every 3 days to avoid the likelihood 
of local delivery to the spinal nerves, OLP-1002 surprisingly reversed the allodynia at 
5 fmol/kg, and was superior or comparable to pregabalin 30 mg/kg, a gold standard for 
neuropathic pain studies. The high potency shown at 5 fmol/kg IP strongly suggests the 
possibility that OLP-1002 is efficiently absorbed by the enteric nervous system, travels to the 
spinal cord, and then redistributes to the spinal nerves of the SNL ligation. This opens the 
possibility of efficient oral delivery of OLP-1002 to the spinal cord. 
When evaluated for their ability to reverse the inflammatory pain in rats inflicted with 
Freund's Complete Adjuvant (FCA)-induced severe paw inflammation, OLP-1002 at 
300 pmol/kg and OLP-1002R at 100 pmol/kg significantly reversed the thermal hyperalgesia, 
and both were more effective than pregabalin 30 mg/kg. 
Paw burn injury induces hyperalgesia in rats and is known to upregulate Nav1.7 expression in 
the L5 and L6 DRGs of the affected side. Burn injury induces a far weaker degree of paw 
inflammation than FCA-induced paw inflammation. OLP-1002 SC administered inhibited the 
thermal hyperalgesia in paw burn injury in a dose-dependent manner. At 25 fmol/kg, OLP-
1002 did not inhibit thermal hyperalgesia. Although OLP-1002 at 625 fmol/kg significantly 
inhibited the thermal hyperalgesia, the efficacy was moderate and weaker than pregabalin 
30 mg/kg. This suggests that SC dosing does not offer the local topical delivery to spinal 
nerves in this model as seen in rats without a dorsal cavity wound. In this study, the Nav1.7 
expression in the DRG of the burn injury side significantly decreased by 58% with 
625 fmol/kg OLP-1002, validating the target engagement for analgesic activity. 
An intraplantar injection of formalin induces severe acute pain. The contributors to acute pain 
are known to be complex and require further elucidation. However, acute peripheral 
inflammation is known to contribute much to Phase II Pain (pain from 10 to 40 min after the 
formalin injection). In this model, OLP-1002 significantly inhibited Phase II Pain at 
comparable or saturated efficacy when SC administered at 10 to 100 pmol/kg (due to 
adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). Thus peripheral acute inflammatory pain could be 
treated with 10 pmol/kg or less. 
1.2.3. 
Ex Vivo Pharmacology Studies 
One day post-SC injection, OLP-1002 and OLP-1002R at 100 pmol/kg significantly inhibited 
the expression of Nav1.7 protein by 39% and 57%, respectively, in the spinal cord of rats 
subjected to SNL.  


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In other rats subjected to SNL, OLP-1002R slowly and gradually reversed the allodynia in a 
dose-dependent manner. OLP-1002R at 30 fmol/kg (the highest dose administered) had the 
greatest effect, but the dose was not high enough to elicit full therapeutic efficacy. OLP-
1002R inhibited expression of Nav1.7 protein in these animals, most notably at 1 fmol/kg, 
and decreased SCN9A mRNA expression by approximately 40% at 1 to 30 fmol/kg. The 
observed inhibitions were largely consistent with the in vivo therapeutic activity findings. 
Taking all the in vivo and ex vivo findings together, OLP-1002R was concluded to inhibit 
neuropathic allodynia by inhibiting the expression of the SCN9A mRNA and the Nav1.7 
protein. 
1.3. 
Summary of Safety Pharmacology 
In vitro, OLP-1002 did not inhibit the human ether-à-go-go-related gene (hERG) channel 
current expressed in human embryonic kidney (HEK) cells at the highest concentration tested 
2 μM (the limit of the validated analytical method for OLP-1002). 
In the in vivo safety pharmacology studies, OLP-1002 SC administered at dose levels up to 
100 nmol/kg had no effect on body temperature, neurological function, or respiratory 
function in rats, and had no significant toxic effect on cardiovascular function in cynomolgus 
monkeys. 
1.4. 
Summary of Toxicology 
In rats, following twice-weekly SC dosing for 13 weeks, OLP-1002-related microscopic 
findings included pigment accumulation in the kidney of males administered 
100 nmol/kg/dose and females administered ≥ 10 nmol/kg/dose, foreign material and 
vacuolated macrophage infiltrates in males and/or females administered ≥ 1 nmol/kg/dose, 
and an increased incidence and/or severity of mononuclear cell infiltrates at the injection sites 
in males and/or females administered ≥ 10 nmol/kg/dose. These findings persisted through 
the recovery phase in animals administered 100 nmol/kg/dose. However, the effects were 
considered non-adverse due to their mild severity and lack of impact on animal health and 
wellbeing. The no-observed-adverse-effect level (NOAEL) was 100 nmol/kg/dose. This dose 
level corresponded to maximum observed plasma concentration (Cmax) and area under the 
plasma concentration-time curve (AUC) from 0 to 24 hours postdose (AUC0-24) values of 
27.6 ng/mL and 174 ng·hr/mL, respectively, in males and 24.9 ng/mL and 128 ng·hr/mL, 
respectively, in females on Day 88 of the dosing phase. 
In cynomolgus monkeys, following twice-weekly SC dosing for 13 weeks, OLP-1002-related 
microscopic findings included mononuclear cell infiltrates at the SC injection sites of animals 
administered ≥ 10 nmol/kg/dose. This finding was not resolved with the completion of the 
recovery phase. However, the effects of 100 nmol/kg/dose were considered non-adverse due 
to the mild severity of findings and the lack of impact on animal health and wellbeing. The 
NOAEL was 100 nmol/kg/dose (equivalent to 462.29 µg/kg/dose), which corresponded to 
Cmax and AUC from 0 to 72 hours postdose (AUC0-72) values of 121 ng/mL and 
2840 ng·hr/mL in males, respectively, and 216 ng/mL and 4840 ng·hr/mL in females, 
respectively, on Day 88 of the dosing phase. 


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The genotoxic and mutagenic potential of OLP-1002 was evaluated with standard Good 
Laboratory Practice (GLP) via in vitro bacterial mutagenicity and chromosomal aberration 
studies, and was found to be negative. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
In rats, following a single SC dose of 14C-OLP-1002, the time of maximum observed 
concentration (Tmax) was 0.5 to 1 hour for both radioactivity and parent compound. Plasma 
concentrations of total radioactivity were quantifiable through the last sampling time of 72 
hours postdose, but was variable for the parent compound. The elimination half-life (t1/2) of 
total radioactivity from plasma was 23 hours. Total radioactivity distributed into tissues, 
including those of the CNS protected by the blood-brain barrier. 14C-OLP-1002-derived total 
radioactivity was not rapidly excreted from rats, with minimal amounts present in urine and 
feces. The bulk of the total radioactivity remained in carcasses, primarily in kidneys (cortex 
and medulla) and liver. Parent 14C-OLP-1002 was present in plasma and tissues, but 
concentrations declined over time and were substantially lower than total radioactivity 
concentrations at the later sampling times.  
After a single SC administration of 14C-OLP-1002 to rats, the highest concentrations of total 
radioactivity were retained predominantly in the liver (10.4% to 13.3% of the dose), kidney 
cortex (3.47% to 4.96%), and kidney medulla (1.10% to 1.59% of the dose) through 168 
hours postdose. For all other tissues, the total amounts of total radioactivity were 
substantially less, ranging from 0.0000203% in the 5th DRG to 0.327% in the spleen. 
Radioactivity was excreted slowly via both the renal and fecal routes of elimination. Total 
average recoveries of radioactivity in urine and feces through 336 hours postdose accounted 
for 2.31% and 1.75% of the administered radioactivity, respectively. The bulk of the 
administered total radioactivity was retained in the rat carcasses through 168, 336, 504, and 
840 hours postdose. The kidney cortex, kidney medulla, and liver were the 3 tissues that 
retained the greatest amounts of the administered radioactivity. 
Following a 16.1-µg/kg dose in rats, the plasma concentrations were still quantifiable at 
72 hours postdose and the rate of elimination was slow, with t1/2 17.5 hours. It was not 
possible to accurately define the elimination phase for the 2.67- and 5.28-µg/kg dose levels. 
In cynomolgus monkeys, following a single SC dose of 14C-OLP-1002, Tmax ranged from 
0.25 to 1 hour for both total radioactivity and parent compound. Concentrations of total 
radioactivity were sustained in blood and plasma through the last sampling time of 144 hours 
postdose. Concentrations of parent compound were sustained in plasma through the last 
sampling time of 144 hours postdose in 2 of 3 monkeys, and were similar to plasma total 
radioactivity concentrations at 8 hours postdose. From 24 to 144 hours postdose, plasma 
concentrations of total radioactivity were substantially higher than for parent 14C-OLP-1002 
plasma concentrations.  
The mean Cmax of parent 14C-OLP-1002 in plasma was 1.96 ng/mL. The mean plasma Tmax 
was 0.833 hours. Plasma exposure of parent 14C-OLP-1002 based on AUC extrapolated to 
infinity (AUC0-∞), was 12.7 ng·h/mL. After reaching Cmax, plasma concentrations of parent 
14C-OLP-1002 declined with a mean t1/2 of 84 hours. 


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1.6. 
Study Rationale 
This is the first time OLP-1002 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when OLP-1002 is administered SC as single 
and multiple doses to healthy subjects. This information, together with the pharmacodynamic 
(PD) and pharmacokinetic (PK) data, will help establish the doses and dosing regimen 
suitable for future studies in patients. The analgesic effects of OLP-1002 on a capsaicin-
induced pain model will also be investigated. 
1.7. 
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 investigational medicinal product 
(IMP), although there may also be some discomfort from collection of blood samples and 
other study procedures. For subjects in the PD assessment groups in Part A there will be 
some additional discomfort from the capsaicin test. More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with OLP-1002 may be 
found in the Investigator’s Brochure4. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is to assess the safety and tolerability of single and 
multiple SC doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the PD effect of OLP-1002 following 
single SC doses in healthy volunteers using a capsaicin pain model, and to monitor the effects 
of single SC doses of OLP-1002 on cardiac QT interval. Where possible, single and/or 
multiple subcutaneous dose pharmacokinetics of OLP-1002 in healthy subjects will be 
determined. 
2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of AEs 
• vital signs measurements (blood pressure, pulse rate, respiratory rate) 
• 12-lead electrocardiogram (ECG) parameters 
• incidence of clinical laboratory abnormalities, based on clinical chemistry, 
hematology, and urinalysis test results 
• physical examinations 
• injection site assessment. 


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• demonstrate that exposure to OLP-1002 does not exceed pre-defined exposure limits 
from non-clinical studies. 
2.2.2. 
Exploratory Endpoints 
The following exploratory objectives will be assessed:  
• pain intensity and duration will be assessed by AUC, maximum pain intensity (Emax), 
and time of maximum pain intensity (tEmax), calculated using a capsaicin-evoked pain 
model. The exploratory endpoint of secondary hyperalgesia will be assessed by the 
area of secondary area of hyperalgesia (Part A only). 
• continuous (24-hour) ECG monitoring will be recorded in this study and archived for 
potential future analysis of OLP-1002 effects on the QT interval (Part A). 
• heat pain threshold measurements and heat pain tolerance measurements. 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from time zero to 
infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable concentration 
(AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-1002 are as 
follows: 
Primary PK: 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 


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Other PK parameters may also be added if deemed necessary. 
3. INVESTIGATIONAL PLAN 
This will be a double-blind, randomized, placebo-controlled, single and multiple SC dose 
study conducted in 2 parts. 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy subjects will 
be studied in 8 groups. Up to 3 additional groups (24 subjects in total) may be included for 
further assessment of safety, tolerability, PK, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Potential subjects for Groups A2, A4, and A6 will 
attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will return 
for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 2 days), and for a 
poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential visits 
may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 10 (216 hours postdose) from the lower dose levels. For doses 
≥ 12 µg, PK data will also be reviewed up to Day 7 prior to dose escalation. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 3 subjects will receive 
OLP-1002 and 1 subject will receive placebo. To assess PD parameters, Groups A2, A4, and 
A6 will consist of 8 subjects; 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo.  
Sentinel dosing will be employed for all groups in Part A. To maintain the blind in a 
4-subject group, the first subject will be dosed 48 hours before the second subject, and the 
second subject will be dosed 48 hours prior to the third and fourth subjects. In PD assessment 
groups, 2 subjects (1 active: 1 placebo) will be dosed 48 hours before the remaining 6 
subjects (5 active: 1 placebo). 
An overview of the study design is shown in Figure 1.


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Figure 1: 
Study Schematic (Part A) 
Group A1 
(30 ng SC)
3 active:
1 placebo
Group A2
(120 ng SC)
6 active:
2 placebo
Group A3
(400 ng SC)
3 active:
1 placebo
Group A4
(1.2 µg SC)
6 active:
2 placebo
Group A5
(3 µg SC)
3 active:
1 placebo
Group A6
(6 µg SC)
6 active:
2 placebo
Group A7
(12 µg SC)
3 active:
1 placebo
Group A8
(20 µg SC)
3 active:
1 placebo
Group A9
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A10
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A11
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
Groups A9 to A11 may be included if required; dose levels will not exceed the maximum proposed dose of 20 µg. 
Three groups consist of 8 subjects (6 active: 2 placebo); all other groups will consist of 4 subjects (3 active: 1 placebo).


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The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 8 weeks. 
3.1.2. 
Part B 
Part B will comprise a multiple-dose, sequential-group study. Overall, 24 subjects will be 
studied in 3 groups (Groups B1 to B3), with each group consisting of 8 subjects. Up to 
3 additional groups (24 subjects in total) may be included for further assessment of safety and 
tolerability (Section 3.3).  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (± 2 days), 22 (± 2 days), 25 
(± 2 days), and 29 (± 2 days), and for a poststudy visit on Day 57 (± 2 days). 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo. For all subjects, a single subcutaneous dose will be administered on Days 1, 4, 7, 10, 
and 13. Prior to each dosing occasion a physician will review the available safety and 
tolerability data from each subject to confirm it is acceptable to continue dosing. The dosing 
frequency in Part B may be changed following review of data from groups in Part A 
(Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to OLP-1002 at 
steady state is predicted to exceed exposures that have been shown to be safe and well 
tolerated in earlier groups in Parts A or B. In the event of sentinel dosing, 2 subjects (1 active, 
1 placebo) will be dosed at least 4 days prior to the remaining 6 subjects (5 active: 1 placebo). 
Safety data for the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 1 and 2 will be 
reviewed prior to the remaining subjects receiving dose 1). In addition, safety data from each 
subject will be reviewed by a physician prior to each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of safety, 
tolerability, and PK data up to Day 22 (216 hours post-final dose) from the lower dose levels. 
Part B may start after a review of the safety, tolerability, and available PK for Groups A1 to 
A6. The total daily dose administered will not exceed the highest single dose given in Part A. 
An overview of the study design is shown in Figure 2. 


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Figure 2: 
Study Schematic (Part B) 
Group B1
(TBC SC)
6 active:
2 placebo
Group B2 
(TBC SC)
6 active:
2 placebo
Group B3
(TBC SC)
6 active:
2 placebo
Group B4
(TBC SC)
6 active:
2 placebo
Group B5 
(TBC SC)
6 active:
2 placebo
Group B6
(TBC SC)
6 active:
2 placebo
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
All doses will be confirmed based on results of Part A; dose levels will not exceed the maximum proposed dose 
of 20 µg..  
Groups B4 to B6 will be included if required. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 12 weeks. 
A Schedule of Assessments is presented in Appendix 6. 
3.2. 
 Start of Study and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, PK, and PD data (where systemic exposure is not 
expected to exceed that stated in the dose escalation stopping criteria [Section 3.7]), 
additional dose groups may be added to the study. The maximum dose for any additional 
group will not exceed 20 µg. Up to 3 further groups of 8 subjects (6 active: 2 placebo) may 
be included in Part A, and up to 3 additional groups of 8 subjects (6 active: 2 placebo) may be 
included in Part B. The requirement for additional groups will be agreed with the Sponsor 
and documented in the Trial Master File (TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For both parts of the study, a sequential-group, ascending-dose design has been chosen for 
safety reasons as OLP-1002 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Subcutaneous doses have been 
chosen for both parts of the study, as this is the intended clinical route of administration. 
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, and PK data up 
to Day 7 will be reviewed for all groups receiving ≥ 12 µg OLP-1002. In Part B, safety, 
tolerability and PK data up to Day 22 will be reviewed for all dose groups. As the t1/2 of 


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OLP-1002 is predicted to be approximately 180 hours (based on non-clinical data) review of 
safety data up to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma exposures are 
anticipated to be low, it is expected that it will only be possible to perform an assessment of 
peak concentrations (Cmax) and therefore PK data to Day 7 (Part A) and Day 22 (Part B) will 
be sufficient. Additionally, a cumulative safety review will occur such that additional 
emerging safety data from earlier groups will be considered when making a dose escalation 
decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of females 
of childbearing potential is in accordance with International Council for Harmonisation (ICH) 
M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be sufficient in 
order to determine safety and tolerability. In order to assess the PD effects of OLP-1002, 
3 groups in Part A will include 8 subjects (6 active; 2 placebo). A full review of the safety 
and tolerability data from Part A will be performed to determine the dose regimen for Part B. 
Part B may start after a full review of all safety and tolerability data from Group A1 to A6. A 
review of PD data may also be performed, at the discretion of the Investigator. Details of the 
dosing regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 57-day 
follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups receiving 
≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring 
in the event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. Dose escalation decisions for doses <12 µg in Part A will not require PK data. 
The rationale for this is that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical species has a 
lower limit of quantification (LLOQ) of 5 ng/mL. The increased sample volume possible 
from humans (compared to small animals) may afford an approximate 10-fold increase in 
sensitivity with possibly an additional 5-fold increase from the use of a more sensitive mass 
spectrometer. This could potentially deliver an LLOQ of around 0.1 ng/mL. Therefore, even 
with the increased assay sensitivity plasma levels from doses at or below 12 µg are not 
expected to be quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose would be 
quantifiable and that a conventional approach to pharmacokinetic will not achieve a full 
definition of the plasma concentration vs time profile or enable an estimation of the terminal 
phase. In addition the planned dose levels have a high safety margin when comparing the 
predicted exposures to the exposures at the NOAEL (see Section 3.5.2), with the 12 µg dose 
level having an expected 312-fold and 255-fold safety margin based on Cmax and AUC0-∞, 
respectively. Therefore if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  


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This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
Continuous ECG monitoring will be recorded in this study and archived for potential future 
analysis of OLP-1002 effects on the QT interval, with a view of supporting a potential 
thorough QT study waiver. 
3.4.1. 
Dose Interval 
Following thorough review of all available nonclinical data (pharmacological and 
toxicological), dosing in Part A for groups consisting of 4 subjects will be such that there will 
be 48 hours between the first and second subjects, and 48 hours between the second and 
remaining 2 subjects in each group. For groups in Part A consisting of 8 subjects, 2 subjects 
(1 active: 1 placebo) will be dosed 48 hours prior to the remaining 6 subjects.  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 at steady state 
is predicted to exceed exposures that have been shown to be safe and well tolerated in earlier 
groups in Parts A or B. When used, two subjects (1 active; 1 placebo), will be dosed 4 days 
prior to the remaining 6 subjects (5 active; 2 placebo). The 2 sentinel subjects will always be 
2 doses ahead of the remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not predicted to 
exceed that tested in Part A will be dosed on the same day. Accumulation of OLP-1002 is 
expected following multiple doses, based on the preclinical data, and will be taken into 
account when determining the doses for Part B (see Section 3.5.3). If it is not possible to 
quantify exposure it will be assumed that multiple dosing results in a 4-fold accumulation 
based on the predicted t1/2 of 180h.  
In Parts A and B, there will be a minimum interval of a 10-minute gap between dosing 
subjects (when dosed on the same day). Continuation to dose the remaining subjects in a 
group will be at the Investigator’s discretion. 
3.4.2. 
Pharmacodynamic Assessment 
Pharmacodynamic assessments will be conducted for subjects in Groups A2, A4, and A6. 
Human experimental pain models using healthy volunteers can be used to assess the effect of 
a drug or treatment under controlled clinical conditions. Capsaicin is a vanilloid responsible 
for the pungent taste of hot peppers. In mammalian species, capsaicin-induced pain is 
mediated through Group C nerve fibers following activation of vanilloid 1 transient receptor 
potential (TRPV1) channels5. Nav1.7 has been implicated in controlling neuropeptide release 
from C-fibers, and suppression of capsaicin-induced neurogenic flair has been demonstrated 
by an NAv1.7 inhibitor6. 


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Several studies have used intradermal capsaicin for human experimental pain studies7,8. It has 
been possible to demonstrate dose-dependent responses, with intradermal injections of 
100 μg generally agreed to be the ideal dosage for these studies. Intradermal injection of 
capsaicin causes a brief stinging/burning pain at the injection site (spontaneous pain) 
followed by development of secondary hyperalgesia, which can be assessed using equipment 
such as Von Frey hairs. A study by Gazerani et al.5 found that the response was site-specific 
and while peak pain intensity and duration were greatest in the forehead it was found that 
areas of visible flare and secondary hyperalgesia were significantly larger in the forearm, 
making the forearm the most suitable site for experimentation. 
Covance CRU, Leeds, UK in 2009 performed a validation study using intradermal capsaicin 
(Covance CRU Study: 9999-004) with between-subject and within-subject variability 
demonstrating that the assessments can be reliably conducted to assess pharmacological 
response. 
For these reasons, it has been decided to: 
• Measure both capsaicin-evoked pain and secondary hyperalgesia. 
• Limit the number of capsaicin tests to 3 for each subject (pre-screening, baseline, and 
48 hours postdose) 
• Exclude subjects who have pain <3 or >9 (using a Visual Analogic Scale [VAS]) at 
the pre-screening visit from PD assessment groups. 
3.5. 
Selection of Doses in the Study 
3.5.1. 
Starting Dose 
The rat has been identified as the most sensitive species in a 13-week SC toxicity study with 
a 4-week recovery phase (Covance study no. 8355564). The NOAEL was the 
100 nmol/kg/dose (462.29 µg/kg/dose). This dose level resulted in Cmax of 27.6 ng/mL and 
24.9 ng/mL in males and females, respectively, and AUC0-24 of 174 ng.h/mL and 
128 ng.h/mL in males and females, respectively4. As the exposure was lower in the female 
rats these data have been used to calculate the safety margins. 
The dose of 462.29 µg/kg/dose corresponds to human equivalent doses (HEDs) of 
74.8 µg/kg/dose, which gives a maximum recommended starting dose (MRSD) of 444 µg for 
a 60-kg human and thus a 15000-fold safety margin to the proposed starting dose of 30 ng 
and 22-fold margin to the proposed maximum dose of 20 µg. Additionally the NOAEL dose 
in the cynomolgus monkey was identified as 100 nmol/kg/dose (462.29 µg/kg/dose), which 
gives a higher HED of 150 µg/kg/dose. 
In vivo, doses of 10 pmol/kg/dose (0.0462µg/kg/dose) or less were found to inhibit peripheral 
acute inflammatory pain. The equivalent human dose for a 60-kg human is 44 ng, thus a dose 
at which minimal biological effect is anticipated has been selected as the starting dose of 
30 ng. 


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3.5.2. 
Exposure 
Human exposures have been estimated from the pharmacokinetics in the cynomolgus 
monkey since a non-human primate represents the most closely related species. 
Approximately dose-proportional exposure was seen in the 13-week toxicity study (Covance 
study no. 8355565) and 14C pharmacokinetic study (Covance study no. 8355568) over a dose 
range of approximately 1.1 to 100 nmol/kg (5.06 to 462.29 µg/kg)4. However, the lowest 
dose (5.06 µg/kg) from the 14C study has been used to estimate the human exposures as it is 
closest to the proposed human dose range and has the sufficient quantifiable data. 
The assumptions made in the human exposure estimation were that human exposure would 
be similar to the cynomolgus monkey and that exposure would be linear with dose. Following 
a dose of 5.06 µg/kg in the cynomolgus monkey, the Cmax was 1.96 ng/mL and AUC0-∞ was 
12.7 ng.h/mL. The extrapolated exposures at the planned human doses are shown in Table 1 
with margins calculated to the exposures at the NOAEL in the female rat. 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 
Human dose 
Single dose to human 
Safety margins for single dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax 
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin  
to Cmax 
Margin  
to AUC0-∞ 
0.03 
0.000500 
0.000194 
0.00125 
129000 
102000 
0.12 
0.00200 
0.000775 
0.00502 
32100 
25500 
0.4 
0.00667 
0.00258 
0.0167 
9640 
7650 
1.2 
0.0200 
0.0077 
0.0502 
3210 
2550 
3 
0.0500 
0.0194 
0.125 
1290 
1020 
6 
0.100 
0.0387 
0.251 
643 
510 
12 
0.200 
0.0775 
0.502 
321 
255 
20 
0.333 
0.129 
0.837 
193 
153 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
The dosing interval currently anticipated for the multiple-ascending-dose part of this study is 
72 hours or 96 hours. Thus the average dosing interval (82 hours) is similar to the half-life 
determined in the monkey 14C study of 84 hours. Dosing at approximately once per half-life 
would be anticipated to result in accumulation of around 2-fold. However, higher levels of 
accumulation were observed (2.28-fold for Cmax and 3.76-fold for AUC0-24) on Day 88 at the 
top dose group (100 nmol/kg, 462.28 µg/kg) in the 13-week cynomologus monkey toxicity 
study following twice-weekly dosing (every 72 or 96 hours). Calculations were performed to 
estimate the likely human half-life using a standard 1-point allometric approach from the 14C 
cynomolgus monkey pharmacokinetic study data. The exponents used were 0.75 for apparent 
total plasma clearance (CL/F) and 1 for apparent volume of distribution (Vz/F) values 
combined with the average body weight of the animal (3.1 kg) and scaling to a 60 kg human 
9–11. This resulted in a human half-life estimate of 180 h which in turn gave an accumulation 
estimate of 3.7-fold based upon a dosing interval of 82 h. This further supports the use of the 
greater than 2-fold accumulation from the 13-week cynomolgus study to estimate exposure 
following multiple dosing. Multiplication of the exposure estimates for the single ascending 


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dose by 2.28 for Cmax and 3.76 for AUC resulted in exposure estimates for multiple dosing 
presented in Table 2. 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 
Human dose 
Multiple dose to human 
Safety margins for multiple dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax  
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin 
to Cmax 
Margin 
to AUC0-τ,ss 
0.03 
0.000500 
0.000442 
0.00472 
56000 
27000 
0.12 
0.00200 
0.00177 
0.0189 
14100 
6800 
0.4 
0.00667 
0.00589 
0.0629 
4230 
2030 
1.2 
0.0200 
0.017663 
0.189 
1410 
680 
3 
0.0500 
0.0442 
0.472 
560 
270 
6 
0.100 
0.0883 
0.944 
282 
136 
12 
0.200 
0.177 
1.89 
141 
68 
20 
0.333 
0.294 
3.15 
85 
41 
30 
0.500 
0.442 
4.72 
56 
27 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
3.5.3. 
Proposed Doses 
The proposed IMP dose levels for Parts A and B are shown in Table 3. 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
Study Part 
Group 
Dose (OLP-1002) 
Part A 
A1 
30 ng or placebo 
 
A2 
120 ng or placebo 
 
A3 
400 ng or placebo 
 
A4 
1.2 µg or placebo 
 
A5 
3 µg or placebo 
 
A6 
6 µg or placebo 
 
A7 
12 µg or placebo 
 
A8 
20 µg or placebo 
 
A9* 
TBC or placebo 
 
A10* 
TBC or placebo 
 
A11* 
TBC or placebo 
 
 
 
Part B 
B1 
TBC or placebo 
 
B2 
TBC or placebo 
 
B3 
TBC or placebo 
 
B4* 
TBC or placebo 
 
B5* 
TBC or placebo 
 
B6* 
TBC or placebo 
Abbreviations: TBC = to be confirmed 
* groups to be included if required. 


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In Parts A and B, there should not be an increase of > 3-fold between dose levels above 
120 ng. 
For Part B, dose levels, dosing frequency, and dosing duration will be decided, in 
consultation with the Sponsor, on the basis of data from Part A of the study. Since predictions 
of human exposure of OLP-1002 suggest that OLP-1002 concentrations may be not be 
quantifiable and human data have been estimated from a single species, it is proposed that the 
highest dose in the multiple-ascending-dose part will be up to 50% of the highest dose in the 
single-ascending-dose part (ie, if the highest dose in the single-ascending-dose part is 20 µg, 
the highest dose in the multiple-ascending-dose part will be 10 µg). Therefore, if the 
predicted accumulation of 3.7-fold occurs, the highest exposure in the multiple-ascending-
dose part will not exceed ~2-fold the maximum exposure in the single-ascending-dose part. 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose administered will 
not exceed 20 µg and predicted systemic exposure will not exceed that stated in the dose 
escalation stopping criteria [Section 3.7]) based on available PK data. 
Details of all doses administered in Parts A and B of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
In Part A, doses will be administered in an escalating manner following satisfactory review 
by the Sponsor and Investigator of the safety, and tolerability data up to Day 7 (144 hours 
postdose) from groups that received lower doses of OLP-1002. For escalation to doses 
> 12 µg, PK data up to Day 7 (144 hours postdose) will also be reviewed. All available 
safety, tolerability, and PK data from previous groups will be reviewed prior to dose 
escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and may be lower than the starting 
dose. Available safety, tolerability, and PK data from all previous groups will be reviewed 
prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups A1, 
A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have been reviewed from the 
previous lower dose group, such that data from a minimum of 3 or 4 subjects, respectively, 
who have received OLP-1002 will be used to make the dose-escalation decision. Dose 
escalation in Part B will only occur if data from a minimum of 6 subjects have been reviewed 
from the previous lower dose group, such that data from a minimum of 4 subjects who have 
received OLP-1002 will be used to make the dose-escalation decision. 
The justification for this is as follows: 
•
The study drug is of a known pharmacological class for which the on-target effects in
humans are well characterized. Based upon nonclinical data, no clinically important
off-target effects are expected within the proposed dose range.


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• A minimum of 3 subjects receiving the active drug is considered sufficient to 
characterize the safety profile for OLP-1002. 
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarizing 
results from all available safety assessments, will be sent to the Sponsor and a dose-escalation 
meeting will occur prior to the start of each successive group. Any clinically significant 
results will be discussed with the Sponsor before dose escalation continues. Interim PD data 
may also be reviewed on an ongoing basis. In the event of a disagreement between Sponsor 
and Investigator on the dose-escalation decision, the decision of the Investigator will be 
upheld. 
3.7. 
Dose Escalation Stopping Criteria 
In Parts A and B, following consultation with the Sponsor, dose escalation will be stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in 
a group that, in the opinion of the Investigator, warrant stopping of dose escalation. 
• One or more subjects experience an SAE that is considered to be related to OLP-1002. 
• Two or more subjects in the same group experience severe non-serious AEs (ie. 
severe non-serious AEs considered as, at least, possibly related to OLP-1002 
administration), independent of whether the AEs are within or not within the same 
system organ class.  
• There is evidence of clinically significant increases in aspartate aminotransferase, 
alanine aminotransferase or alkaline phosphatase (defined as 3 times the upper limit 
of normal), or total bilirubin (defined as 2 times the upper limit of normal) that are 
considered to be related to OLP-1002 in 2 or more subjects in a group. Results will be 
confirmed with repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose for 
Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat measurement) 
in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 110 mmHg) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 1 occasion within a 24-hour interval in ≥1 subject in a 
group. 
• The dose will not exceed 20 µg or the systemic exposure for any individual subject is 
predicted to exceed a Cmax of 24.9 ng/mL (plasma) and/or an AUC0-24 of 128 ng/mL; 
i.e., systemic exposure will be no greater than the NOAEL in the most sensitive 
species (100,000 pmol/kg in rat [462 µg/kg]). 


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If the sponsor deems it appropriate to resume dosing after the internal safety review, it 
can be done after the approval of a substantial protocol amendment. 
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. Healthy male or females of any race, between 18 and 60 years of age, inclusive. 
2. Body mass index (BMI) between 18.0 and 28.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, single 12-lead ECG (resting heart rate > 45 bpm and 
< 90 bpm), vital signs measurements, and clinical laboratory evaluations (congenital 
nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome based on total 
and direct bilirubin] is not acceptable) at Screening as assessed by the Investigator (or 
designee).  
4. Willing to abide by the contraception requirements 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: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. Any of the following: 
• QTcF > 450 ms confirmed by repeat measurement. 
• QRS duration > 110 ms confirmed by repeat measurement. 
• PR interval > 220 ms confirmed by repeat measurement. 
• findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
• history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalemia, family history of long QT syndrome). 
4. Female subjects who are pregnant or breastfeeding. 
5. History of alcoholism or drug/chemical abuse within 1 year prior to Screening. 


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6. Alcohol consumption of > 21 units per week for males and >14 units per week for 
females. 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. 
7. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
8. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
9. Active skin conditions such as dermatitis, allergy, eczema, psoriasis, or abnormal 
healing. 
10. Tattoos, scars, or moles that in the opinion of the Investigator are likely to interfere 
with dosing or study assessments at any of the potential injection sites. 
11. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days or 5 half-lives of the investigational product, 
whichever is longer, prior to Check-in. 
12. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 
13. Use or intend to use any prescription medications/products other than hormone-
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 
contraceptive concomitant medications within 14 days prior to Check-in, unless 
deemed acceptable by the Investigator (or designee). 
14. 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). 
15. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee) and/or 
Sponsor have given their prior consent. 
16. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.  
17. Receipt of blood products within 60 days prior to Check-in. 
18. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening.  
19. Poor peripheral venous access. 
20. Have previously completed or withdrawn from this study or any other study 
investigating OLP-1002, and have previously received the investigational product. 
21. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
22. Part A – PD assessment groups only 
• Subjects considered non-acceptable responders to the intradermal capsaicin 
test at screening, defined as maximum VAS score of < 3.0 or > 9.0. 


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4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomization. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, in Part A, Subjects 101, 102, 
etc., in Part B Subjects 201, 202, etc.). Replacement subjects (Section 4.4) will be assigned a 
subject number corresponding to the number of the subject he/she is replacing plus 1000 
(eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least possibly related to 
OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE considered to 
at least possibly related to OLP-1002 administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements). 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the 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 stabilized. 


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Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• 
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) 
• 
medical or ethical reasons affecting the continued performance of the study 
• 
difficulties in the recruitment of subjects 
• 
cancelation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Vials of OLP-1002 Injection Solution 100 µg/mL (1.5 mL in 5-mL vials) and the Diluent for 
OLP-1002 Injection Solution (5 mL in 10-mL vials) will be supplied by the Sponsor, along 
with the batch/lot number and Certificate of Analysis. The Diluent for OLP-1002 Injection 
Solution will also be used as the Placebo formulation. A certificate of batch certification and 
release, authorized by a Qualified Person in the European Union (EU) will also be issued, by 
a Covance CRU Qualified Person, for each batch of IMP imported into the EU. 
The IMPs will be stored according to the instructions on the label at the CRU in a location 
that is locked with restricted access. 
Dose solutions (OLP-1002 Injection Solution diluted with the Diluent for OLP-1002 
Injection Solution) will be prepared by Covance CRU Pharmacy staff in accordance with 
instructions provided in the Pharmacy Manual. The Placebo formulation will be the Diluent 
for OLP-1002 Injection Solution without further manipulation. 
5.2. 
Study Treatment Administration 
Subjects will be administered the IMP in numerical order. OLP-1002 will be administered by 
SC injection in the upper arm. If subcutaneous dosing of OLP-1002 in the upper arm is not 
possible, the subject may be dosed in the abdomen at the Investigator’s discretion. For 
subjects in Groups A2, A4, and A6, dosing will be on the opposite arm to the intradermal 
capsaicin test. 
5.3. 
Randomization 
The randomization code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. In Part A, 1 subject in groups 


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consisting of 4 subjects, and 2 subjects in groups consisting of 8 subjects, will be randomly 
assigned to receive placebo. In Part B, 2 subjects per group will be randomly assigned to 
receive placebo. All other subjects in a group will be randomized to receive OLP-1002. 
Prior to the start of the study, a copy of the master randomization code will be supplied into 
the Covance CRU pharmacy staff (in sealed envelopes). 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo solution will be identical in appearance to the OLP-1002. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 
To maintain the blind, the Investigator will be provided with sealed randomization 
code-break envelopes for each subject, containing details of their treatment. These individual 
sealed envelopes will be kept in a limited access area that is accessible 24 hours a day. In 
order to manage subject safety or to support dose-escalation decisions (in the event of 
possibly treatment-related SAEs or severe AEs), the decision to unblind resides solely with 
the Investigator. Whenever possible, and providing it does not interfere with or delay any 
decision in the best interest of the subject, the Investigator will discuss the intended code-
break with the Sponsor. If it becomes necessary to break the code during the study, the date, 
time, and reason will be recorded in the subject’s source data and on the individual envelope 
and will be witnessed by a second person. 
5.5. 
Treatment Compliance 
All doses of IMP will be administered by suitably qualified study site staff. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 


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6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription medications/products from 14 days prior to 
dosing until the Follow-up visit, and non-prescription medications/products from 7 days prior 
to dosing until the Follow-up visit, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone-replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary 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 standardized 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 safety laboratory tests. On dosing days, 
subjects will receive a light breakfast approximately 2 hours prior to dosing. Meals will be 
provided as appropriate at other times and water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Check-in until the Follow-up visit. 
Xanthine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until Discharge from the site. Xanthine-containing foods and beverages will also not be 
allowed form 36 hours before non-residential site visits. 
Chili pepper/hot sauce will not be allowed for 48 hours prior to Check-in for all subjects. 
Subjects in Groups A2, A4, and A6 will not be allowed chili pepper/hot sauce for 48 hours 
prior to their pre-screening visit. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until 
Discharge. Following discharge, up to 2 units/day of alcohol are permitted until 36 hours 
before each non-residential visit and 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 3 days before Check-in until the 
Follow-up visit and will otherwise maintain their normal level of physical activity during this 


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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. Subjects should not be in receipt of blood products for 
60 days prior to check-in. 
6.6. 
Other Restrictions 
Subjects in Groups A2, A4, and A6 will not be allowed to shower within 1 hour prior to the 
capsaicin-evoked pain tests at prescreening, predose, and postdose. 
Subjects will not be allowed to apply moisturizing creams or oils to the dosing site within 
1 hour prior to dosing, or to the assessment site within 1 hour prior to the capsaicin-evoked 
pain test.  
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): 
•
dosing
•
vital signs
•
blood samples
•
cardiac monitoring/ECG extractions
•
any other procedures.
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times indicated in the 
Schedule of Assessments (Appendix 6). Furthermore, additional blood samples may be taken 
from each subject per treatment period, with the maximum volume of blood withdrawn per 
subject not exceeding the limit detailed in Appendix 3. Any changes to the scheduled times of 
PK assessments will be agreed with the Sponsor and documented in the TMF. Samples taken 
from subjects who received placebo will not be analyzed. 
In Part A, PK analysis will initially only be conducted for groups receiving ≥ 12 µg 
OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the 


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event of PK data being quantifiable at doses ≥ 12 µg and if supported by bioanalytical 
stability data. In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 
7.2. 
Pharmacodynamic Assessments 
Capsaicin intradermal test will be performed for subjects in Groups A2, A4, and A6. Each 
subject will be tested at a pre-screening visit before being tested twice during the study (1 
predose and 1 postdose). 
7.2.1. 
Capsaicin-evoked Pain Model 
The capsaicin model will be conducted by intradermal injection of capsaicin (100 μg in 
100 μL of sterile saline containing 8% [w/w] Tween 80) into the skin of the anterior aspect of 
the forearm, midway between the elbow and the wrist. The bleb area (wheal) will be a sign of 
local plasma extravasation. An assessment of the pain intensity related to capsaicin injection 
will be estimated by repeated use of a VAS from injection to 5 minutes post-injection or until 
the pain intensity returned to zero. The AUC, Emax, and tEmax will be calculated and reported 
using dedicated software. 
7.2.2. 
Secondary Hyperalgesia 
The area of secondary hyperalgesia will be quantified with a 60-g weighted von Frey hair, by 
stimulating along 8 linear paths (4 vectors crossing at the location of the injection site) 
arranged vertically and horizontally around the stimulation site in 5-mm steps (starting 
approximately 6 cm away from the injection site). The area of secondary hyperalgesia will be 
evaluated at 5 and 30 minutes post-capsaicin injection. 
7.3. 
Safety and Tolerability Assessments 
Safety and tolerability assessments will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). Timepoints may be adjusted based on an ongoing review of the 
data, and additional assessments may be conducted if deemed necessary by the Investigator 
or designee. 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs 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 


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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. 
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 drug. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a follicle-stimulating hormone (FSH) test and 
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. 
7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and 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. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. 
Subjects must be supine for at least 5 minutes before blood pressure, pulse rate, and 
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7.3.4. 
Electrocardiogram 
7.3.4.1. 
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: 
• QTcF value > 500 msec 
• QTcF change from the mean baseline (Day 1 predose) is > 60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.3.4.2. 
Continuous (24-hour) Electrocardiogram 
At the times indicated in the Schedule of Assessments (Appendix 6), continuous (24-hour) 
ECGs will be performed.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint. Each extraction will last for 5 minutes. 
Environmental distractions (eg, television, playing games, radio, conversation) should be 
avoided during the pre-ECG time window.  
Continuous 24-hour ECGs are not planned for Part B of the study but may be implemented if 
any clinically significant findings are identified in the data from Part A. 
7.3.5. 
Heat Pain Threshold Test 
Heat pain threshold tests will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). 
A computer-controlled thermal sensory analyzer device will be used to measure the heat pain 
threshold and tolerance level of the subjects. The heat pain assessments will be conducted on 
the subject’s thigh. 
Heat Pain Threshold: 
For heat pain threshold measurements, the thermode will be placed directly on the skin of the 
right thigh, within an area selected before the start of the experiment and defined by surgical 
marking. The thermode will have a baseline temperature of 32 °C, and will be programmed to 
gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 


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their dominant hand, to indicate when the heat pain threshold (first sensation of heat pain) is 
reached by pushing a button. At that time, the test will be stopped and the temperature 
returned to baseline within 1 second. This process will be repeated a further 2 times, with an 
interval of at least 1 minute between measurements (from start to start). The computer will 
record the average value of 3 experiments. 
Heat Pain Tolerance: 
For heat pain tolerance measurements, the thermode will be placed within the same surgically 
marked skin area of the anterior side of the right thigh, which was used to assess heat pain 
threshold. The thermode will have a baseline temperature of 32 °C, and will be programmed 
to gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 
their dominant hand, to indicate when the heat-evoked pain has reached an intensity that is no 
longer tolerable, by pushing a button. At that time, the test will be stopped and the 
temperature returned to baseline within 1 second. This process will be repeated a further 
2 times, with an interval of at least 1 minute between measurements (from start to start). The 
computer will record the average value of 3 experiments. 
Safety Precautions 
As there is a risk that OLP-1002 may affect the heat pain threshold, Covance CRU will put 
appropriate safety measures in place to ensure that subjects are not exposed to extremes of 
temperature when taking a shower or consuming hot drinks. During the heat pain safety 
assessments, the cut-off temperature for either test is 53 °C in order to prevent skin injury. 
7.3.6. 
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.  
7.3.7. 
Body Weight and Height 
Body weight (in underclothes) and height will be recorded at the times indicated in the 
Schedule of Assessments in Appendix 6. BMI will be calculated using the following formula: 
BMI = body weight (kg)      (kg/m2) 
                  (height [m])2 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time OLP-1002 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. In order to achieve PD endpoints 
in Part A, additional subjects will be included in 3 groups (8 subjects in total; 6 active: 
2 placebo). Up to 3 additional groups may be added to Part A, consisting of either 4 subjects 


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(3 active; 1 placebo) or 8 subjects (6 active; 2 placebo). Up to 3 additional groups of 
8 subjects may be added to Part B (6 active; 2 placebo). 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of OLP-1002 that 
have evaluable PK data and have had no AEs or protocol deviations considered to impact PK. 
8.2.2. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo and for whom PD can be evaluated. 
8.2.3. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of OLP-1002 or 
placebo. 
8.3. 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma concentration data, 
using commercial software such as Phoenix® WinNonlin®. Plasma concentrations of OLP-
1002 and PK parameters will be listed and summarized using descriptive statistics. Individual 
and arithmetic mean OLP-1002 concentration-time profiles will also be presented 
graphically. 
8.4. 
Pharmacodynamic Analyses 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No 
formal statistical analysis of PD data is planned. 
8.5. 
Safety Analysis 
Safety parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 
9. REFERENCES 
1.  Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A 
channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 
14;444(7121):894–8.  
2.  Goldberg YP, Price N, Namdari R, Cohen CJ, Lamers MH, Winters C, et al. Treatment of 
Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel 
blocker. Pain. 2012 Jan;153(1):80–5.  


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3.  Jones HM, Butt RP, Webster RW, Gurrell I, Dzygiel P, Flanagan N, et al. Clinical Micro-
Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of 
Human Nav1.7 Voltage-Dependent Sodium Channels. Clin Pharmacokinet. 
2016;55(7):875–87.  
4.  Investigator Brochure - OLP-1002. 2018.  
5.  Gazerani P, Andersen OK, Arendt-Nielsen L. Site-specific, dose-dependent, and sex-
related responses to the experimental pain model induced by intradermal injection of 
capsaicin to the foreheads and forearms of healthy humans. J Orofac Pain. 
2007;21(4):289–302.  
6.  Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, et al. 
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in 
Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE 
[Internet]. 2016 Apr 6 [cited 2018 Jun 15];11(4). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822888/ 
7.  Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-
dependent pain, allodynia, and hyperalgesia in humans. J Investig Med Off Publ Am Fed 
Clin Res. 2006 Jul;54(5):238–44.  
8.  Anderson WS, Sheth RN, Bencherif B, Frost JJ, Campbell JN. Naloxone increases pain 
induced by topical capsaicin in healthy human volunteers. Pain. 2002 Sep;99(1–2):207–
16.  
9.  Pharmacokinetics and Metabolism in Drug Design, 3rd Edition [Internet]. Wiley.com. 
[cited 2018 Aug 21]. Available from: https://www.wiley.com/en-
us/Pharmacokinetics+and+Metabolism+in+Drug+Design%2C+3rd+Edition-p-
9783527329540 
10.  Mahmood I. Pharmacokinetic allometric scaling of antibodies: application to the first-in-
human dose estimation. J Pharm Sci. 2009 Oct;98(10):3850–61.  
11.  Offman E, Edginton AN. Pharmacokinetic Time Course Scaling of a Subcutaneously 
Administered Pegylated Peptide Conjugate for a First-in-Human Investigation. Eur J 
Drug Metab Pharmacokinet. 2017 Feb;42(1):69–78.  
 
 


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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 unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but posing no 
significant or permanent risk of harm to the subject. 
• 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 drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
• 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. 
• 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. 
• Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized 
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 
stabilized. 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: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize 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 Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization 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 
Covance Drug Safety Services (DSS) Europe, Maidenhead, UK are 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 facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the Safety 
Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of the 
SAE within 2 working days of the initial notification to DSS. Drug Safety Services 
will delete any information from the SAE report forms that may identify the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined in 
the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions 
and forward to the Ethics Committee, Medicines and Healthcare Products Regulatory 
Agency, Principal 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. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfill regulatory requirements any pregnancy reported by female subjects or 


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the female partners of male subjects should be reported following the SAE process to collect 
data on the outcome for both mother and fetus. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Urea 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
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  
Serologya: 
Drug screenb: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
MDMA 
Alcohol breath test 
Follicle-stimulating hormonea  
Serum pregnancy test (human 
chorionic gonadotropin)a 
Urine pregnancy testc 
a Only analyzed at Screening. 
b Only analyzed at Screening and Check-in. 
c A positive urine pregnancy test will be confirmed with a serum pregnancy test. 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
Part A 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis* 
4 
19 
 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
109.5  
Part B 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
194.5  
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
during the study will not exceed that donated during a standard blood donation 
(approximately 500 mL). 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
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Appendix 4: Contraception Guidance 
Definitions 
Females of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Females of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 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-estrogens, or selective estrogen 
receptor modulators.  
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. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary highly effective and 1 secondary method) of birth control from the time of signing 
the informed consent form until 90 days after the Follow-up visit. Primary highly effective 
methods of contraception include:  
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  
• hormonal or non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject). 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 52 of 75 
Secondary (barrier) methods of contraception include:  
• male condom with spermicide 
• female condom with spermicide  
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects can only choose a cervical cap or diaphragm if they have already had a 
prescription and fitting by their healthcare provider to ensure protocol requirements are met. 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in until 90 days after the Follow-up 
visit. Acceptable methods of contraception include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide 
• vasectomised male subject (sterilization 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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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
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Sexual Abstinence and Same-sex Relationships 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 54 of 75 
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: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with Clinical Research Unit personnel, subjects will sign 
2 copies of the ICF in the presence of a suitably trained member of staff to indicate that they 
are freely giving their informed consent. One copy will be given to the subject, and the other 
will be maintained in the subject’s records. 
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 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 55 of 75 
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 Organization (CRO) auditors or other 
authorized personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All 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.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality tolerance 
thresholds, controls, and mitigation plans will be documented in a risk management 
register. Additional details of quality checking to be performed on the data may be 
included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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. 
• 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.  


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
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Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 Code of Federal 
Regulations 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 the Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled and randomized subject, according to the 
eCRF completion instructions. The Sponsor, or CRO, will review the supporting source 
documentation against the data entered into the eCRFs to verify the accuracy of the electronic 
data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 
information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
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Appendix 6: Schedule of Assessments 


Protocol 
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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 58 of 75 
Study Plan – Part A (Single Dose) 
 
Pre- 
screening
d 
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
 
X 
X 
 
 
 
 
 
 
 
Alcohol breath test 
 
X 
X 
 
 
 
 
 
 
 
Cotinine test 
 
X 
X 
 
 
 
 
 
 
 
Serology 
 
X 
 
 
 
 
 
 
 
 
Hormone panel 
 
X 
 
 
 
 
 
 
 
 
Urine pregnancy testa 
 
X 
X 
 
 
 
 
 
 
X 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
 
 
Check-in 
 
 
X 
 
 
 
 
 
 
 
Check-out 
 
 
 
 
Day 3 (48 hours 
postdose) 
 
 
 
 
 
Non-residential visit 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
 
 
Day 1 (0 hours)  
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
 
 
Adverse event recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, pulse 
rate, respiratory rate, and 
body temperature 
 
X 
 
 
Predose, 1, 2, 4, 
8, 24 (± 1 hour), 
and 48 hours 
postdose 
X 
X 
X 
X 
X 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 59 of 75 
 
 
Pre- 
screening
d 
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Supine 12-lead ECG 
 
X 
 
 
Predose, 4, 24 
(± 1 hour) and 48 
hours postdose 
 
X 
 
X 
X 
Continuous ECG 
extractionb,c 
 
 
 
-24,  
-23.5,  
-23,   
-22.5,  
-22,  
-21.5,  
-21,  
-20, 
-18,  
-16,   
-12 
hours 
Day 1: Predose, 
0.5, 1, 1.5, 2, 2.5, 
3, 4, 6, 8, and 12 
hours 
 
 
 
 
 
 
Heat pain threshold test 
(heat pain threshold and heat 
pain tolerance) 
 
 
 
 
Day 1: predose, 
2, 4, 12, and 24 
hours postdose (± 
1 hour) 
 
 
 
 
 
Clinical chemistry, 
haematology, and urinalysis 
 
X 
 
 
48 hours 
postdose 
 
X 
 
X 
X 
Height and BMI 
 
X 
 
 
 
 
 
 
 
 
Body weight  
 
X 
X 
 
 
 
 
 
 
X 
Physical examination 
 
X 
 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
 
 
Prior to discharge 
 
X 
 
X 
X 


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Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 60 of 75 
Abbreviations: BMI = body mass index; ECG = electrocardiogram. 
a A positive urine pregnancy test result will be confirmed with a serum pregnancy test. 
b All times are relative to dosing with OLP-1002. 
c Continuous ECG recording may begin at approximately 25 hours before dosing to allow for checks to be completed prior to the first extraction timepoint and will continue for 24 hours 
postdose, ie, until after the last timepoint for ECG extraction (24 hours postdose). At timepoints for ECG extractions, subjects will be supinely resting for a total of 15 minutes (10-minute supine 
rest period, 5-minute extraction). Data will be archived for potential future analysis and will not be available for review during the study. 
d Pharmacodynamic assessment groups only. 
e PK analysis in Part A will initially only be conducted for groups receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower dose groups occurring in the event of PK data 
being quantifiable at doses ≥ 12 µg and if supported by bioanalytical stability data. 
 
 
 
Pre- 
screening
d 
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Injection site assessment  
 
 
 
 
Predose, 1, 2, 4, 
8, 24, 48 hours 
postdose 
 
X 
 
X 
X 
Pharmacokineticse 
 
 
 
 
 
 
 
 
 
 
Blood sampling 
 
 
 
 
Predose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 
12, 16, 24, 36 and 
48 hours 
postdose 
X 
X 
X 
X 
X 
Pharmacodynamicsd: 
 
 
 
 
 
 
 
 
 
 
Intradermal capsaicin test 
(capsaicin-evoked pain and 
secondary hyperalgesia 
measurement) 
X 
 
X 
 
Day 2 (The area 
of secondary area 
of hyperalgesia 
will be evaluated 
at 5 and 30 
minutes post-
capsaicin 
injection) 
 
 
 
 
 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 61 of 75 
Study Plan – Part B (Multiple Dose) 
 
Screening 
Day -1 
Days 1-15 
Day 18 
(± 2 days) 
Day 22 
(± 2 days) 
Day 25 
(± 2 days) 
Day 29 
(± 2 days) 
Poststudy 
(Day 57 
± 2 days) 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Urine drugs of abuse screen 
X 
X 
 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
Cotinine test 
X 
X 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
Hormone panel 
X 
 
 
 
 
 
 
 
Urine pregnancy testa 
X 
X 
 
 
X 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
Study residency: 
 
 
 
 
 
 
 
 
Check-in 
 
X 
 
 
 
 
 
 
Check-out 
 
 
Day 15 (48 hours postdose) 
 
 
 
 
 
Non-residential visit 
X 
 
 
X 
X 
X 
X 
X 
Study drug 
administration: 
 
 
Days 1, 4, 7, 10, and 13 
 
 
 
 
 
Safety and tolerability: 
 
 
 
 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording  
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Supine blood pressure, 
pulse rate, respiratory rate, 
and body temperature 
X 
 
Day 1: predose, 1, 2, 4 and 8 hours 
postdose 
Day 2, Day 4 (postdose), Day 5, Day 7 
(postdose), Day 9, Day 10 (postdose), 
Day 12, Day 13: predose, 1, 2, 4 and 8 
hours postdose, and Day 15 
 
X 
X 
X 
X 
X 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 62 of 75 
Abbreviations: BMI = body mass index; ECG = electrocardiogram. 
a Positive urine pregnancy test results will be confirmed with a serum pregnancy test. 
b  PK timepoints will be reviewed based on emerging data and may be updated.
 
Screening 
Day -1 
Days 1-15 
Day 18 
Day 22 
Day 25 
Day 29 
Poststudy 
(Day 57 
± 2 days) 
Heat pain threshold test 
(heat pain threshold and 
heat pain tolerance) 
X 
 
Day 1 and Day 13: predose, 1, 2, 4, 8, 
24 hours postdose 
 
 
 
 
 
Supine 12-lead ECG 
X 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Clinical chemistry, 
haematology, and urinalysis 
X 
X 
Days 2, 4, 7, 10, 13 
 
X 
 
X 
X 
Height and BMI 
X 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
 
 
 
 
X 
Physical examination 
X 
 
 
 
 
 
 
 
Symptom-directed physical 
examination 
 
 
Days 1, 4, 7, 10, 13 
 
X 
 
X 
X 
Injection site assessment  
 
 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
 
X 
 
X 
X 
Pharmacokinetics: 
 
 
 
 
 
 
 
 
Blood samplingb 
 
 
Day 1 and Day 15: Pre dose, 0.5, 1, 
1.5, 2, 3, 4, 6, 8 and 12 hours post dose 
Days 4, 8, 11, 15 Predose 
X 
X 
X 
X 
X 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 63 of 75 
Appendix 7: Protocol Amendment Summary of Changes 
Protocol Amendment 1 (Version 2; XX October 2018) 
This amendment has been generated following the non-acceptance of the original 
protocol (version 1) by the Medicines and Healthcare products Regulatory Agency 
(MHRA) on 20 September 2018. All changes made have been in response to 
comments provided by the MHRA. 
The primary changes in this amendment are: 
1. Inclusion of PK sampling in Parts A and B: 
• PK objective and exploratory endpoints added (Section 2). 
• Discussion of PK included Section 3.4. 
• PK stopping criteria added to Section 3.7. 
• PK assessments included in Section 7.1. 
• PK population and analysis (Section 8.2.1). 
• Blood volumes updated to include samples for PK assessments 
(Appendix 3). 
2. Exclusion and stopping criteria updated 
• Women who are pregnant or breastfeeding have been excluded from 
the study (Section 4.2). 
• Liver function tests, tachycardia, and hypertension stopping criteria 
have been updated (Section 3.7 and Section 4.4). 
• Stopping criteria for SAEs and serious AEs have been added 
(Section 3.7 and Section 4.4). 
3. Safety, tolerability, and PK data up to Day 22 in Part B will be reviewed prior 
to dose escalation (Section 3.1.2). 
4. Sentinel dosing included in Part B (Section 3.1.2). 
5. It has been specified that the maximum dose for additional groups will not 
exceed 20 µg (Section 3.5.3). 
Minor changes: 
1. Additional clinical laboratory evaluations have been included on Day 14 in 
Part A. 
2. The definition of the Safety population has been updated to include all 
subjects who receive OLP-1002. 
3. Typographical errors and formatting errors were corrected, as necessary. 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
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A detailed summary of changes is presented below. For each section, deleted text is 
shown in strikethrough, and new text is shown in bold: 
Section 1.6 
Previously read: 
This information, together with the pharmacodynamic (PD data, will help establish 
the doses and dosing regimen suitable for future studies in patients. 
Now reads: 
This information, together with the pharmacodynamic (PD) and pharmacokinetic 
(PK) data, will help establish the doses and dosing regimen suitable for future 
studies in patients. 
Section 2.1  
Objective added: 
Where possible, single and/or multiple subcutaneous dose pharmacokinetics of 
OLP-1002 in healthy subjects will be determined. 
Section 2.2.1 
Endpoint added: 
• demonstrate that exposure to OLP-1002 does not exceed pre-defined 
exposure limits from non-clinical studies. 
Section 2.2.2 
Endpoints added: 
• For Part A, the single ascending dose, PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o area under the plasma concentration-time curve (AUC) from 
time zero to infinity (AUC0-∞) (actual and dose normalized [DN]) 
o AUC from time zero to the time of the last quantifiable 
concentration (AUC0-tlast) (actual and DN) 
o maximum observed plasma concentration (Cmax) (actual and 
DN) 
Secondary PK 
o time of the maximum observed plasma concentration (tmax) 
o apparent plasma terminal elimination half-life (t1/2) 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 65 of 75 
• For Part B, the multiple ascending dose PK outcome endpoints of OLP-
1002 are as follows: 
Primary PK 
o AUC over a dosing interval (AUC0-τ) (actual and DN) 
o AUC0-∞ (actual and DN) 
o Cmax (actual and DN) 
Secondary PK 
o minimum observed plasma concentration (Cmin) 
o tmax 
o t1/2 
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ) 
o observed accumulation ratio based on Cmax (RACmax). 
o Temporal change parameter (TCP) 
Other PK parameters may also be added if deemed necessary. 
Section 3.1.1 
Previously read: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 7 (144 hours postdose) from the lower dose 
levels. 


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Protocol Reference: OLP-1002-001 
Protocol Version 2, 02 October 2018 
Page 66 of 75 
Now reads: 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy 
subjects will be studied in 8 groups. Up to 3 additional groups (24 subjects in total) 
may be included for further assessment of safety, tolerability, PK, and PD 
(Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study 
within 28 days prior to the first dose administration. Potential subjects for Groups 
A2, A4, and A6 will attend a pre-screening visit for an intradermal capsaicin test 
(Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the 
Clinical Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All 
subjects will return for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), 
and 14 (± 2 days), and for a poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-
residential visits may be required. The number of additional visits per subject will 
not exceed 3 and will not extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 10 (216 hours postdose) from the lower dose 
levels. For doses ≥ 12 µg, PK data will also be reviewed up to Day 7 prior to 
dose escalation. 
Figure 1 – footnote 
Text added:  
Groups A9 to A11 may be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Figure 2 – footnote 
Text added: 
Groups B4 to B6 will be included if required; dose levels will not exceed the 
maximum proposed dose of 20 µg. 
Section 3.1.2 
Previously read: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. There will be no sentinel dosing in Part B. For all subjects, a single 
subcutaneous dose will be administered on Days 1, 4, 7, 10, and 13. The dosing 


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frequency in Part B may be changed following review of data from groups in Part 
A (Section 3.4).  
Doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 18 (120 hours post-final dose) from the lower 
dose levels. Part B may start after a review of the safety and tolerability for Groups 
A1 to A6. The total daily dose administered will not exceed the highest single dose 
given in Part A. 
Now reads: 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will 
receive placebo. For all subjects, a single subcutaneous dose will be administered 
on Days 1, 4, 7, 10, and 13. Prior to each dosing occasion a physician will review 
the available safety and tolerability data from each subject to confirm it is 
acceptable to continue dosing. The dosing frequency in Part B may be changed 
following review of data from groups in Part A (Section 3.4).  
Sentinel dosing will only occur in Part B at dose levels where exposure to 
OLP-1002 at steady state is predicted to exceed exposures that have been 
shown to be safe and well tolerated in earlier groups in Parts A or B. In the 
event of sentinel dosing, 2 subjects (1 active, 1 placebo) will be dosed at least 
4 days prior to the remaining 6 subjects (5 active: 1 placebo). Safety data for 
the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 
1 and 2 will be reviewed prior to the remaining subjects receiving dose 1). In 
addition, safety data from each subject will be reviewed by a physician prior to 
each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from the 
lower dose levels. Part B may start after a review of the safety, tolerability, and 
available PK data for Groups A1 to A6. The total daily dose administered will not 
exceed the highest single dose given in Part A. 
Section 3.3 
Previously read: 
Following review of the safety, tolerability, and PD data, additional dose groups 
may be added to the study. 
Now reads: 
Following review of the safety, tolerability, PK, and PD data (where systemic 
exposure is not expected to exceed that stated in the dose escalation stopping 
criteria [Section 3.7]), additional dose groups may be added to the study. The 
maximum dose for any additional group will not exceed 20 µg. 


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Section 3.4 
Previously read: 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis will not be conducted in this study. The bioanalytical 
method used for preclinical species has a lower limit of quantification (LLOQ) of 
5 ng/mL. The increased sample volume possible from humans (compared to small 
animals) may afford an approximate 10-fold increase in sensitivity with possibly an 
additional 5-fold increase from the use of a more sensitive mass spectrometer. This 
could potentially deliver an LLOQ of around 0.1 ng/mL. It is apparent from the 
predicted plasma concentrations (see Section 3.5.2) that only a small number of 
samples around Cmax at the highest doses would be quantifiable and that a 
conventional approach to pharmacokinetic will not achieve a full definition of the 
plasma concentration vs time profile or enable an estimation of the terminal phase. 
Thus, the additional burden of sampling procedures would not be justified by the 
quality of the data which it would generate. 
Now reads:  
In Part A, safety data up to Day 10 will be reviewed prior to dose escalation, 
and PK data up to Day 7 will be reviewed for all groups receiving ≥ 12 µg 
OLP-1002. In Part B, safety, tolerability and PK data up to Day 22 will be 
reviewed for all dose groups. As the t1/2 of OLP-1002 is predicted to be 
approximately 180 hours (based on non-clinical data) review of safety data up 
to Day 10 (Part A) and Day 22 (Part B) is considered sufficient to ensure data 
from at least one half-life is included in the review. In addition, as plasma 
exposures are anticipated to be low, it is expected that it will only be possible 
to perform an assessment of peak concentrations (Cmax) and therefore PK data 
to Day 7 (Part A) and Day 22 (Part B) will be sufficient. Additionally, a 


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cumulative safety review will occur such that additional emerging safety data 
from earlier groups will be considered when making a dose escalation decision. 
Healthy male and female subjects will be recruited into this study. The inclusion of 
females of childbearing potential is in accordance with International Council for 
Harmonisation (ICH) M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be 
sufficient in order to determine safety and tolerability. In order to assess the PD 
effects of OLP-1002, 3 groups in Part A will include 8 subjects (6 active; 2 
placebo). A full review of the safety and tolerability data from Part A will be 
performed to determine the dose regimen for Part B. Part B may start after a full 
review of all safety and tolerability data from Group A1 to A6. A review of PD data 
may also be performed, at the discretion of the Investigator. Details of the dosing 
regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 
57-day follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis in Part A will initially only be conducted for groups 
receiving ≥ 12 µg OLP-1002, with retrospective analyses of samples from lower 
dose groups occurring in the event of PK data being quantifiable at doses ≥ 12 
µg and if supported by bioanalytical stability data. Dose escalation decisions 
for doses <12 µg in Part A will not require PK data. The rationale for this is 
that maximum plasma concentrations at 12 µg are expected to be 
approximately 0.078 ng/mL and the bioanalytical method used for preclinical 
species has a lower limit of quantification (LLOQ) of 5 ng/mL. The increased 
sample volume possible from humans (compared to small animals) may afford an 
approximate 10-fold increase in sensitivity with possibly an additional 5-fold 
increase from the use of a more sensitive mass spectrometer. This could potentially 
deliver an LLOQ of around 0.1 ng/mL. Therefore, even with the increased assay 
sensitivity plasma levels from doses at or below 12 µg are not expected to be 
quantifiable. It is apparent from the predicted plasma concentrations (see 
Section 3.5.2) that only a small number of samples around Cmax at the highest dose 
would be quantifiable and that a conventional approach to pharmacokinetic will not 
achieve a full definition of the plasma concentration vs time profile or enable an 
estimation of the terminal phase. In addition the planned dose levels have a high 
safety margin when comparing the predicted exposures to the exposures at the 
NOAEL (see Section 3.5.2), with the 12 µg dose level having an expected 312-
fold and 255-fold safety margin based on Cmax and AUC0-∞, respectively. 
Therefore if exposure is significantly higher than predicted it is not expected to 
exceed the PK stopping criteria.  
 
Section 3.4.1 
Previously read: 


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In Part B, all subjects in a group will be dosed on the same day. Accumulation of 
OLP-1002 is expected following multiple doses, based on the preclinical data, and 
will be taken into account when determining the doses for Part B (see 
Section 3.5.3). 
Now reads:  
In Part B, sentinel dosing will be used in groups where exposure to OLP-1002 
at steady state is predicted to exceed exposures that have been shown to be safe 
and well tolerated in earlier groups in Parts A or B. When used, two subjects 
(1 active; 1 placebo), will be dosed 4 days prior to the remaining 6 subjects 
(5 active; 2 placebo). The 2 sentinel subjects will always be 2 doses ahead of the 
remaining subjects (ie. sentinel subjects will receive dose 2 before the 
remaining subjects receive dose 1). Subjects in groups where exposure is not 
predicted to exceed that tested in Part A will be dosed on the same day. 
Accumulation of OLP-1002 is expected following multiple doses, based on the 
preclinical data, and will be taken into account when determining the doses for Part 
B (see Section 3.5.3). If it is not possible to quantify exposure it will be assumed 
that multiple dosing results in a 4-fold accumulation based on the predicted t1/2 
of 180h. 
Section 3.5.3 
Text added: 
If additional groups (A9-11 or B3-6) are required, the maximum daily dose 
administered will not exceed 20 µg and predicted systemic exposure will not 
exceed that stated in the dose escalation stopping criteria [Section 3.7]) based 
on available PK data. 
Section 3.6 
Previously read:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety and tolerability data up to Day 18 (120 hours post-final dose) from 
groups that received lower doses of OLP-1002. Doses may be reduced and may be 
lower than the starting dose. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 5 subjects, who have received OLP-1002 will be used to make the dose-
escalation decision. Dose escalation in Part B will only occur if data from a 
minimum of 6 subjects have been reviewed from the previous lower dose group, 


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such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
Now reads:  
In Part A, doses will be administered in an escalating manner following satisfactory 
review by the Sponsor and Investigator of the safety, and tolerability data up to 
Day 7 (144 hours postdose) from groups that received lower doses of OLP-1002. 
For escalation to doses > 12 µg, PK data up to Day 7 (144 hours postdose) will 
also be reviewed. All available safety, tolerability, and PK data from previous 
groups will be reviewed prior to dose escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory 
review of safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) 
from groups that received lower doses of OLP-1002. Doses may be reduced and 
may be lower than the starting dose. Available safety, tolerability, and PK data 
from all previous groups will be reviewed prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects 
(Groups A1, A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have 
been reviewed from the previous lower dose group, such that data from a minimum 
of 3 or 4 subjects, respectively, who have received OLP-1002 will be used to make 
the dose-escalation decision. Dose escalation in Part B will only occur if data from 
a minimum of 6 subjects have been reviewed from the previous lower dose group, 
such that data from a minimum of 4 subjects who have received OLP-1002 will be 
used to make the dose-escalation decision. 
 
Section 3.7 
Previously read: 
In Parts A and B, following consultation with the Sponsor, dose escalation will be 
stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping 
of dose escalation. 
• There is evidence of clinically significant increases in liver function tests 
(aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase 
and total bilirubin) defined as 3 times the upper limit of normal in 3 or more 
subjects in a group (confirmed with repeat testing). 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement) in 2 or more subjects in a group. 


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• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in 
at least 2 subjects in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 2 occasions within a 24-hour interval in 
at least 2 subjects in a group. 
Now reads: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more 
subjects in a group that, in the opinion of the Investigator, warrant stopping 
of dose escalation. 
• One or more subjects experience an SAE that is considered to be 
related to OLP-1002. 
• Two or more subjects in the same group experience severe non-serious 
AEs (ie. severe non-serious AEs considered as, at least, possibly related 
to OLP-1002 administration), independent of whether the AEs are 
within or not within the same system organ class.  
• There is evidence of clinically significant increases in aspartate 
aminotransferase, alanine aminotransferase or alkaline phosphatase (defined 
as 3 times the upper limit of normal), or total bilirubin (defined as 2 times 
the upper limit of normal) that are considered to be related to OLP-
1002 in 2 or more subjects in a group. Results will be confirmed with 
repeat testing. 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 
predose for Part B) and/or absolute QTcF values > 500 msec (confirmed by 
repeat measurement) in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in 
≥1 subject in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 110 mmHg) in the resting supine position (confirmed by 
2 repeat measurements) on at least 1 occasion within a 24-hour interval in 
≥1 subject in a group. 
• The dose will not exceed 20 µg or the systemic exposure for any 
individual subject is predicted to exceed a Cmax of 24.9 ng/mL (plasma) 
and/or an AUC0-24 of 128 ng/mL; i.e., systemic exposure will be no 
greater than the NOAEL in the most sensitive species (100,000 pmol/kg 
in rat [462 µg/kg]). 
 
Section 4.2 


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Exclusion criteria added: 
4. 
Female subjects who are pregnant or breastfeeding. 
Section 4.4 
Previously read: 
• any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal 
Now reads: 
• any clinically relevant sign or symptom that, in the opinion of the 
Investigator (or designee), warrants subject withdrawal, including: 
o a serious adverse reaction (i.e., a SAE considered at least 
possibly related to OLP-1002 administration), 
o severe non-serious adverse reaction (i.e., severe non-serious AE 
considered to at least possibly related to OLP-1002 
administration), 
o elevated AST, ALT, ALK (3 x ULN) or total bilirubin (2 x ULN), 
o QTcF increases > 60 msec compared to baseline (predose for 
Part A or Day 1 predose for Part B) and/or absolute QTcF 
values > 500 msec (confirmed by repeat measurement), 
o Tachycardia (> 150 beats/min) in the resting supine position 
(confirmed by 2 repeat measurements), 
o Severe hypertension (systolic blood pressure > 180 mmHg 
and/or diastolic blood pressure > 110 mmHg) in the resting 
supine position (confirmed by 2 repeat measurements). 
Section 7.1 
Section added: 
7.1 Pharmacokinetic Assessments 
7.1.1 Sample Collection and Processing 
Blood samples will be collected by venipuncture or cannulation at the times 
indicated in the Schedule of Assessments (Appendix 6). Furthermore, 
additional blood samples may be taken from each subject per treatment 
period, with the maximum volume of blood withdrawn per subject not 
exceeding the limit detailed in Appendix 3. Any changes to the scheduled times 
of PK assessments will be agreed with the Sponsor and documented in the 
TMF. Samples taken from subjects who received placebo will not be analyzed. 
In Part A, only samples collected from subjects that received >12 µg OLP-1002 
will be initially analyzed. If PK data is quantifiable at concentrations of OLP-


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1002 >12 µg, samples from lower dose groups will be retrospectively analyzed. 
In Part B, PK samples will be analyzed for all groups. 
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 OLP-1002 will be determined using validated 
analytical procedures. Specifics of the analytical methods will be provided in 
separate documents. 
Section 8.2 
Previously read: 
8.2.1 Pharmacodynamic population 
The PD population will include all subjects who received at least 1 dose of study 
treatment OLP-1002 or placebo and for whom PD can be evaluated. 
8.2.2 Safety Population 
The safety population will include all subjects who received at least 1 dose of study 
treatment or placebo and have at least 1 postdose safety assessment. 
Now reads: 
8.2.1 Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of 
OLP-1002 that have evaluable PK data and have had no AEs or protocol 
deviations considered to impact PK. 
8.2.2 Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of OLP-
1002 or placebo and for whom PD can be evaluated. 
8.2.3 Safety Population 
The safety population will include all subjects who received at least 1 dose of 
OLP-1002 or placebo. 
8.3 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma and 
urine concentration data, using commercial software such as Phoenix® 
WinNonlin®. Plasma concentrations of OLP-1002 and PK parameters will be 
listed and summarized using descriptive statistics. Individual and arithmetic 
mean OLP-1002 concentration-time profiles will also be presented graphically. 


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Appendix 3 
Table updated: 
Part A 
 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis* 
4 
19 
76 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
33.5109.5  
Part B 
 
Volume per 
blood sample 
(mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Pharmacokinetic 
analysis 
4 
29 
116 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
78.5194.5  
Appendix 6 
PK and Blood sampling rows added to the schedule of events for Part A and Part B. 
In the Schedule of events for Part A, footnote e was added. In the Schedule of 
events for Part B, footnote b was added. 
Clinical chemistry, hematology, and urinalysis was added to the Schedule of events 
for Part A on Day 14.  
 
 


TITLE PAGE 
Protocol 
OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single 
and Multiple Subcutaneous Dose, Safety, Tolerability, and 
Pharmacodynamic Study in Healthy Male and Female Subjects 
Protocol Status: Final 
Protocol Date: 31 August 2018 
Protocol Version: 1 
Investigational Product: OLP-1002 
 
Protocol Reference Number: OLP-1002-001 
Covance Study Number: 8379789 
EudraCT Number: 2018-003085-13 
 
 
Sponsor: 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung-gu, Yongin, Gyeonggi 17015 
Republic of Korea 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street  
Leeds, LS2 9LH 
United Kingdom 
 
 
Sponsor Signatory: 
 
 
Principal Investigator: 
 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
Covance Study: 8379789 
CONFIDENTIAL 
Protocol Reference: OLP-1 002-001 
SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
 
Protocol Version 1, 3 I August 2018 
Date 
Page 2 of 59 


Protocol 
Co vance Study: 83 79789 
CONFIDENTIAL 
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INVESTIGATOR AGREEMENT 
I have read the protocol and agree to conduct the study as described herein. 
 
Principal Investigator 
Protocol Version I, 31 August 2018 
Date 
Page 3 of 59 


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STUDY IDENTIFICATION 
Sponsor 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Study Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Sponsor’s Medical Contact 
 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung, Yongin, Gyeonggi 17015 
Republic of Korea 
Medical Monitor 
(24-hour emergency 
medical contact) 
 
 
 
 
 
Study Site 
Covance Clinical Research Unit Ltd. 
Springfield House, 
Hyde Street, 
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 
 
Project Physician 
 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street 
Leeds, LS2 9LH 
United Kingdom 


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Clinical Laboratory 
 
 
 
Statistician 
 
Covance 


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SYNOPSIS 
Title of study: OLP-1002 – A first-in-human, double-blind, placebo-controlled, single and multiple 
subcutaneous dose, safety, tolerability, and pharmacodynamic study in healthy male and female 
subjects 
Objectives:  
The primary objective of the study is to assess the safety and tolerability of single and multiple 
subcutaneous doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the pharmacodynamic effect of OLP-1002 
following single subcutaneous doses in healthy volunteers using a capsaicin pain model, and to 
monitor the effects of a single subcutaneous doses of OLP-1002 on cardiac QT interval. 
Study design: 
This will be a double-blind, randomized, placebo-controlled, single and multiple subcutaneous dose 
study conducted in 2 parts, including healthy male and female subjects. 
Number of subjects: 
Part A: 44 subjects will be studied in 8 groups (5 groups of 4 and 3 groups of 8). 
Part B: 24 subjects will be studied in 3 groups (Groups B1 to B3). 
Up to 24 additional subjects may be recruited into Part A and Part B of the study if required. 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged between 18 and 60 years (inclusive) with a body mass index 
between 18.0 and 28.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test product: OLP-1002 
Proposed dose levels for Part A: 30 ng, 120 ng, 400 ng, 1.2 µg, 3 µg, 6 µg, 12 µg, and 20 µg. 
Proposed dose levels for Part B: the doses for Part B will be decided in consultation with the 
Sponsor and on the basis of data from Part A of the study. The highest dose in Part B will be up to 
50% of the highest dose in Part A. 
Administration route: subcutaneous 
Reference product and mode of administration: 
Reference product: placebo 
Administration route: subcutaneous 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks. 
Planned study duration (Screening to Follow-up): approximately 8 weeks for Part A and 
approximately 12 weeks for Part B. 
Endpoints: 
Pharmacodynamics: 
In Part A, the analgesic effect of OLP-1002 will be investigated in 3 groups consisting of 8 subjects 
(6 active: 2 placebo) using experimental capsaicin-evoked pain methods. Measurement of 
capsaicin-evoked pain will be performed at pre-screening, baseline and on Day 2, and secondary 
hyperalgesia at 5 and 30 minutes post-capsaicin injection. Continuous electrocardiogram (ECG) 
recording will be conducted to investigate the effect of OLP-1002 on cardiac function. 
Safety: 
Adverse events, clinical laboratory evaluations (clinical chemistry, hematology, urinalysis), 12-lead 
ECGs, vital signs measurements, injection site assessment, and physical examinations. 


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Statistical methods: 
Pharmacodynamics: 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of pharmacodynamic data is planned. 
Safety: 
Safety parameters will be listed and summarized using descriptive statistics. No formal statistical 
analysis of safety data is planned. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................6 
TABLE OF CONTENTS ...........................................................................................................8 
LIST OF TABLES AND FIGURES........................................................................................10 
LIST OF ABBREVIATIONS ..................................................................................................11 
1. 
INTRODUCTION ...........................................................................................................12 
1.1. 
Overview ................................................................................................................12 
1.2. 
Summary of Nonclinical Pharmacology ................................................................12 
1.2.1. 
In Vitro Pharmacology Studies ....................................................................12 
1.2.2. 
In Vivo Pharmacology Studies ....................................................................13 
1.2.3. 
Ex Vivo Pharmacology Studies ...................................................................14 
1.3. 
Summary of Safety Pharmacology ........................................................................15 
1.4. 
Summary of Toxicology ........................................................................................15 
1.5. 
Summary of Nonclinical Pharmacokinetics ...........................................................16 
1.6. 
Study Rationale ......................................................................................................17 
1.7. 
Benefit-risk Assessment .........................................................................................17 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................17 
2.1. 
Objectives ..............................................................................................................17 
2.2. 
Endpoints ...............................................................................................................17 
2.2.1. 
Primary Endpoints .......................................................................................17 
2.2.2. 
Exploratory Endpoints .................................................................................18 
3. 
INVESTIGATIONAL PLAN ..........................................................................................18 
3.1. 
Overall Study Design and Plan ..............................................................................18 
3.1.1. 
Part A ...........................................................................................................18 
3.1.2. 
Part B ...........................................................................................................21 
3.2. 
Start of Study and End of Study Definitions .........................................................22 
3.3. 
Additional Groups ..................................................................................................22 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................22 
3.4.1. 
Dose Interval ................................................................................................23 
3.4.2. 
Pharmacodynamic Assessment ....................................................................23 
3.5. 
Selection of Doses in the Study .............................................................................24 
3.5.1. 
Starting Dose ................................................................................................24 
3.5.2. 
Exposure ......................................................................................................24 
3.5.3. 
Proposed Doses ............................................................................................26 


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3.6. 
Dose Escalation ......................................................................................................27 
3.7. 
Dose Escalation Stopping Criteria .........................................................................28 
4. 
SELECTION OF STUDY POPULATION .....................................................................28 
4.1. 
Inclusion Criteria ...................................................................................................28 
4.2. 
Exclusion Criteria ..................................................................................................29 
4.3. 
Subject Number and Identification ........................................................................30 
4.4. 
Subject Withdrawal and Replacement ...................................................................30 
4.5. 
Study Termination .................................................................................................31 
5. 
STUDY TREATMENTS .................................................................................................31 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................31 
5.2. 
Study Treatment Administration ............................................................................32 
5.3. 
Randomization .......................................................................................................32 
5.4. 
Blinding..................................................................................................................32 
5.5. 
Treatment Compliance ...........................................................................................32 
5.6. 
Drug Accountability...............................................................................................32 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................33 
6.1. 
Concomitant Therapies ..........................................................................................33 
6.2. 
Diet .........................................................................................................................33 
6.3. 
Smoking .................................................................................................................34 
6.4. 
Exercise ..................................................................................................................34 
6.5. 
Blood Donation ......................................................................................................34 
6.6. 
Other Restrictions ..................................................................................................34 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................34 
7.1. 
Pharmacodynamic Assessments ............................................................................35 
7.1.1. 
Capsaicin-evoked Pain Model .....................................................................35 
7.1.2. 
Secondary Hyperalgesia ...............................................................................35 
7.2. 
Safety and Tolerability Assessments .....................................................................35 
7.2.1. 
Adverse Events ............................................................................................35 
7.2.2. 
Clinical Laboratory Evaluations ..................................................................36 
7.2.3. 
Vital Signs ....................................................................................................36 
7.2.4. 
Electrocardiogram ........................................................................................36 
7.2.5. 
Heat Pain Threshold Test .............................................................................37 
7.2.6. 
Physical Examination...................................................................................38 
7.2.7. 
Body Weight and Height .............................................................................38 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................38 
8.1. 
Determination of Sample Size ...............................................................................38 
8.2. 
Analysis Populations ..............................................................................................38 
8.2.1. 
Pharmacodynamic Population .....................................................................38 
8.2.2. 
Safety Population .........................................................................................39 


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8.3. 
Pharmacodynamic Analyses ..................................................................................39 
8.4. 
Safety Analysis ......................................................................................................39 
9. 
REFERENCES ................................................................................................................39 
10. APPENDICES .................................................................................................................41 
Appendix 1: Adverse Event Reporting ..............................................................................42 
Appendix 2: Clinical Laboratory Evaluations ...................................................................46 
Appendix 3: Total Blood Volume ......................................................................................47 
Appendix 4: Contraception Guidance ................................................................................48 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................51 
Appendix 6: Schedule of Assessments ..............................................................................54 
 
LIST OF TABLES AND FIGURES 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 ........................25 
Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 ....................26 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B ..........................................................................................................26 
 
Figure 1: 
Study Schematic (Part A)...........................................................................20 
Figure 2: 
Study Schematic (Part B) ...........................................................................21 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve extrapolated to infinity 
AUC0-24 
area under the plasma concentration-time curve from 0 to 24 hours postdose 
BMI 
body mass index 
Cmax 
maximum observed plasma concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
DRG 
dorsal root ganglion 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Emax 
maximum pain intensity 
FCA 
Freund's Complete Adjuvant 
GCP 
Good Clinical Practice 
HED 
human equivalent dose 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
NOAEL 
no-observed-adverse-effect level 
PD 
pharmacodynamic(s) 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SNL 
spinal nerve ligation 
t1/2 
elimination half-life 
tEmax 
time of maximum pain intensity 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
VAS 
Visual Analogic Scale 
VGSC 
voltage-gated sodium channel 


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1. INTRODUCTION 
1.1. 
Overview 
OLP-1002 is a novel peptide nucleic acid (PNA) derivative which acts as a specific voltage-
gated sodium channel (VGSC) protein (Nav1.7) inhibitor, and is being developed by OliPass 
for the treatment of pain. 
The Nav1.7 protein is a subtype of VGSCs. Nav1.7 is particularly important in nociception 
and pain signaling, with congenital loss-of-function mutations in Nav1.7 resulting in the 
inability to experience pain. Selective Nav1.7 inhibitors are believed to have the potential to 
treat severe pain safely1. The active sites of VGSC subtypes are virtually indistinguishable by 
their 3-dimensional structure and thus the discovery of selective Nav1.7 small molecule 
inhibitors has been extremely challenging. Since inhibition of Nav1.5 subtype elicits long QT 
cardiotoxicity, inhibition of Nav1.5 subtype should be avoided at therapeutic doses. 
To date, there are several Nav1.7 inhibitors claimed to be selective that have been evaluated 
in human subjects: 
• Vixotrigine (formerly known as raxatrigine) inhibits Nav1.7 as well as other VGSC 
subtypes. Vixotrigine is in phase III clinical development for trigeminal neuralgia. 
Due to the limited Nav1.7 selectivity over Nav1.5, vixotrigine was evaluated primarily 
in patients with a low heart risk. 
• Funapide is a Nav1.7 inhibitor with limited Nav1.7 selectivity, and was in phase IIb 
clinical trials as of July 2014. Although funapide showed analgesic activity in a small 
number of erythromelalgia patients, dose-limiting adverse events (AEs), including 
dizziness and somnolence, were observed2. The central nervous system (CNS) AEs 
were due to its poor Nav1.7 selectivity. 
• PF-05089771 is a Nav1.7 selective inhibitor with a claimed Nav1.7 selectivity of 
> 2000-fold versus other subtypes of sodium channel and was evaluated in patients of 
erythromelalgia or dental pain. It is thought low drug concentrations achieved in the 
target tissue could be a possible explanation for its poor analgesic activity in human 
patients3. 
OLP-1002 is fully complementary to a 14-mer RNA sequence spanning the junction of 
intron 4 and exon 5 in the human SCN9A pre-mRNA which codes for the Nav1.7 channel. 
OLP-1002 yields SCN9A mRNA splice variant(s) encoding variant Nav1.7 protein(s) lacking 
the sodium channel activity (ie, a non-functional channel), thereby inhibiting Nav1.7 channel 
function. 
1.2. 
Summary of Nonclinical Pharmacology 
1.2.1. 
In Vitro Pharmacology Studies 
Overall, results from the in vitro pharmacology studies showed OLP-1002 elicits responses 
consistent with its designed function4. It inhibits SCN9A mRNA expression and yields the 


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Nav1.7 variant protein or proteins lacking sodium channel activity. Its effects are highly 
selective, which may provide for an improved margin of safety compared to other Nav1.7 
inhibitors. 
OLP-1002 at 1 to 100 zM in PC3 prostate carcinoma cells induced exon skipping and yielded 
SCN9A mRNA splice variant(s) encoding a Nav1.7 variant protein or proteins lacking 
sodium channel activity.  
In rat dorsal root ganglion (DRG) neuronal cells, OLP-1002 at 1000 zM inhibited Nav1.7 
protein expression by > 50%, while OLP-1002R at 100 and 1000 zM inhibited Nav1.7 
expression almost completely. As OLP-1002R is fully complementary to rat SCN9A pre-
mRNA, OLP-1002R would be predicted to be more potent than OLP-1002 in this cell type. 
SCN9A mRNA expression level was evaluated by quantitative polymerase chain reaction 
(qPCR). OLP-1002 inhibited the expression of the SCN9A mRNA in PC3 cells with sub-
attomolar potency.  
In SH-SY5Y human neuroblastoma cells stimulated with tumor necrosis factor (TNF)-1α to 
upregulate the expression of SCN9A mRNA, OLP-1002 decreased expression by 46% to 
49% at 1 fM to 10 pM. In rat DRG neuronal cells, OLP-1002 at 1 fM significantly decreased 
SCN9A mRNA expression by 54%. 
In rat DRG neuronal cells, OLP-1002 markedly and significantly inhibited the sodium current 
by 77% at 0.1 aM and 73% at 1 aM, while for OLP-1002R, the inhibition was 66% at 0.1 aM 
and 70% at 1 aM. Given that rat DRG neuronal cells express various subtypes of sodium 
channel, the observed inhibitions of 66% to 77% correspond to the complete knockout of the 
Nav1.7 sodium channel subtype with OLP-1002 or OLP-1002R. 
The Nav1.7 selectivity over Nav1.5 was evaluated in H9C2 rat cardiomyocytes which are 
known to abundantly express the rat Nav1.5 sodium channel subtype. Following incubation 
with OLP-1002 or OLP-1002R at 1 aM or 1 pM, there were no notable decreases in the 
sodium current. Considering that OLP-1002 and OLP-1002R inhibit the expression of Nav1.7 
protein at 1 aM or lower in rat DRG neuronal cells, the Nav1.7 selectivity of OLP-1002 and 
OLP-1002R over Nav1.5 is estimated to be in excess of one million-fold. Such a large Nav1.7 
selectivity over Nav1.5 has not been realized with small molecule Nav1.7 inhibitors, 
suggesting that OLP-1002 potentially offers pain management with much greater 
cardiovascular safety. 
1.2.2. 
In Vivo Pharmacology Studies 
Spinal nerve ligation (SNL) has been widely applied as a rat model for neuropathic pain. 
OLP-1002 and OLP-1002R were found to be very potent, but highly variable in potency, in 
reversing neuropathic allodynia in this model. Analyses of the therapeutic potency strongly 
suggested that a marked proportion of subcutaneously (SC) administered OLP-1002 or OLP-
1002R may have been topically delivered directly to the spinal nerves exposed in the dorsal 
cavity created during the SNL modelling. In addition, the variability of the therapeutic 
potency may be due to a variable degree of healing of the SNL surgery wound. If an animal 


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recovers slowly, the animal tends to be left with a dorsal cavity. Therefore, estimations of 
potency in these studies with this model should be treated with caution. 
In one study using the SNL model, allodynia in rats was slowly and gradually reversed by 
OLP-1002 SC administered at nominal doses of 1, 3, and 6 pmol/kg once every 2 days (due 
to adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). As the onset time for pain reduction was 4 days, 
the doses used were not sufficient for fast onset of activity. In this study, the animals should 
have reasonably recovered from the dorsal wound, and therefore less susceptible to topical 
delivery directly to the exposed spinal nerves. However, in another study in this model, when 
OLP-1002 was intraperitoneally (IP) administered once every 3 days to avoid the likelihood 
of local delivery to the spinal nerves, OLP-1002 surprisingly reversed the allodynia at 
5 fmol/kg, and was superior or comparable to pregabalin 30 mg/kg, a gold standard for 
neuropathic pain studies. The high potency shown at 5 fmol/kg IP strongly suggests the 
possibility that OLP-1002 is efficiently absorbed by the enteric nervous system, travels to the 
spinal cord, and then redistributes to the spinal nerves of the SNL ligation. This opens the 
possibility of efficient oral delivery of OLP-1002 to the spinal cord. 
When evaluated for their ability to reverse the inflammatory pain in rats inflicted with 
Freund's Complete Adjuvant (FCA)-induced severe paw inflammation, OLP-1002 at 
300 pmol/kg and OLP-1002R at 100 pmol/kg significantly reversed the thermal hyperalgesia, 
and both were more effective than pregabalin 30 mg/kg. 
Paw burn injury induces hyperalgesia in rats and is known to upregulate Nav1.7 expression in 
the L5 and L6 DRGs of the affected side. Burn injury induces a far weaker degree of paw 
inflammation than FCA-induced paw inflammation. OLP-1002 SC administered inhibited the 
thermal hyperalgesia in paw burn injury in a dose-dependent manner. At 25 fmol/kg, OLP-
1002 did not inhibit thermal hyperalgesia. Although OLP-1002 at 625 fmol/kg significantly 
inhibited the thermal hyperalgesia, the efficacy was moderate and weaker than pregabalin 
30 mg/kg. This suggests that SC dosing does not offer the local topical delivery to spinal 
nerves in this model as seen in rats without a dorsal cavity wound. In this study, the Nav1.7 
expression in the DRG of the burn injury side significantly decreased by 58% with 
625 fmol/kg OLP-1002, validating the target engagement for analgesic activity. 
An intraplantar injection of formalin induces severe acute pain. The contributors to acute pain 
are known to be complex and require further elucidation. However, acute peripheral 
inflammation is known to contribute much to Phase II Pain (pain from 10 to 40 min after the 
formalin injection). In this model, OLP-1002 significantly inhibited Phase II Pain at 
comparable or saturated efficacy when SC administered at 10 to 100 pmol/kg (due to 
adhesion to the dosing equipment, the actual doses administered were estimated to be 
approximately 10% of the nominal values). Thus peripheral acute inflammatory pain could be 
treated with 10 pmol/kg or less. 
1.2.3. 
Ex Vivo Pharmacology Studies 
One day post-SC injection, OLP-1002 and OLP-1002R at 100 pmol/kg significantly inhibited 
the expression of Nav1.7 protein by 39% and 57%, respectively, in the spinal cord of rats 
subjected to SNL.  


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In other rats subjected to SNL, OLP-1002R slowly and gradually reversed the allodynia in a 
dose-dependent manner. OLP-1002R at 30 fmol/kg (the highest dose administered) had the 
greatest effect, but the dose was not high enough to elicit full therapeutic efficacy. OLP-
1002R inhibited expression of Nav1.7 protein in these animals, most notably at 1 fmol/kg, 
and decreased SCN9A mRNA expression by approximately 40% at 1 to 30 fmol/kg. The 
observed inhibitions were largely consistent with the in vivo therapeutic activity findings. 
Taking all the in vivo and ex vivo findings together, OLP-1002R was concluded to inhibit 
neuropathic allodynia by inhibiting the expression of the SCN9A mRNA and the Nav1.7 
protein. 
1.3. 
Summary of Safety Pharmacology 
In vitro, OLP-1002 did not inhibit the human ether-à-go-go-related gene (hERG) channel 
current expressed in human embryonic kidney (HEK) cells at the highest concentration tested 
2 μM (the limit of the validated analytical method for OLP-1002). 
In the in vivo safety pharmacology studies, OLP-1002 SC administered at dose levels up to 
100 nmol/kg had no effect on body temperature, neurological function, or respiratory 
function in rats, and had no significant toxic effect on cardiovascular function in cynomolgus 
monkeys. 
1.4. 
Summary of Toxicology 
In rats, following twice-weekly SC dosing for 13 weeks, OLP-1002-related microscopic 
findings included pigment accumulation in the kidney of males administered 
100 nmol/kg/dose and females administered ≥ 10 nmol/kg/dose, foreign material and 
vacuolated macrophage infiltrates in males and/or females administered ≥ 1 nmol/kg/dose, 
and an increased incidence and/or severity of mononuclear cell infiltrates at the injection sites 
in males and/or females administered ≥ 10 nmol/kg/dose. These findings persisted through 
the recovery phase in animals administered 100 nmol/kg/dose. However, the effects were 
considered non-adverse due to their mild severity and lack of impact on animal health and 
wellbeing. The no-observed-adverse-effect level (NOAEL) was 100 nmol/kg/dose. This dose 
level corresponded to maximum observed plasma concentration (Cmax) and area under the 
plasma concentration-time curve (AUC) from 0 to 24 hours postdose (AUC0-24) values of 
27.6 ng/mL and 174 ng·hr/mL, respectively, in males and 24.9 ng/mL and 128 ng·hr/mL, 
respectively, in females on Day 88 of the dosing phase. 
In cynomolgus monkeys, following twice-weekly SC dosing for 13 weeks, OLP-1002-related 
microscopic findings included mononuclear cell infiltrates at the SC injection sites of animals 
administered ≥ 10 nmol/kg/dose. This finding was not resolved with the completion of the 
recovery phase. However, the effects of 100 nmol/kg/dose were considered non-adverse due 
to the mild severity of findings and the lack of impact on animal health and wellbeing. The 
NOAEL was 100 nmol/kg/dose (equivalent to 462.29 µg/kg/dose), which corresponded to 
Cmax and AUC from 0 to 72 hours postdose (AUC0-72) values of 121 ng/mL and 
2840 ng·hr/mL in males, respectively, and 216 ng/mL and 4840 ng·hr/mL in females, 
respectively, on Day 88 of the dosing phase. 


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The genotoxic and mutagenic potential of OLP-1002 was evaluated with standard Good 
Laboratory Practice (GLP) via in vitro bacterial mutagenicity and chromosomal aberration 
studies, and was found to be negative. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
In rats, following a single SC dose of 14C-OLP-1002, the time of maximum observed 
concentration (Tmax) was 0.5 to 1 hour for both radioactivity and parent compound. Plasma 
concentrations of total radioactivity were quantifiable through the last sampling time of 72 
hours postdose, but was variable for the parent compound. The elimination half-life (t1/2) of 
total radioactivity from plasma was 23 hours. Total radioactivity distributed into tissues, 
including those of the CNS protected by the blood-brain barrier. 14C-OLP-1002-derived total 
radioactivity was not rapidly excreted from rats, with minimal amounts present in urine and 
feces. The bulk of the total radioactivity remained in carcasses, primarily in kidneys (cortex 
and medulla) and liver. Parent 14C-OLP-1002 was present in plasma and tissues, but 
concentrations declined over time and were substantially lower than total radioactivity 
concentrations at the later sampling times.  
After a single SC administration of 14C-OLP-1002 to rats, the highest concentrations of total 
radioactivity were retained predominantly in the liver (10.4% to 13.3% of the dose), kidney 
cortex (3.47% to 4.96%), and kidney medulla (1.10% to 1.59% of the dose) through 168 
hours postdose. For all other tissues, the total amounts of total radioactivity were 
substantially less, ranging from 0.0000203% in the 5th DRG to 0.327% in the spleen. 
Radioactivity was excreted slowly via both the renal and fecal routes of elimination. Total 
average recoveries of radioactivity in urine and feces through 336 hours postdose accounted 
for 2.31% and 1.75% of the administered radioactivity, respectively. The bulk of the 
administered total radioactivity was retained in the rat carcasses through 168, 336, 504, and 
840 hours postdose. The kidney cortex, kidney medulla, and liver were the 3 tissues that 
retained the greatest amounts of the administered radioactivity. 
Following a 16.1-µg/kg dose in rats, the plasma concentrations were still quantifiable at 
72 hours postdose and the rate of elimination was slow, with t1/2 17.5 hours. It was not 
possible to accurately define the elimination phase for the 2.67- and 5.28-µg/kg dose levels. 
In cynomolgus monkeys, following a single SC dose of 14C-OLP-1002, Tmax ranged from 
0.25 to 1 hour for both total radioactivity and parent compound. Concentrations of total 
radioactivity were sustained in blood and plasma through the last sampling time of 144 hours 
postdose. Concentrations of parent compound were sustained in plasma through the last 
sampling time of 144 hours postdose in 2 of 3 monkeys, and were similar to plasma total 
radioactivity concentrations at 8 hours postdose. From 24 to 144 hours postdose, plasma 
concentrations of total radioactivity were substantially higher than for parent 14C-OLP-1002 
plasma concentrations.  
The mean Cmax of parent 14C-OLP-1002 in plasma was 1.96 ng/mL. The mean plasma Tmax 
was 0.833 hours. Plasma exposure of parent 14C-OLP-1002 based on AUC extrapolated to 
infinity (AUC0-∞), was 12.7 ng·h/mL. After reaching Cmax, plasma concentrations of parent 
14C-OLP-1002 declined with a mean t1/2 of 84 hours. 


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1.6. 
Study Rationale 
This is the first time OLP-1002 will be administered to humans. The principal aim of this 
study is to obtain safety and tolerability data when OLP-1002 is administered SC as single 
and multiple doses to healthy subjects. This information, together with the pharmacodynamic 
(PD) data, will help establish the doses and dosing regimen suitable for future studies in 
patients. The analgesic effects of OLP-1002 on a capsaicin-induced pain model will also be 
investigated. 
1.7. 
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 investigational medicinal product 
(IMP), although there may also be some discomfort from collection of blood samples and 
other study procedures. For subjects in the PD assessment groups in Part A there will be 
some additional discomfort from the capsaicin test. More information about the known and 
expected benefits, risks, and reasonably anticipated AEs associated with OLP-1002 may be 
found in the Investigator’s Brochure4. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is to assess the safety and tolerability of single and 
multiple SC doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the PD effect of OLP-1002 following 
single SC doses in healthy volunteers using a capsaicin pain model, and to monitor the effects 
of single SC doses of OLP-1002 on cardiac QT interval. 
2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of AEs 
• vital signs measurements (blood pressure, pulse rate, respiratory rate) 
• 12-lead electrocardiogram (ECG) parameters 
• incidence of clinical laboratory abnormalities, based on clinical chemistry, 
hematology, and urinalysis test results 
• physical examinations 
• injection site assessment. 


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2.2.2. 
Exploratory Endpoints 
The following exploratory objectives will be assessed:  
• pain intensity and duration will be assessed by AUC, maximum pain intensity (Emax), 
and time of maximum pain intensity (tEmax), calculated using a capsaicin-evoked pain 
model. The exploratory endpoint of secondary hyperalgesia will be assessed by the 
area of secondary area of hyperalgesia (Part A only). 
• continuous (24-hour) ECG monitoring will be recorded in this study and archived for 
potential future analysis of OLP-1002 effects on the QT interval (Part A). 
• heat pain threshold measurements and heat pain tolerance measurements. 
3. INVESTIGATIONAL PLAN 
This will be a double-blind, randomized, placebo-controlled, single and multiple SC dose 
study conducted in 2 parts. 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Part A 
Part A will comprise a single-dose, sequential-group design. Overall, 44 healthy subjects will 
be studied in 8 groups. Up to 3 additional groups (24 subjects in total) may be included for 
further assessment of safety, tolerability, and PD (Section 3.3). 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Potential subjects for Groups A2, A4, and A6 will 
attend a pre-screening visit for an intradermal capsaicin test (Section 3.4.2). 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will return 
for non-residential visits on Days 4, 7 (± 2 days), 10 (± 2 days), and 14 (± 2 days), and for a 
poststudy visit on Day 28 (± 2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential visits 
may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond Day 28 (± 2 days). 
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 7 (144 hours postdose) from the lower dose levels. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 3 subjects will receive 
OLP-1002 and 1 subject will receive placebo. To assess PD parameters, Groups A2, A4, and 
A6 will consist of 8 subjects; 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo.  
Sentinel dosing will be employed for all groups in Part A. To maintain the blind in a 
4-subject group, the first subject will be dosed 48 hours before the second subject, and the 


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second subject will be dosed 48 hours prior to the third and fourth subjects. In PD assessment 
groups, 2 subjects (1 active: 1 placebo) will be dosed 48 hours before the remaining 6 
subjects (5 active: 1 placebo). 
An overview of the study design is shown in Figure 1.


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Figure 1: 
Study Schematic (Part A) 
Group A1 
(30 ng SC)
3 active:
1 placebo
Group A2
(120 ng SC)
6 active:
2 placebo
Group A3
(400 ng SC)
3 active:
1 placebo
Group A4
(1.2 µg SC)
6 active:
2 placebo
Group A5
(3 µg SC)
3 active:
1 placebo
Group A6
(6 µg SC)
6 active:
2 placebo
Group A7
(12 µg SC)
3 active:
1 placebo
Group A8
(20 µg SC)
3 active:
1 placebo
Group A9
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A10
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
Group A11
(TBC SC)
3 active:
1 placebo
Or
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
Groups A9 to A11 may be included if required. 
Three groups consist of 8 subjects (6 active: 2 placebo); all other groups will consist of 4 subjects (3 active: 1 placebo).


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The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 8 weeks. 
3.1.2. 
Part B 
Part B will comprise a multiple-dose, sequential-group study. Overall, 24 subjects will be 
studied in 3 groups (Groups B1 to B3), with each group consisting of 8 subjects. Up to 
3 additional groups (24 subjects in total) may be included for further assessment of safety and 
tolerability (Section 3.3).  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (± 2 days), 22 (± 2 days), 25 
(± 2 days), and 29 (± 2 days), and for a poststudy visit on Day 57 (± 2 days). 
In each of Groups B1 to B3, 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo. There will be no sentinel dosing in Part B. For all subjects, a single subcutaneous 
dose will be administered on Days 1, 4, 7, 10, and 13. The dosing frequency in Part B may be 
changed following review of data from groups in Part A (Section 3.4).  
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 18 (120 hours post-final dose) from the lower dose levels. 
Part B may start after a review of the safety and tolerability for Groups A1 to A6. The total 
daily dose administered will not exceed the highest single dose given in Part A. 
An overview of the study design is shown in Figure 2. 
Figure 2: 
Study Schematic (Part B) 
Group B1
(TBC SC)
6 active:
2 placebo
Group B2 
(TBC SC)
6 active:
2 placebo
Group B3
(TBC SC)
6 active:
2 placebo
Group B4
(TBC SC)
6 active:
2 placebo
Group B5 
(TBC SC)
6 active:
2 placebo
Group B6
(TBC SC)
6 active:
2 placebo
 
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
All doses will be confirmed based on results of Part A.  
Groups B4 to B6 will be included if required. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 12 weeks. 


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A Schedule of Assessments is presented in Appendix 6. 
3.2. 
 Start of Study and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, and PD data, additional dose groups may be 
added to the study. Up to 3 further groups of 8 subjects (6 active: 2 placebo) may be included 
in Part A, and up to 3 additional groups of 8 subjects (6 active: 2 placebo) may be included in 
Part B. The requirement for additional groups will be agreed with the Sponsor and 
documented in the Trial Master File (TMF). 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
For both parts of the study, a sequential-group, ascending-dose design has been chosen for 
safety reasons as OLP-1002 is in the early stages of clinical development, with Part A of the 
study being the first time it will be administered to humans. Subcutaneous doses have been 
chosen for both parts of the study, as this is the intended clinical route of administration. 
Healthy male and female subjects will be recruited into this study. The inclusion of females 
of childbearing potential is in accordance with International Council for Harmonisation (ICH) 
M3, based on the short dosing duration (< 2 weeks). 
In Part A, it is anticipated that groups of 4 subjects (3 active: 1 placebo) will be sufficient in 
order to determine safety and tolerability. In order to assess the PD effects of OLP-1002, 
3 groups in Part A will include 8 subjects (6 active; 2 placebo). A full review of the safety 
and tolerability data from Part A will be performed to determine the dose regimen for Part B. 
Part B may start after a full review of all safety and tolerability data from Group A1 to A6. A 
review of PD data may also be performed, at the discretion of the Investigator. Details of the 
dosing regimen and duration used for Part B of the study will be documented in the TMF. 
Based upon the nonclinical data, the duration of a 28-day follow-up in Part A, and a 57-day 
follow-up in Part B is considered adequate to achieve the study objectives. 
Pharmacokinetic analysis will not be conducted in this study. The bioanalytical method used 
for preclinical species has a lower limit of quantification (LLOQ) of 5 ng/mL. The increased 
sample volume possible from humans (compared to small animals) may afford an 
approximate 10-fold increase in sensitivity with possibly an additional 5-fold increase from 
the use of a more sensitive mass spectrometer. This could potentially deliver an LLOQ of 
around 0.1 ng/mL. It is apparent from the predicted plasma concentrations (see Section 3.5.2) 
that only a small number of samples around Cmax at the highest doses would be quantifiable 
and that a conventional approach to pharmacokinetic will not achieve a full definition of the 
plasma concentration vs time profile or enable an estimation of the terminal phase. Thus, the 


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additional burden of sampling procedures would not be justified by the quality of the data 
which it would generate. 
This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications. 
Continuous ECG monitoring will be recorded in this study and archived for potential future 
analysis of OLP-1002 effects on the QT interval, with a view of supporting a potential 
thorough QT study waiver. 
3.4.1. 
Dose Interval 
Following thorough review of all available nonclinical data (pharmacological and 
toxicological), dosing in Part A for groups consisting of 4 subjects will be such that there will 
be 48 hours between the first and second subjects, and 48 hours between the second and 
remaining 2 subjects in each group. For groups in Part A consisting of 8 subjects, 2 subjects 
(1 active: 1 placebo) will be dosed 48 hours prior to the remaining 6 subjects.  
In Part B, all subjects in a group will be dosed on the same day. Accumulation of OLP-1002 
is expected following multiple doses, based on the preclinical data, and will be taken into 
account when determining the doses for Part B (see Section 3.5.3). 
In Parts A and B, there will be a minimum interval of a 10-minute gap between dosing 
subjects (when dosed on the same day). Continuation to dose the remaining subjects in a 
group will be at the Investigator’s discretion. 
3.4.2. 
Pharmacodynamic Assessment 
Pharmacodynamic assessments will be conducted for subjects in Groups A2, A4, and A6. 
Human experimental pain models using healthy volunteers can be used to assess the effect of 
a drug or treatment under controlled clinical conditions. Capsaicin is a vanilloid responsible 
for the pungent taste of hot peppers. In mammalian species, capsaicin-induced pain is 
mediated through Group C nerve fibers following activation of vanilloid 1 transient receptor 
potential (TRPV1) channels5. Nav1.7 has been implicated in controlling neuropeptide release 
from C-fibers, and suppression of capsaicin-induced neurogenic flair has been demonstrated 
by an NAv1.7 inhibitor6. 
Several studies have used intradermal capsaicin for human experimental pain studies7,8. It has 
been possible to demonstrate dose-dependent responses, with intradermal injections of 
100 μg generally agreed to be the ideal dosage for these studies. Intradermal injection of 
capsaicin causes a brief stinging/burning pain at the injection site (spontaneous pain) 
followed by development of secondary hyperalgesia, which can be assessed using equipment 
such as Von Frey hairs. A study by Gazerani et al.5 found that the response was site-specific 


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and while peak pain intensity and duration were greatest in the forehead it was found that 
areas of visible flare and secondary hyperalgesia were significantly larger in the forearm, 
making the forearm the most suitable site for experimentation. 
Covance CRU, Leeds, UK in 2009 performed a validation study using intradermal capsaicin 
(Covance CRU Study: 9999-004) with between-subject and within-subject variability 
demonstrating that the assessments can be reliably conducted to assess pharmacological 
response. 
For these reasons, it has been decided to: 
• Measure both capsaicin-evoked pain and secondary hyperalgesia. 
• Limit the number of capsaicin tests to 3 for each subject (pre-screening, baseline, and 
48 hours postdose) 
• Exclude subjects who have pain <3 or >9 (using a Visual Analogic Scale [VAS]) at 
the pre-screening visit from PD assessment groups. 
3.5. 
Selection of Doses in the Study 
3.5.1. 
Starting Dose 
The rat has been identified as the most sensitive species in a 13-week SC toxicity study with 
a 4-week recovery phase (Covance study no. 8355564). The NOAEL was the 
100 nmol/kg/dose (462.29 µg/kg/dose). This dose level resulted in Cmax of 27.6 ng/mL and 
24.9 ng/mL in males and females, respectively, and AUC0-24 of 174 ng.h/mL and 
128 ng.h/mL in males and females, respectively4. As the exposure was lower in the female 
rats these data have been used to calculate the safety margins. 
The dose of 462.29 µg/kg/dose corresponds to human equivalent doses (HEDs) of 
74.8 µg/kg/dose, which gives a maximum recommended starting dose (MRSD) of 444 µg for 
a 60-kg human and thus a 15000-fold safety margin to the proposed starting dose of 30 ng 
and 22-fold margin to the proposed maximum dose of 20 µg. Additionally the NOAEL dose 
in the cynomolgus monkey was identified as 100 nmol/kg/dose (462.29 µg/kg/dose), which 
gives a higher HED of 150 µg/kg/dose. 
In vivo, doses of 10 pmol/kg/dose (0.0462µg/kg/dose) or less were found to inhibit peripheral 
acute inflammatory pain. The equivalent human dose for a 60-kg human is 44 ng, thus a dose 
at which minimal biological effect is anticipated has been selected as the starting dose of 
30 ng. 
3.5.2. 
Exposure 
Human exposures have been estimated from the pharmacokinetics in the cynomolgus 
monkey since a non-human primate represents the most closely related species. 
Approximately dose-proportional exposure was seen in the 13-week toxicity study (Covance 
study no. 8355565) and 14C pharmacokinetic study (Covance study no. 8355568) over a dose 
range of approximately 1.1 to 100 nmol/kg (5.06 to 462.29 µg/kg)4. However, the lowest 


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dose (5.06 µg/kg) from the 14C study has been used to estimate the human exposures as it is 
closest to the proposed human dose range and has the sufficient quantifiable data. 
The assumptions made in the human exposure estimation were that human exposure would 
be similar to the cynomolgus monkey and that exposure would be linear with dose. Following 
a dose of 5.06 µg/kg in the cynomolgus monkey, the Cmax was 1.96 ng/mL and AUC0-∞ was 
12.7 ng.h/mL. The extrapolated exposures at the planned human doses are shown in Table 1 
with margins calculated to the exposures at the NOAEL in the female rat. 
Table 1: 
Estimated Human Exposure and Safety Margins to the NOAEL in the 
Female Rat for Single Dose Administration of OLP-1002 
Human dose 
Single dose to human 
Safety margins for single dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax 
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin  
to Cmax 
Margin  
to AUC0-∞ 
0.03 
0.000500 
0.000194 
0.00125 
129000 
102000 
0.12 
0.00200 
0.000775 
0.00502 
32100 
25500 
0.4 
0.00667 
0.00258 
0.0167 
9640 
7650 
1.2 
0.0200 
0.0077 
0.0502 
3210 
2550 
3 
0.0500 
0.0194 
0.125 
1290 
1020 
6 
0.100 
0.0387 
0.251 
643 
510 
12 
0.200 
0.0775 
0.502 
321 
255 
20 
0.333 
0.129 
0.837 
193 
153 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
The dosing interval currently anticipated for the multiple-ascending-dose part of this study is 
72 hours or 96 hours. Thus the average dosing interval (82 hours) is similar to the half-life 
determined in the monkey 14C study of 84 hours. Dosing at approximately once per half-life 
would be anticipated to result in accumulation of around 2-fold. However, higher levels of 
accumulation were observed (2.28-fold for Cmax and 3.76-fold for AUC0-24) on Day 88 at the 
top dose group (100 nmol/kg, 462.28 µg/kg) in the 13-week cynomologus monkey toxicity 
study following twice-weekly dosing (every 72 or 96 hours). Calculations were performed to 
estimate the likely human half-life using a standard 1-point allometric approach from the 14C 
cynomolgus monkey pharmacokinetic study data. The exponents used were 0.75 for apparent 
total plasma clearance (CL/F) and 1 for apparent volume of distribution (Vz/F) values 
combined with the average body weight of the animal (3.1 kg) and scaling to a 60 kg human 
9–11. This resulted in a human half-life estimate of 180 h which in turn gave an accumulation 
estimate of 3.7-fold based upon a dosing interval of 82 h. This further supports the use of the 
greater than 2-fold accumulation from the 13-week cynomolgus study to estimate exposure 
following multiple dosing. Multiplication of the exposure estimates for the single ascending 
dose by 2.28 for Cmax and 3.76 for AUC resulted in exposure estimates for multiple dosing 
presented in Table 2. 
 
 


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Table 2: 
Estimated Human Exposure and Safety Margin to the NOAEL in the 
Female Rat for Multiple Dose Administration of OLP-1002 
Human dose 
Multiple dose to human 
Safety margins for multiple dose 
 
 
(µg) 
 
 
(µg/kg) 
Predicted  
Cmax  
(ng/mL) 
Predicted 
AUC0-∞ 
(ng.h/mL) 
Margin 
to Cmax 
Margin 
to AUC0-τ,ss 
0.03 
0.000500 
0.000442 
0.00472 
56000 
27000 
0.12 
0.00200 
0.00177 
0.0189 
14100 
6800 
0.4 
0.00667 
0.00589 
0.0629 
4230 
2030 
1.2 
0.0200 
0.017663 
0.189 
1410 
680 
3 
0.0500 
0.0442 
0.472 
560 
270 
6 
0.100 
0.0883 
0.944 
282 
136 
12 
0.200 
0.177 
1.89 
141 
68 
20 
0.333 
0.294 
3.15 
85 
41 
30 
0.500 
0.442 
4.72 
56 
27 
Abbreviations: AUC0-∞ = area under the plasma concentration-time curve extrapolated to infinity; Cmax = maximum 
observed plasma concentration. 
3.5.3. 
Proposed Doses 
The proposed IMP dose levels for Parts A and B are shown in Table 3. 
Table 3: 
Proposed Investigational Medicinal Product Dose Levels for Parts A 
and B 
Study Part 
Group 
Dose (OLP-1002) 
Part A 
A1 
30 ng or placebo 
 
A2 
120 ng or placebo 
 
A3 
400 ng or placebo 
 
A4 
1.2 µg or placebo 
 
A5 
3 µg or placebo 
 
A6 
6 µg or placebo 
 
A7 
12 µg or placebo 
 
A8 
20 µg or placebo 
 
A9* 
TBC or placebo 
 
A10* 
TBC or placebo 
 
A11* 
TBC or placebo 
 
 
 
Part B 
B1 
TBC or placebo 
 
B2 
TBC or placebo 
 
B3 
TBC or placebo 
 
B4* 
TBC or placebo 
 
B5* 
TBC or placebo 
 
B6* 
TBC or placebo 
Abbreviations: TBC = to be confirmed 
* groups to be included if required. 
In Parts A and B, there should not be an increase of > 3-fold between dose levels above 
120 ng. 


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For Part B, dose levels, dosing frequency, and dosing duration will be decided, in 
consultation with the Sponsor, on the basis of data from Part A of the study. Since predictions 
of human exposure of OLP-1002 suggest that OLP-1002 concentrations may be not be 
quantifiable and human data have been estimated from a single species, it is proposed that the 
highest dose in the multiple-ascending-dose part will be up to 50% of the highest dose in the 
single-ascending-dose part (ie, if the highest dose in the single-ascending-dose part is 20 µg, 
the highest dose in the multiple-ascending-dose part will be 10 µg). Therefore, if the 
predicted accumulation of 3.7-fold occurs, the highest exposure in the multiple-ascending-
dose part will not exceed ~2-fold the maximum exposure in the single-ascending-dose part. 
Details of all doses administered in Parts A and B of the study will be documented in the 
TMF. 
3.6. 
Dose Escalation 
In Part A, doses will be administered in an escalating manner following satisfactory review 
by the Sponsor and Investigator of the safety and tolerability data up to Day 7 (144 hours 
postdose) from groups that received lower doses of OLP-1002. 
In Part B, doses will be administered in an escalating manner following satisfactory review of 
safety and tolerability data up to Day 18 (120 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and may be lower than the starting 
dose. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups A1, 
A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, and A6) have been reviewed from the 
previous lower dose group, such that data from a minimum of 5 subjects who have received 
OLP-1002 will be used to make the dose-escalation decision. Dose escalation in Part B will 
only occur if data from a minimum of 6 subjects have been reviewed from the previous lower 
dose group, such that data from a minimum of 4 subjects who have received OLP-1002 will 
be used to make the dose-escalation decision. 
The justification for this is as follows: 
• The study drug is of a known pharmacological class for which the on-target effects in 
humans are well characterized. Based upon nonclinical data, no clinically important 
off-target effects are expected within the proposed dose range. 
• A minimum of 3 subjects receiving the active drug is considered sufficient to 
characterize the safety profile for OLP-1002. 
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarizing 
results from all available safety assessments, will be sent to the Sponsor and a dose-escalation 
meeting will occur prior to the start of each successive group. Any clinically significant 
results will be discussed with the Sponsor before dose escalation continues. Interim PD data 
may also be reviewed on an ongoing basis. In the event of a disagreement between Sponsor 
and Investigator on the dose-escalation decision, the decision of the Investigator will be 
upheld. 


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3.7. 
Dose Escalation Stopping Criteria 
In Parts A and B, following consultation with the Sponsor, dose escalation will be stopped if: 
• Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in 
a group that, in the opinion of the Investigator, warrant stopping of dose escalation. 
• There is evidence of clinically significant increases in liver function tests (aspartate 
aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin) 
defined as 3 times the upper limit of normal in 3 or more subjects in a group 
(confirmed with repeat testing). 
• QT interval corrected for heart rate using Fridericia’s method (QTcF) 
increases > 60 msec compared to baseline (predose for Part A or Day 1 predose for 
Part B) and/or absolute QTcF values > 500 msec (confirmed by repeat measurement) 
in 2 or more subjects in a group. 
• Tachycardia (> 150 beats/min) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 2 occasions within a 24-hour interval in at least 2 subjects 
in a group. 
• Severe hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 110 mmHg) in the resting supine position (confirmed by 2 repeat 
measurements) on at least 2 occasions within a 24-hour interval in at least 2 subjects 
in a group. 
If the sponsor deems it appropriate to resume dosing after the internal safety review, it 
can be done after the approval of a substantial protocol amendment. 
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. Healthy male or females of any race, between 18 and 60 years of age, inclusive. 
2. Body mass index (BMI) between 18.0 and 28.0 kg/m2, inclusive. 
3. In good health, determined by no clinically significant findings from medical history, 
physical examination, single 12-lead ECG (resting heart rate > 45 bpm and 
< 90 bpm), vital signs measurements, and clinical laboratory evaluations (congenital 
nonhemolytic hyperbilirubinemia [eg, suspicion of Gilbert’s syndrome based on total 
and direct bilirubin] is not acceptable) at Screening as assessed by the Investigator (or 
designee).  
4. Willing to abide by the contraception requirements as detailed in Appendix 4. 
5. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 


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4.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
Screening visit unless otherwise stated: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
3. Any of the following: 
• QTcF > 450 ms confirmed by repeat measurement. 
• QRS duration > 110 ms confirmed by repeat measurement. 
• PR interval > 220 ms confirmed by repeat measurement. 
• findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
• history of additional risk factors for torsades de pointes (eg, heart failure, 
hypokalemia, family history of long QT syndrome). 
4. History of alcoholism or drug/chemical abuse within 1 year prior to Screening. 
5. Alcohol consumption of > 21 units per week for males and >14 units per week for 
females. 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. 
6. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) 
at Screening or Check-in. 
7. Positive hepatitis panel and/or positive human immunodeficiency virus test 
(Appendix 2). 
8. Active skin conditions such as dermatitis, allergy, eczema, psoriasis, or abnormal 
healing. 
9. Tattoos, scars, or moles that in the opinion of the Investigator are likely to interfere 
with dosing or study assessments at any of the potential injection sites. 
10. Participation in a clinical study involving administration of an investigational drug 
(new chemical entity) in the past 90 days or 5 half-lives of the investigational product, 
whichever is longer, prior to Check-in. 
11. Use or intend to use any medications/products known to alter drug absorption, 
metabolism, or elimination processes, including St. John’s wort, within 30 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee). 
12. Use or intend to use any prescription medications/products other than hormone-
replacement therapy, oral, implantable, transdermal, injectable, or intrauterine 


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contraceptive concomitant medications within 14 days prior to Check-in, unless 
deemed acceptable by the Investigator (or designee). 
13. 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). 
14. Use or intend to use any nonprescription medications/products including vitamins, 
minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior 
to Check-in, unless deemed acceptable by the Investigator (or designee) and/or 
Sponsor have given their prior consent. 
15. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.  
16. Receipt of blood products within 60 days prior to Check-in. 
17. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening.  
18. Poor peripheral venous access. 
19. Have previously completed or withdrawn from this study or any other study 
investigating OLP-1002, and have previously received the investigational product. 
20. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
21. Part A – PD assessment groups only 
• Subjects considered non-acceptable responders to the intradermal capsaicin 
test at screening, defined as maximum VAS score of < 3.0 or > 9.0. 
4.3. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomization. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (eg, in Part A, Subjects 101, 102, 
etc., in Part B Subjects 201, 202, etc.). Replacement subjects (Section 4.4) will be assigned a 
subject number corresponding to the number of the subject he/she is replacing plus 1000 
(eg, Subject 1101 replaces Subject 101). 
Subjects will be identified by subject number only on all study documentation. A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.4. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
• noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
• any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 


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If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the 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 stabilized. 
Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of AEs 
thought to be related to the study drug will generally not be replaced. 
4.5. 
Study Termination 
The study may be discontinued at the discretion of the Investigator (or designee), Sponsor, or 
Sponsor’s Medical Monitor if any of the following criteria are met: 
• 
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) 
• 
medical or ethical reasons affecting the continued performance of the study 
• 
difficulties in the recruitment of subjects 
• 
cancelation of drug development. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
Vials of OLP-1002 Injection Solution 100 µg/mL (1.5 mL in 5-mL vials) and the Diluent for 
OLP-1002 Injection Solution (5 mL in 10-mL vials) will be supplied by the Sponsor, along 
with the batch/lot number and Certificate of Analysis. The Diluent for OLP-1002 Injection 
Solution will also be used as the Placebo formulation. A certificate of batch certification and 
release, authorized by a Qualified Person in the European Union (EU) will also be issued, by 
a Covance CRU Qualified Person, for each batch of IMP imported into the EU. 
The IMPs will be stored according to the instructions on the label at the CRU in a location 
that is locked with restricted access. 
Dose solutions (OLP-1002 Injection Solution diluted with the Diluent for OLP-1002 
Injection Solution) will be prepared by Covance CRU Pharmacy staff in accordance with 
instructions provided in the Pharmacy Manual. The Placebo formulation will be the Diluent 
for OLP-1002 Injection Solution without further manipulation. 


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5.2. 
Study Treatment Administration 
Subjects will be administered the IMP in numerical order. OLP-1002 will be administered by 
SC injection in the upper arm. If subcutaneous dosing of OLP-1002 in the upper arm is not 
possible, the subject may be dosed in the abdomen at the Investigator’s discretion. For 
subjects in Groups A2, A4, and A6, dosing will be on the opposite arm to the intradermal 
capsaicin test. 
5.3. 
Randomization 
The randomization code will be produced by the statistics department at Covance using a 
computer-generated pseudo-random permutation procedure. In Part A, 1 subject in groups 
consisting of 4 subjects, and 2 subjects in groups consisting of 8 subjects, will be randomly 
assigned to receive placebo. In Part B, 2 subjects per group will be randomly assigned to 
receive placebo. All other subjects in a group will be randomized to receive OLP-1002. 
Prior to the start of the study, a copy of the master randomization code will be supplied into 
the Covance CRU pharmacy staff (in sealed envelopes). 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
• The placebo solution will be identical in appearance to the OLP-1002. 
• The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 
To maintain the blind, the Investigator will be provided with sealed randomization 
code-break envelopes for each subject, containing details of their treatment. These individual 
sealed envelopes will be kept in a limited access area that is accessible 24 hours a day. In 
order to manage subject safety or to support dose-escalation decisions (in the event of 
possibly treatment-related SAEs or severe AEs), the decision to unblind resides solely with 
the Investigator. Whenever possible, and providing it does not interfere with or delay any 
decision in the best interest of the subject, the Investigator will discuss the intended code-
break with the Sponsor. If it becomes necessary to break the code during the study, the date, 
time, and reason will be recorded in the subject’s source data and on the individual envelope 
and will be witnessed by a second person. 
5.5. 
Treatment Compliance 
All doses of IMP will be administered by suitably qualified study site staff. 
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 


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will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused 
assembled unit doses will be retained until completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription medications/products from 14 days prior to 
dosing until the Follow-up visit, and non-prescription medications/products from 7 days prior 
to dosing until the Follow-up visit, unless the Investigator (or designee) and/or Sponsor have 
given their prior consent.  
Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone-replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary 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 standardized 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 safety laboratory tests. On dosing days, 
subjects will receive a light breakfast approximately 2 hours prior to dosing. Meals will be 
provided as appropriate at other times and water will be freely available at all times. 
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be 
allowed from 7 days prior to Check-in until the Follow-up visit. 
Xanthine-containing foods and beverages will not be allowed from 36 hours before Check-in 
until Discharge from the site. Xanthine-containing foods and beverages will also not be 
allowed form 36 hours before non-residential site visits. 
Chili pepper/hot sauce will not be allowed for 48 hours prior to Check-in for all subjects. 
Subjects in Groups A2, A4, and A6 will not be allowed chili pepper/hot sauce for 48 hours 
prior to their pre-screening visit. 
Consumption of alcohol will not be permitted from 36 hours prior to Check-in until 
Discharge. Following discharge, up to 2 units/day of alcohol are permitted until 36 hours 
before each non-residential visit and the Follow-up visit. 


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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 3 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. Subjects should not be in receipt of blood products for 
60 days prior to check-in. 
6.6. 
Other Restrictions 
Subjects in Groups A2, A4, and A6 will not be allowed to shower within 1 hour prior to the 
capsaicin-evoked pain tests at prescreening, predose, and postdose. 
Subjects will not be allowed to apply moisturizing creams or oils to the dosing site within 
1 hour prior to dosing, or to the assessment site within 1 hour prior to the capsaicin-evoked 
pain test.  
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): 
• dosing 
• vital signs 
• blood samples 
• cardiac monitoring/ECG extractions 
• any other procedures. 


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7.1. 
Pharmacodynamic Assessments 
Capsaicin intradermal test will be performed for subjects in Groups A2, A4, and A6. Each 
subject will be tested at a pre-screening visit before being tested twice during the study (1 
predose and 1 postdose). 
7.1.1. 
Capsaicin-evoked Pain Model 
The capsaicin model will be conducted by intradermal injection of capsaicin (100 μg in 
100 μL of sterile saline containing 8% [w/w] Tween 80) into the skin of the anterior aspect of 
the forearm, midway between the elbow and the wrist. The bleb area (wheal) will be a sign of 
local plasma extravasation. An assessment of the pain intensity related to capsaicin injection 
will be estimated by repeated use of a VAS from injection to 5 minutes post-injection or until 
the pain intensity returned to zero. The AUC, Emax, and tEmax will be calculated and reported 
using dedicated software. 
7.1.2. 
Secondary Hyperalgesia 
The area of secondary hyperalgesia will be quantified with a 60-g weighted von Frey hair, by 
stimulating along 8 linear paths (4 vectors crossing at the location of the injection site) 
arranged vertically and horizontally around the stimulation site in 5-mm steps (starting 
approximately 6 cm away from the injection site). The area of secondary hyperalgesia will be 
evaluated at 5 and 30 minutes post-capsaicin injection. 
7.2. 
Safety and Tolerability Assessments 
Safety and tolerability assessments will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). Timepoints may be adjusted based on an ongoing review of the 
data, and additional assessments may be conducted if deemed necessary by the Investigator 
or designee. 
7.2.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs 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. 
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 drug. 


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Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. 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 (including 
clinical chemistry, hematology, urinalysis, and serology) at the times indicated in the 
Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a follicle-stimulating hormone (FSH) test and 
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, respiratory rate, and 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. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. 
Subjects must be supine for at least 5 minutes before blood pressure, pulse rate, and 
respiratory rate measurements. 
7.2.4. 
Electrocardiogram 
7.2.4.1. 
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: 
• QTcF value > 500 msec 
• QTcF change from the mean baseline (Day 1 predose) is > 60 msec. 


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Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated once if outside the relevant 
clinical reference ranges. 
7.2.4.2. 
Continuous (24-hour) Electrocardiogram 
At the times indicated in the Schedule of Assessments (Appendix 6), continuous (24-hour) 
ECGs will be performed.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint. Each extraction will last for 5 minutes. 
Environmental distractions (eg, television, playing games, radio, conversation) should be 
avoided during the pre-ECG time window.  
Continuous 24-hour ECGs are not planned for Part B of the study but may be implemented if 
any clinically significant findings are identified in the data from Part A. 
7.2.5. 
Heat Pain Threshold Test 
Heat pain threshold tests will be conducted at the times indicated in the Schedule of 
Assessments (Appendix 6). 
A computer-controlled thermal sensory analyzer device will be used to measure the heat pain 
threshold and tolerance level of the subjects. The heat pain assessments will be conducted on 
the subject’s thigh. 
Heat Pain Threshold: 
For heat pain threshold measurements, the thermode will be placed directly on the skin of the 
right thigh, within an area selected before the start of the experiment and defined by surgical 
marking. The thermode will have a baseline temperature of 32 °C, and will be programmed to 
gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 
their dominant hand, to indicate when the heat pain threshold (first sensation of heat pain) is 
reached by pushing a button. At that time, the test will be stopped and the temperature 
returned to baseline within 1 second. This process will be repeated a further 2 times, with an 
interval of at least 1 minute between measurements (from start to start). The computer will 
record the average value of 3 experiments. 
Heat Pain Tolerance: 
For heat pain tolerance measurements, the thermode will be placed within the same surgically 
marked skin area of the anterior side of the right thigh, which was used to assess heat pain 
threshold. The thermode will have a baseline temperature of 32 °C, and will be programmed 


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to gradually increase at a rate of 1.0 °C per second. The subject will be given a controller in 
their dominant hand, to indicate when the heat-evoked pain has reached an intensity that is no 
longer tolerable, by pushing a button. At that time, the test will be stopped and the 
temperature returned to baseline within 1 second. This process will be repeated a further 
2 times, with an interval of at least 1 minute between measurements (from start to start). The 
computer will record the average value of 3 experiments. 
Safety Precautions 
As there is a risk that OLP-1002 may affect the heat pain threshold, Covance CRU will put 
appropriate safety measures in place to ensure that subjects are not exposed to extremes of 
temperature when taking a shower or consuming hot drinks. During the heat pain safety 
assessments, the cut-off temperature for either test is 53 °C in order to prevent skin injury. 
7.2.6. 
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.  
7.2.7. 
Body Weight and Height 
Body weight (in underclothes) and height will be recorded at the times indicated in the 
Schedule of Assessments in Appendix 6. BMI will be calculated using the following formula: 
BMI = body weight (kg)      (kg/m2) 
                  (height [m])2 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time OLP-1002 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. In order to achieve PD endpoints 
in Part A, additional subjects will be included in 3 groups (8 subjects in total; 6 active: 
2 placebo). Up to 3 additional groups may be added to Part A, consisting of either 4 subjects 
(3 active; 1 placebo) or 8 subjects (6 active; 2 placebo). Up to 3 additional groups of 
8 subjects may be added to Part B (6 active; 2 placebo). 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of study treatment 
OLP-1002 or placebo and for whom PD can be evaluated. 


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8.2.2. 
Safety Population 
The safety population will include all subjects who received at least 1 dose of study treatment 
OLP-1002 or placebo and have at least 1 postdose safety assessment. 
8.3. 
Pharmacodynamic Analyses 
Pharmacodynamic parameters will be listed and summarized using descriptive statistics. No 
formal statistical analysis of PD data is planned. 
8.4. 
Safety Analysis 
Safety parameters will be listed and summarized using descriptive statistics. No formal 
statistical analysis of safety data is planned. Each AE will be coded using the Medical 
Dictionary for Regulatory Activities. 
9. REFERENCES 
1.  Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, et al. An SCN9A 
channelopathy causes congenital inability to experience pain. Nature. 2006 Dec 
14;444(7121):894–8.  
2.  Goldberg YP, Price N, Namdari R, Cohen CJ, Lamers MH, Winters C, et al. Treatment of 
Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel 
blocker. Pain. 2012 Jan;153(1):80–5.  
3.  Jones HM, Butt RP, Webster RW, Gurrell I, Dzygiel P, Flanagan N, et al. Clinical Micro-
Dose Studies to Explore the Human Pharmacokinetics of Four Selective Inhibitors of 
Human Nav1.7 Voltage-Dependent Sodium Channels. Clin Pharmacokinet. 
2016;55(7):875–87.  
4.  Investigator Brochure - OLP-1002. 2018.  
5.  Gazerani P, Andersen OK, Arendt-Nielsen L. Site-specific, dose-dependent, and sex-
related responses to the experimental pain model induced by intradermal injection of 
capsaicin to the foreheads and forearms of healthy humans. J Orofac Pain. 
2007;21(4):289–302.  
6.  Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, et al. 
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in 
Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release. PLoS ONE 
[Internet]. 2016 Apr 6 [cited 2018 Jun 15];11(4). Available from: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822888/ 
7.  Scanlon GC, Wallace MS, Ispirescu JS, Schulteis G. Intradermal capsaicin causes dose-
dependent pain, allodynia, and hyperalgesia in humans. J Investig Med Off Publ Am Fed 
Clin Res. 2006 Jul;54(5):238–44.  


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8.  Anderson WS, Sheth RN, Bencherif B, Frost JJ, Campbell JN. Naloxone increases pain 
induced by topical capsaicin in healthy human volunteers. Pain. 2002 Sep;99(1–2):207–
16.  
9.  Pharmacokinetics and Metabolism in Drug Design, 3rd Edition [Internet]. Wiley.com. 
[cited 2018 Aug 21]. Available from: https://www.wiley.com/en-
us/Pharmacokinetics+and+Metabolism+in+Drug+Design%2C+3rd+Edition-p-
9783527329540 
10.  Mahmood I. Pharmacokinetic allometric scaling of antibodies: application to the first-in-
human dose estimation. J Pharm Sci. 2009 Oct;98(10):3850–61.  
11.  Offman E, Edginton AN. Pharmacokinetic Time Course Scaling of a Subcutaneously 
Administered Pegylated Peptide Conjugate for a First-in-Human Investigation. Eur J 
Drug Metab Pharmacokinet. 2017 Feb;42(1):69–78.  
 
 


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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 unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:  
• Mild: Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of daily 
living. 
• Moderate: Usually alleviated with additional specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but posing no 
significant or permanent risk of harm to the subject. 
• 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 drug using a 4-category system according to the following guidelines: 
• Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
• 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. 
• 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. 
• Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized 
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 
stabilized. 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: 
• results in death 
• is life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
• results in a congenital anomaly/birth defect 
• results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize 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 Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization 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 
Covance Drug Safety Services (DSS) Europe, Maidenhead, UK are 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 facsimile or email to 
DSS and the Sponsor immediately (within 24 hours) upon becoming aware of an SAE. 
The responsibilities of Covance DSS include the following: 
• Prepare an AE reporting plan prior to the start of the study. Where this plan differs 
from the applicable CRU standard operating procedure on SAE reporting, the Safety 
Management Plan will always take precedence. 
• Receive and review SAE report forms from the CRU and inform the Sponsor of the 
SAE within 2 working days of the initial notification to DSS. Drug Safety Services 
will delete any information from the SAE report forms that may identify the subject. 
• Write case narratives and enter the case into Covance’s safety database as defined in 
the AE reporting plan. 
• Produce appropriate reports of all Suspected Unexpected Serious Adverse Reactions 
and forward to the Ethics Committee, Medicines and Healthcare Products Regulatory 
Agency, Principal 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. 
Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfill regulatory requirements any pregnancy reported by female subjects or 


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the female partners of male subjects should be reported following the SAE process to collect 
data on the outcome for both mother and fetus. 
 
 


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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Inorganic phosphate 
Potassium  
Sodium  
Total bilirubin 
Total protein 
Urea 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
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  
Serologya: 
Drug screenb: 
Hormone panel - females 
only: 
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) antibodies 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants 
Cotinine test 
MDMA 
Alcohol breath test 
Follicle-stimulating hormonea  
Serum pregnancy test (human 
chorionic gonadotropin)a 
Urine pregnancy testc 
a Only analyzed at Screening. 
b Only analyzed at Screening and Check-in. 
c 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. 
Part A 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
4 
30 
Serology 
3.5 
1 
3.5 
Total: 
33.5 
Part B 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations (excluding 
serology) 
7.5 
10 
75 
Serology 
3.5 
1 
3.5 
Total: 
 
 
78.5 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
during the study will not exceed that donated during a standard blood donation 
(approximately 500 mL). 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 48 of 59 
Appendix 4: Contraception Guidance 
Definitions 
Females of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Females of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 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-estrogens, or selective estrogen 
receptor modulators.  
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. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary highly effective and 1 secondary method) of birth control from the time of signing 
the informed consent form until 90 days after the Follow-up visit. Primary highly effective 
methods of contraception include:  
• surgical method performed at least 3 months prior to the Screening visit:  
o bilateral tubal ligation  
o Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes  
• hormonal implant eg, Implanon (as prescribed)  
• hormonal or non-hormonal intrauterine device with appropriate re-insertion period (as 
prescribed) 
• vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject). 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 49 of 59 
Secondary (barrier) methods of contraception include:  
• male condom with spermicide 
• female condom with spermicide  
• over-the-counter sponge with spermicide 
• cervical cap with spermicide (as prescribed) 
• diaphragm with spermicide (as prescribed). 
Female subjects can only choose a cervical cap or diaphragm if they have already had a 
prescription and fitting by their healthcare provider to ensure protocol requirements are met. 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (ie, male condom with spermicide) in addition to 
a second method of acceptable contraception from Check-in until 90 days after the Follow-up 
visit. Acceptable methods of contraception include: 
• hormonal injection 
• combined oral contraceptive pill or progestin/progestogen-only pill 
• combined hormonal patch 
• combined hormonal vaginal ring 
• surgical method (bilateral tubal ligation or Essure® [hysteroscopic bilateral tubal 
occlusion])  
• hormonal implant 
• hormonal or non-hormonal intrauterine device 
• over-the-counter sponge with spermicide 
• cervical cap with spermicide 
• diaphragm with spermicide 
• vasectomised male subject (sterilization 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. 
 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 50 of 59 
Sexual Abstinence and Same-sex Relationships 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 51 of 59 
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: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
• Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the 
Investigator and reviewed and approved by the EC before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct 
of the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any nonsubstantial changes, as defined by 
regulatory requirements.  
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 
study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with Clinical Research Unit personnel, subjects will sign 
2 copies of the ICF in the presence of a suitably trained member of staff to indicate that they 
are freely giving their informed consent. One copy will be given to the subject, and the other 
will be maintained in the subject’s records. 
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 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 52 of 59 
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 Organization (CRO) auditors or other 
authorized personnel appointed by the Sponsor, by appropriate EC members, and by 
inspectors from regulatory authorities. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All 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.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• The Investigator must permit study-related monitoring, audits, EC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Covance is responsible for the data management of this study including quality 
checking of the data. Predefined agreed risks, monitoring thresholds, quality tolerance 
thresholds, controls, and mitigation plans will be documented in a risk management 
register. Additional details of quality checking to be performed on the data may be 
included in a Data Management Plan. 
• A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized 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. 
• 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.  


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 53 of 59 
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 Code of Federal 
Regulations 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 the Covance electronically, will be integrated with the subject’s eCRF data in 
accordance with the Data Management Plan. 
An eCRF must be completed for each enrolled and randomized subject, according to the 
eCRF completion instructions. The Sponsor, or CRO, will review the supporting source 
documentation against the data entered into the eCRFs to verify the accuracy of the electronic 
data. The Investigator will ensure that corrections are made to the eCRFs and that data 
queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 
information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


Protocol
CONFIDENTIAL
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 54 of 59 
Appendix 6: Schedule of Assessments 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 55 of 59 
Study Plan – Part A (Single Dose) 
Pre- 
screeningd
Screening 
Day 
-2 
Day 
 -1 
Days 1 to 3 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Inclusion/exclusion criteria 
X 
Demographic data 
X 
Medical history 
X 
Urine drugs of abuse screen 
X 
X
Alcohol breath test 
X 
X
Cotinine test 
X 
X 
Serology
 
X
Hormone panel 
X 
Urine pregnancy testa 
X 
X
X
Informed consent
X
X
Study residency:
Check-in
X
Check-out 
Day 3 (48 hours 
postdose) 
Non-residential visit
X
X
X 
X
X
X
X
Study drug administration: 
Day 1 (0 hours)  
Safety and tolerability: 
Adverse event recording 
X 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording 
X 
X 
X
 
Ongoing
X 
X
X
X
X
Supine blood pressure, pulse 
rate, respiratory rate, and 
body temperature
X 
Predose, 1, 2, 4, 
8, 24 (± 1 hour), 
and 48 hours 
postdose 
X 
X 
X 
X 
X 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 56 of 59 
Pre- 
screeningd
Screening 
Day
-2 
Day 
 -1 
Day 
4 
Day 7 
(± 2 days) 
Day 10 
(± 2 days) 
Day 14 
(± 2 days) 
Poststudy 
(Day 28 
± 2 days) 
Supine 12-lead ECG 
X 
X
X
X
Continuous ECG 
extractionb,c
-24,
-23.5,  
-23,  
-22.5,  
-22,  
-21.5,  
-21,  
-20, 
-18,  
-16,  
-12 
hours 
     Days 1 to 3 
Predose, 4, 24     
(± 1 hour) and 48 
hours postdose 
Day 1: Predose, 
0.5, 1, 1.5, 2, 2.5, 
3, 4, 6, 8, and 12 
hours 
Heat pain threshold test 
(heat pain threshold and heat 
pain tolerance) 
Day 1: predose, 2, 
4, 12, and 24 
hours postdose (± 
1 hour) 
Clinical chemistry, 
haematology, and urinalysis 
X 
48 hours postdose 
X 
X 
Height and BMI 
X 
Body weight  
X 
X 
X 
Physical examination 
X
Symptom-directed physical 
examination 
Prior to discharge 
X 
X 
X 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 57 of 59 
Abbreviations: BMI = body mass index; ECG = electrocardiogram. 
a A positive urine pregnancy test result will be confirmed with a serum pregnancy test. 
b All times are relative to dosing with OLP-1002. 
c Continuous ECG recording may begin at approximately 25 hours before dosing to allow for checks to be completed prior to the first extraction timepoint and will continue for 24 hours 
postdose, ie, until after the last timepoint for ECG extraction (24 hours postdose). At timepoints for ECG extractions, subjects will be supinely resting for a total of 15 minutes (10-minute supine 
rest period, 5-minute extraction). Data will be archived for potential future analysis and will not be available for review during the study.  
d Pharmacodynamic assessment groups only. 
Pre- 
screeningd 
Screening
Day
-2
Day 
 -1
Day 
4
Day 7 
(± 2 days)
Day 10 
(± 2 days)
Day 14 
(± 2 days)
Poststudy 
(Day 28 
± 2 days) 
Injection site assessment 
    Days 1 to 3 
Predose, 1, 2, 4, 
8, 24, 48 hours 
postdose 
X
X
X
Pharmacodynamicsd: 
Intradermal capsaicin test 
(capsaicin-evoked pain and 
secondary hyperalgesia 
measurement) 
X 
X 
Day 2 (The area 
of secondary area 
of hyperalgesia 
will be evaluated 
at 5 and 30 
minutes post-
capsaicin 
injection) 


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 58 of 59 
Study Plan – Part B (Multiple Dose) 
Screening 
Day -1 
Days 1-15 
Day 18 
(± 2 days) 
Day 22 
(± 2 days) 
Day 25 
(± 2 days) 
Day 29 
(± 2 days) 
Poststudy 
(Day 57 
± 2 days) 
Inclusion/exclusion criteria 
X
Demographic data
X
Medical history
X
Urine drugs of abuse screen 
X
X
Alcohol breath test 
X 
X
Cotinine test
X 
X
Serology
X
Hormone panel
X
Urine pregnancy testa
X 
X
X
X
X
Informed consent
X
Study residency:
Check-in
 
X
Check-out 
Day 15 (48 hours postdose) 
Non-residential visit
X
X
X
X
X
X
Study drug 
administration: 
Days 1, 4, 7, 10, and 13 
Safety and tolerability: 
Adverse event recording 
X 
X 
Ongoing 
X 
X 
X 
X 
X 
Concomitant medication 
recording  
X
X 
Ongoing 
X
X
X
X
X
Supine blood pressure, 
pulse rate, respiratory rate, 
and body temperature
X
Day 1: predose, 1, 2, 4 and 8 hours 
postdose 
Day 2, Day 4 (postdose), Day 5, Day 7 
(postdose), Day 9, Day 10 (postdose), 
Day 12, Day 13: predose, 1, 2, 4 and 8 
hours postdose, and Day 15 
X
X
X
X
X


Protocol 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Protocol Version 1, 31 August 2018 
Page 59 of 59 
Abbreviations: BMI = body mass index; ECG = electrocardiogram. 
a  Positive urine pregnancy test results will be confirmed with a serum pregnancy test. 
Screening 
Day -1 
Days 1-15 
Day 18 
Day 22 
Day 25 
Day 29 
Poststudy 
(Day 57 
± 2 days) 
Heat pain threshold test 
(heat pain threshold and 
heat pain tolerance) 
X
Day 1 and Day 13: predose, 1, 2, 4, 8, 
24 hours postdose 
Supine 12-lead ECG 
X
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
X
X
X
Clinical chemistry, 
haematology, and 
urinalysis 
X
X
Days 2, 4, 7, 10, 13 
X
X
X
Height and BMI 
X 
Body weight
X 
X
X
Physical examination
X
Symptom-directed physical 
examination 
Days 1, 4, 7, 10, 13 
X
X
X
Injection site assessment 
Day 1: predose and 4 hours postdose 
Day 4: predose and 4 hours postdose 
Day 7: predose and 4 hours postdose 
Day 10: predose and 4 hours postdose 
Day 13: predose and 4 hours postdose 
Day 15 
X
X
X

SAP_001.pdf: 
Document Type: Final Statistical Analysis Plan 
Document Date: 10 October 2019 
Study Title: OLP-1002 – A First-in-human, Double-blind, Placebo-controlled, Single and 
Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic 
Study in Healthy Male and Female Subjects 
Protocol Reference Number: OLP-1002-001 
NCT Number: NCT03760913 


TITLE PAGE 
Statistical Analysis Plan 
OLP-1002 – A First-in-human, Double blind, Placebo controlled, Single 
and Multiple Subcutaneous Dose, Safety, Tolerability, Pharmacokinetic, 
and Pharmacodynamic Study in Healthy Male and Female Subjects 
SAP Version: 1 
SAP Status: Final 
SAP Date: 10 October 2019 
Investigational Product: OLP-1002 
Protocol Reference: OLP-1002-001 
Covance Study: 8379789 
Sponsor: 
OliPass Corporation 
Ace Dongbaek Tower 20th Floor 
16 Beon-gil, 16-4 Dongbaek Jungang-ro 
Giheung-gu, Yongin, Gyeonggi 17015 
Republic of Korea 
Study Site: 
Covance Clinical Research Unit Ltd. 
Springfield House 
Hyde Street  
Leeds, LS2 9LH 
United Kingdom 
Principal Investigator: 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 


SAP 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
Page 2 of 25 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3.1. Primary Endpoints ........................................................................................................... 6 
3.2. Exploratory Endpoints .................................................................................................... 7 
4. STUDY DESIGN................................................................................................................... 8 
4.1. Part A .............................................................................................................................. 8 
4.2. Part B ............................................................................................................................... 9 
5. SAMPLE SIZE JUSTIFICATION ...................................................................................... 10 
6. STUDY TREATMENTS ..................................................................................................... 10 
6.1. Part A ............................................................................................................................ 10 
6.2. Part B ............................................................................................................................. 11 
7. DEFINITIONS OF POPULATIONS .................................................................................. 11 
7.1. All Subjects Population ................................................................................................. 12 
7.2. Safety Population .......................................................................................................... 12 
7.3. Pharmacokinetic Population ......................................................................................... 12 
7.4. Pharmacodynamic Population ....................................................................................... 12 
8. STATISTICAL METHODOLOGY .................................................................................... 12 
8.1. General .......................................................................................................................... 12 
8.1.1. Calculation of the Summary Statistics ................................................................... 12 
8.1.2. Triplicate Readings................................................................................................. 13 
8.1.3. Repeat and Unscheduled Readings ........................................................................ 13 
8.1.4. Definitions of Baseline and Change from Baseline ............................................... 13 
8.2. Subject Disposition and Population Assignment .......................................................... 14 
8.3. Screening Demographics .............................................................................................. 14 
8.4. Prior and Concomitant Medication ............................................................................... 14 
8.5. Pharmacokinetic Assessments ...................................................................................... 14 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 14 
8.5.2. Presentation Pharmacokinetic Plasma Concentration Data.................................... 17 


SAP 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
Page 3 of 25 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 17 
8.6. Pharmacodynamic Assessments (Part A Only)............................................................. 18 
8.6.1. Capsaicin-evoked Pain Model ................................................................................ 18 
8.6.2. Secondary Hyperalgesia ......................................................................................... 18 
8.6.3. Pharmacodynamic Statistical Methodology ........................................................... 18 
8.7. Safety and Tolerability Assessments ............................................................................ 18 
8.7.1. Adverse Events ....................................................................................................... 18 
8.7.2. Clinical Laboratory Parameters .............................................................................. 20 
8.7.3. Vital Signs Parameters ........................................................................................... 20 
8.7.4. 12-lead Electrocardiogram Parameters .................................................................. 20 
8.7.5. Heat Pain Threshold and Tolerance Tests .............................................................. 21 
8.7.6. Injection Site Assessments ..................................................................................... 21 
8.7.7. Other Assessments ................................................................................................. 22 
8.7.8. Safety and Tolerability Statistical Methodology .................................................... 22 
9. INTERIM ANALYSES ....................................................................................................... 23 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 23 
11. REFERENCES .................................................................................................................. 23 
12. APPENDICES ................................................................................................................... 25 


SAP 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
Page 4 of 25 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]). 
ADaM 
analysis data model 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 extrapolated to 
infinity 
AUC0-tlast 
area under the plasma concentration-time curve from time 0 to the time of 
last quantifiable plasma concentration (tlast) 
AUC0-τ 
area under the plasma concentration-time curve calculated over the dosing 
interval (τ) 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CRU 
Clinical Research Unit 
CSR 
clinical study report 
DN 
dose normalized  
ECG 
electrocardiogram 
Emax 
maximum pain intensity 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
not calculated 
NR 
no result 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
R2-adj 
adjusted coefficient for determination of exponential fit 
RAAUC0-τ 
observed accumulation ratio based on AUC0-τ 
RACmax 
observed accumulation ratio based on Cmax 
SAP 
statistical analysis plan 
SC 
subcutaneous  
SD 
standard deviation 


SAP 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
Page 5 of 25 
t1/2 
apparent plasma terminal elimination half-life 
TCP 
temporal change parameter 
TEAE 
treatment-emergent adverse event 
tEmax 
time of maximum pain intensity 
TFL 
table, figure, and listing 
tmax 
time of maximum observed  plasma concentration 
WHODrug 
World Health Organization Drug Dictionary 
%AUCextrap 
percentage of AUC that is due to extrapolation from the last measurable 
plasma concentration to infinity 


SAP 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
Page 6 of 25 
1. INTRODUCTION
This SAP has been developed after review of the clinical study protocol (Final Version 5 
dated 27 September 2019) and electronic case report form. 
This SAP describes the planned analysis of the pharmacokinetic (PK), pharmacodynamic 
(PD), and 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 OliPass Corporation. 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 for this study. When the SAP and 
TFL shells are approved, they will serve as the template for this study’s CSR. 
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 OliPass Corporation and identified in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2 
The document history is presented in Appendix 1. 
2. STUDY OBJECTIVES
The primary objective of the study is to assess the safety and tolerability of single and 
multiple subcutaneous (SC) doses of OLP-1002 in healthy subjects. 
The exploratory objectives of the study are to evaluate the PD effect of OLP-1002 following 
single SC doses in healthy volunteers using a capsaicin pain model, and to monitor the effects 
of single SC doses of OLP-1002 on cardiac QT interval. Where possible, single and/or 
multiple subcutaneous dose PK of OLP-1002 in healthy subjects will be determined. 
3. STUDY ENDPOINTS
3.1. Primary Endpoints 
The primary safety endpoints for this study are as follows: 
●incidence and severity of adverse events (AEs)
●vital signs measurements (blood pressure, pulse rate, respiratory rate)
●12-lead electrocardiogram (ECG) parameters


SAP 
CONFIDENTIAL 
Covance Study: 8379789 
Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
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●incidence of clinical laboratory abnormalities, based on clinical chemistry, hematology,
and urinalysis test results
●physical examinations
●injection site assessment
●demonstrate that exposure to OLP-1002 does not exceed pre-defined exposure limits
from non-clinical studies.
3.2. Exploratory Endpoints 
The following exploratory objectives will be assessed:  
●pain intensity and duration will be assessed by area under the curve (AUC), maximum
pain intensity (Emax), and time of maximum pain intensity (tEmax), calculated using a
capsaicin-evoked pain model. The exploratory endpoint of secondary hyperalgesia will
be assessed by the area of secondary area of hyperalgesia (Part A only).
●continuous (24-hour) ECG monitoring will be recorded in this study and archived for
potential future analysis of OLP-1002 effects on the QT interval (Part A only).
●heat pain threshold measurements and heat pain tolerance measurements.
●For Part A, the single ascending dose, PK outcome endpoints of OLP-1002 are as
follows:
Primary PK
o area under the plasma concentration-time curve (AUC) from time 0 to infinity
(AUC0-∞) (actual and dose normalized [DN])
o AUC from time 0 to the time of the last quantifiable concentration (AUC0-tlast)
(actual and DN)
o maximum observed plasma concentration (Cmax) (actual and DN)
Secondary PK 
o time of the maximum observed plasma concentration (tmax)
o apparent plasma terminal elimination half-life (t1/2)
●For Part B, the multiple ascending dose PK outcome endpoints of OLP-1002 are as
follows:
Primary PK
o AUC over a dosing interval (AUC0-τ) (actual and DN)
o AUC0-∞ (actual and DN)


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Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
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o Cmax (actual and DN)
Secondary PK 
o minimum observed plasma concentration (Cmin)
o tmax
o t1/2
o observed accumulation ratio based on AUC0-τ (RAAUC0-τ)
o observed accumulation ratio based on Cmax (RACmax).
o Temporal change parameter (TCP)
Other PK parameters may also be added if deemed necessary. 
4. STUDY DESIGN
This will be a double-blind, randomized, placebo-controlled, single and multiple SC dose 
study conducted in 2 parts. 
4.1. Part A 
Part A will comprise a single-dose, sequential-group design. Overall, 68 healthy subjects will 
be studied in 11 groups.  
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Potential subjects for Groups A2, A4, A6, A9, A10, and 
A11 will attend a pre-screening visit for an intradermal capsaicin test. 
Each subject will participate in 1 treatment period only, and will reside at the Clinical 
Research Unit (CRU) from Day -2 (2 days before dosing) to Day 3. All subjects will return 
for non-residential visits on Days 4, 7 (±2 days), 10 (±2 days), and 14 (±2 days), and for a 
poststudy visit on Day 28 (±2 days). 
Based on the ongoing review of the safety and tolerability, additional non-residential visits 
may be required. The number of additional visits per subject will not exceed 3 and will not 
extend beyond Day 28 (±2 days). 
Doses will be administered in an escalating manner following satisfactory review of safety 
and tolerability data up to Day 10 (216 hours postdose) from the lower dose levels. For doses 
≥12 µg, PK data will also be reviewed up to Day 7 prior to dose escalation. 
In Part A, Groups A1, A3, A5, A7, and A8 will consist of 4 subjects; 3 subjects will receive 
OLP-1002 and 1 subject will receive placebo. To assess PD parameters, Groups A2, A4, A6, 
A9, A10, and A11 will consist of 8 subjects; 6 subjects will receive OLP-1002 and 2 subjects 
will receive placebo.  


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Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
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Sentinel dosing will be employed for all groups in Part A. To maintain the blind in a 
4-subject group, the first subject will be dosed 48 hours before the second subject, and the
second subject will be dosed 48 hours prior to the third and fourth subjects. In PD assessment
groups, 2 subjects (1 active: 1 placebo) will be dosed 48 hours before the remaining 6
subjects (5 active: 1 placebo).
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 8 weeks. 
A schematic of the study design is presented in Figure 1. 
Figure 1: Study Design (Part A) 
Group A1 
(30 ng SC)
3 active:
1 placebo
Group A2
(120 ng SC)
6 active:
2 placebo
Group A3
(400 ng SC)
3 active:
1 placebo
Group A4
(1.2 µg SC)
6 active:
2 placebo
Group A5
(3 µg SC)
3 active:
1 placebo
Group A6
(6 µg SC)
6 active:
2 placebo
Group A7
(12 µg SC)
3 active:
1 placebo
Group A8
(20 µg SC)
3 active:
1 placebo
Group A9
(40 µg SC)
6 active:
2 placebo
Group A10
(80 µg SC)
6 active:
2 placebo
Group A11
(160 µg SC)
6 active:
2 placebo
Active = OLP-1002; SC = subcutaneous 
6 groups consist of 8 subjects (6 active: 2 placebo); all other groups will consist of 4 subjects (3 active: 1 placebo). 
4.2. Part B 
Part B will comprise a multiple-dose, sequential-group study. Overall, 32 subjects will be 
studied in 4 groups (Groups B1 to B4), with each group consisting of 8 subjects. Up to 
2 additional groups (16 subjects in total) may be included for further assessment of safety and 
tolerability. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Each subject will participate in 1 treatment period only 
and reside at the CRU from Day -1 until Day 15. 
All subjects will return for non-residential visits on Days 18 (±2 days), 22 (±2 days), 25 
(±2 days), and 29 (±2 days), and for a poststudy visit on Day 57 (±2 days). 
In each of Groups B1 to B4, 6 subjects will receive OLP-1002 and 2 subjects will receive 
placebo. For all subjects, a single SC dose will be administered on Days 1, 4, 7, 10, and 13. 
Prior to each dosing occasion a physician will review the available safety and tolerability data 
from each subject to confirm it is acceptable to continue dosing. The dosing frequency in Part 
B may be changed following review of data from groups in Part A. 
Sentinel dosing will only occur in Part B at dose levels where exposure to OLP-1002 at 
steady state is predicted to exceed exposures that have been shown to be safe and well 


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Version 1, Sponsor Final, 10 October 2019 
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tolerated in earlier groups in Parts A or B. In the event of sentinel dosing, 2 subjects (1 active, 
1 placebo) will be dosed at least 4 days prior to the remaining 6 subjects (5 active: 1 placebo). 
Safety data for the sentinel subjects from at least 2 additional doses will be reviewed prior to 
dosing the remaining subjects (i.e. sentinel subjects’ safety data after doses 1 and 2 will be 
reviewed prior to the remaining subjects receiving dose 1). In addition, safety data from each 
subject will be reviewed by a physician prior to each dose to approve continued dosing. 
Doses will be administered in an escalating manner following satisfactory review of safety, 
tolerability, and PK data up to Day 22 (216 hours post-final dose) from the lower dose levels. 
Part B may start after a review of the safety, tolerability, and available PK for Groups A1 to 
A6. The total daily dose administered will not exceed the highest single dose given in Part A. 
The total duration of study participation for each subject (from Screening through Follow-up 
visit) is anticipated to be approximately 12 weeks. 
A schematic of the study design is presented in Figure 2. 
Figure 2: Study Design (Part B) 
Group B1
(TBC SC)
6 active:
2 placebo
Group B2 
(TBC SC)
6 active:
2 placebo
Group B3
(TBC SC)
6 active:
2 placebo
Group B4
(TBC SC)
6 active:
2 placebo
Group B5 
(TBC SC)
6 active:
2 placebo
Group B6
(TBC SC)
6 active:
2 placebo
Active = OLP-1002; SC = subcutaneous; TBC = to be confirmed. 
All doses will be confirmed based on results of Part A and previous groups in Part B 
Groups B5 and B6 will be included if required. 
5. SAMPLE SIZE JUSTIFICATION
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time OLP-1002 is being administered to humans. However, the number of subjects in 
each part of the present study is common in early clinical pharmacology studies and is 
considered sufficient to achieve the objectives of the study. As part of Protocol Version 5, 3 
additional groups will be included in Part A (Groups A9, A10, and A11) and 1 additional 
group will be included in Part B (Group B4). Up to 2 additional groups of 8 subjects may be 
added to Part B (6 active; 2 placebo). 
6. STUDY TREATMENTS
6.1. Part A 
The study treatment names and ordering to be used in the TFLs are presented in Table 1. 


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Protocol Reference: OLP-1002-001 
Version 1, Sponsor Final, 10 October 2019 
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Table 1: 
Presentation of Study Treatments in TFLs (Part A) 
Group 
Study Treatment 
Order in TFLs 
A1 to A11 
Placeboa 
1 
A1 
30 ng OLP-1002 
2 
A2 
120 ng OLP-1002 
3 
A3 
400 ng OLP-1002 
4 
A4 
1.2 µg OLP-1002 
5 
A5 
3 µg OLP-1002 
6 
A6 
6 µg OLP-1002 
7 
A7 
12 µg OLP-1002 
8 
A8 
20 µg OLP-1002 
9 
A9b 
40 µg OLP-1002 
10 
A10b 
80 µg OLP-1002 
11 
A11b 
160 µg OLP-1002 
12 
a Placebo will be pooled across all groups 
b Groups to be included if required 
All treatments described above are the planned treatments. The TFLs will reflect the actual 
treatments received, and dose levels will be displayed in increasing order. 
6.2. Part B 
The study treatment names and ordering to be used in the TFLs are presented in Table 2. 
Table 2: 
Presentation of Study Treatments in TFLs (Part B) 
Group 
Study Treatment 
Order in TFLs 
B1 to B6 
Placeboa 
1 
B1 
XX µg OLP-1002 
2 
B2 
XX µg OLP-1002 
3 
B3 
XX µg OLP-1002 
4 
B4b 
XX µg OLP-1002 
5 
B5b 
XX µg OLP-1002 
6 
B6b 
XX µg OLP-1002 
7 
a Placebo will be pooled across all groups 
b Groups to be included if required 
The TFLs will reflect the actual treatments received, and dose levels will be displayed in 
increasing order. The following footnote will be applied in all applicable Part B TFLs: 
“Dosing regimen was a single subcutaneous dose administered on Days 1, 4, 7, 10 and 13.” 
7. DEFINITIONS OF POPULATIONS
Any protocol deviations will be considered prior to database lock for their importance and 
taken into consideration when assigning subjects to populations. 


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7.1. All Subjects Population 
The all subjects population will include all subjects who signed the informed consent form 
(ICF) and had any study assessment recorded in the database per the protocol. 
7.2. Safety Population 
The safety population will include all subjects who received a dose of study treatment 
(OLP-1002 or Placebo).  
7.3. Pharmacokinetic Population 
The PK population will include all subjects who received a dose of study treatment 
(OLP-1002), have at least 1 quantifiable PK concentration, and have had no AEs or protocol 
deviations considered to impact PK.  
7.4. Pharmacodynamic Population 
The PD population will include all subjects who received at least 1 dose of study treatment 
(OLP-1002 or Placebo) and have at least 1 postdose PD assessment. 
8. STATISTICAL METHODOLOGY
8.1. 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. Any subject who discontinued the 
study will be identified accordingly in the listings. Summaries 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 upversioned 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 upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.1 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, baseline derivation, changes from baseline, and any parameter derivations. 
8.1.1. 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.


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Protocol Reference: OLP-1002-001 
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●If number of subjects with valid observations (n) <3, summary statistics will not be
calculated, with the exception of n, minimum, and maximum.
●As Early Termination data is not associated with any scheduled timepoint, it will be
excluded from all calculations of summary statistics.
For categorical data the following rules will be applied: 
●If the categories of a parameter are ordered (eg, AE severity), all categories between the
possible minimum and maximum categories will be included, even if n = 0 for a given
category. If the categories are not ordered (eg, race), only those categories for which
there is at least 1 subject represented will be included.
●Missing values will not be imputed, with the exception of AEs where the ‘worst-case’
approach will be taken (see Section 8.7.1), or 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.
8.1.2. Triplicate Readings 
For vital signs data only, where triplicate readings are taken, the median of triplicate readings 
will replace the original readings in all calculations. 
For electrocardiogram (ECG) data only, where triplicate readings are taken, the mean of 
triplicate readings will replace the original 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 based on the number of readings available. 
8.1.3. Repeat and Unscheduled Readings 
For vital signs and 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, with 
the exception of the ECG outlier analysis (see Section 8.7.4). 
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 8.1.4) and ECG outlier analysis (see Section 10.7.4). 
8.1.4. Definitions of Baseline and Change from Baseline 
The baseline will be defined as the last value recorded prior to dosing (Part A) or the first 
dose (Part B). If the date/time of the value is incomplete or missing, it will be excluded from 


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Version 1, Sponsor Final, 10 October 2019 
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the baseline calculation, unless the incomplete date/time indicates the value was recorded 
prior to dosing (Part A) or the first dose (Part B). 
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from baseline will be 
defined as the mean of the individual changes from baseline for all subjects. 
See Section 8.1.3 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 8.1.2 for more detail on handling of triplicate readings in the 
calculations. 
8.2. Subject Disposition and Population Assignment 
Subject disposition and population assignment will be listed. 
A summary table by treatment will be provided, based on the all subjects population. 
8.3. Screening Demographics 
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed. 
A summary table by treatment will be provided, based on the safety population. 
8.4. Prior and Concomitant Medication 
Prior medication will be defined as medication that ends prior to dosing (Part A) or the first 
dose (Part B). Concomitant medication will be defined as medication that starts after dosing 
(Part A) or the first dose (Part B) or starts but does not end prior to dosing (Part A) or the first 
dose (Part B). 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version March 2018 (or later if upversioned 
during the study). Prior and concomitant medications will be listed. 
8.5. Pharmacokinetic Assessments 
8.5.1. Pharmacokinetic Analysis 
The following PK parameters will be determined where possible from the plasma 
concentrations of OLP-1002 using non-compartmental methods performed using Phoenix 
WinNonlin (Version 8.1 or higher): 
Part A 
Parameter 
Definition 
AUC0-tlast 
area under the plasma concentration-time curve from time 0 to the time of last 
quantifiable plasma concentration (tlast), calculated using the linear trapezoidal rule 
for increasing plasma concentrations and the logarithmic rule for decreasing plasma 
concentrations 


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AUC0-∞ 
area under the plasma concentration-time curve from time 0 extrapolated to infinity 
%AUCextrap
percentage of AUC that is due to extrapolation from the last measurable plasma 
concentration to infinity 
Cmax 
maximum observed plasma concentration 
tmax 
time of maximum observed plasma concentration 
t1/2 
apparent plasma terminal elimination half-life 
Part B 
Parameter 
Definition 
AUC0-τ 
area under the plasma concentration-time curve calculated over the dosing interval 
(τ) 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 extrapolated to infinity 
%AUCextrap
percentage of AUC that is due to extrapolation from the last measurable plasma 
concentration to infinity 
Cmax 
maximum observed plasma concentration 
Ctrough 
concentration observed at the end of the dosing interval 
tmax 
time of maximum observed plasma concentration 
t1/2 
apparent plasma terminal elimination half-life 
RAAUC0-τ
observed accumulation ratio based on AUC0-τ, calculated as AUC0-τ on profile day 
15 / AUC0-τ on profile day 1 
RACmax 
observed accumulation ratio based on Cmax, calculated as Cmax on profile day 15 / 
Cmax on profile day 1 
TCP 
temporal change parameter, calculated as AUC0-τ on profile day 15 / AUC0-∞ on 
profile day 1 
The DN AUC0-∞, DN AUC0-tlast and DN Cmax will be calculated by dividing the original PK 
parameter by dose. 
Additional PK parameters may be determined where appropriate. 
The PK analysis will, where possible, be carried out using actual postdose times recorded in 
the raw data. If actual times are missing, nominal times may be used. 
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of 
concentration and resulting PK parameters, with amount or concentration in the unit, will be 
presented as they are received from the analytical laboratory.  
Cmax and tmax will be obtained directly from the plasma concentration-time profiles. 
For multiple peaks, the highest postdose concentration will be reported as Cmax. In the case 
that multiple peaks are of equal magnitude, the earliest tmax will be reported.  
8.5.1.1. Criteria for handling concentrations below the limit of quantification in 
Pharmacokinetic analysis 
●Concentration values that are below the level of quantification (BLQ) will be set to 0,
with defined exceptions as follows;


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Version 1, Sponsor Final, 10 October 2019 
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o Any embedded BLQ value (between 2 quantifiable concentrations) and BLQ values
following the last quantifiable concentration in a profile will be set to missing for the
purposes of PK analysis.
o If there are late positive concentration values following 2 BLQ concentration values
in the apparent terminal phase, these values will be evaluated. If these values are
considered to be anomalous, they will be set to missing.
o If an entire concentration-time profile is BLQ, the profile will be excluded from the
PK analysis.
o If a predose concentration is missing in Part A or on Day 1 of Part B, these values
may be set to 0 with sponsor approval.
8.5.1.2. Criteria for the Calculation of an Apparent Terminal Elimination Half-Life 
8.5.1.2.1. Number of Data Points 
●At least 3 data points will be included in the regression analysis and preferably should
not include Cmax.
8.5.1.2.2. Goodness of Fit 
●When assessing terminal elimination phases, the adjusted coefficient for determination
of exponential fit (R2-adj) will be used as a measure of the goodness of fit of the data
points to the determined line.
●Regression based parameters (AUC0-∞, t1/2) will only be calculated if the R2-adj ≥0.7.
8.5.1.2.3. Period of Estimation 
●Time period used for the estimation of t1/2, where possible, will be over at least 2
half-lives. The regression listing will include the time period over which the t1/2 was
derived as a ratio of the determined t1/2 for each subject.
●Where an elimination half-life is estimated over a time period <2 half-lives, it will be
flagged in the data listings at the discretion of the pharmacokineticist, and the
robustness of the value should be discussed in the CSR.
8.5.1.3. Calculation of AUC 
●The minimum requirement for the calculation of AUC will be the inclusion of at least 3
consecutive plasma concentrations above the lower limit of quantification (LLOQ),
with at least 1 of these concentrations following Cmax.
●For any partial AUC determination (i.e. AUC over a dosing interval), nominal time will
generally be used for the end of the interval. Actual times for partial AUC intervals
may be used at the discretion of the Pharmacokineticist.


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Protocol Reference: OLP-1002-001 
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●AUC0-∞ values where the percentage extrapolation <20% will be reported. AUC0-∞
values where the percentage extrapolation is between 20 to 30% will be flagged and
included in the summary statistics, whilst AUC0-∞ values where the percentage
extrapolation is >30% will be reported and flagged but excluded from summary
statistics.
●If AUC0-∞ cannot be determined for all subjects or all dose levels, an alternative AUC
measure, such as AUC to a fixed time point, may be used in the assessment of dose
proportionality.
8.5.1.4. Anomalous Values 
●If a value is considered to be anomalous due to being inconsistent with the expected PK
profile, it may be appropriate to exclude this point from the PK analysis. However, the
exclusion of data must have strong justification and will be documented in the raw data
and CSR.
●Embedded BLQ values may be considered anomalous depending on the route of
administration and the characteristics of the drug.
●Positive predose value(s) >5% of Cmax may be excluded from the summary statistics of
PK tables and statistical analysis at the discretion of the pharmacokineticist.
8.5.2. Presentation Pharmacokinetic Plasma Concentration Data 
●The following rules will be applied if there are values that are BLQ or if there are
missing values in a plasma concentration data series to be summarized.
o For the calculation of summary statistics, BLQ values will be set to 0.
o If an embedded BLQ value is considered anomalous within the concentration-time
profile, this value will be excluded from the summary statistics.
o If the value of the arithmetic mean or median is BLQ, these values will be presented
as 0 and the geometric mean and geometric coefficient of variation will not be
calculated.
o Concentrations collected with a time deviation from nominal time >10% will be
reported and flagged but excluded from summary statistics.
8.5.3. Pharmacokinetic Statistical Methodology 
All PK concentrations and parameters will be listed. 
Summary tables, 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 and semi-logarithmic scales, with 
the exception of figures across all days (for Part B only), which will be produced on the linear 
scale only. The +SD bars will be only displayed on the linear scale. 


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Summary tables by treatment will be provided for all PK parameters, with the exception of 
regression-related PK parameters.  
No inferential statistical analyses are planned.  
8.6. Pharmacodynamic Assessments (Part A Only) 
Capsaicin intradermal test will be performed for subjects in Groups A2, A4, A6, A9, A10 and 
A11. Each subject will be tested at a pre-screening visit before being tested twice during the 
study (1 predose and 1 postdose). 
8.6.1. Capsaicin-evoked Pain Model 
The capsaicin model will be conducted by intradermal injection of capsaicin (100 μg in 
100 μL of sterile saline containing 8% [w/w] Tween 80) into the skin of the anterior aspect of 
the forearm, midway between the elbow and the wrist. The bleb area (wheal) will be a sign of 
local plasma extravasation. An assessment of the pain intensity related to capsaicin injection 
will be estimated by repeated use of a VAS from injection to 5 minutes post-injection or until 
the pain intensity returned to 0. The AUC, Emax, and tEmax will be calculated and reported 
using dedicated software. 
8.6.2. Secondary Hyperalgesia 
The area of secondary hyperalgesia will be quantified with a 60-g weighted von Frey hair, by 
stimulating along 8 linear paths (4 vectors crossing at the location of the injection site) 
arranged vertically and horizontally around the stimulation site in 5-mm steps (starting 
approximately 6 cm away from the injection site). The area of secondary hyperalgesia will be 
evaluated at 5 and 30 minutes post-capsaicin injection. 
8.6.3. Pharmacodynamic Statistical Methodology 
All PD data and parameters will be listed. 
Summary tables and mean figures by treatment and timepoint will be provided for all PD 
parameters. 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, 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. 
No inferential statistical analyses are planned. 
8.7. Safety and Tolerability Assessments 
8.7.1. Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 22.0 (or higher if upversioned during the study). 


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A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after dosing (Part A) or the first dose (Part B), or starts prior to dosing (Part A) or the first 
dose (Part B) and increases in severity after dosing (Part A) or the first dose (Part B). 
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. 
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 
dosing TEAEs only. 
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
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
●System organ class, preferred term, day of onset, and treatment (Part B only)
For the AE data the following rules will apply: 
●For the derivation of TEAE status: If the start date/time of an AE is incomplete or
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time or
the end date/time indicates an AE started prior to dosing (Part A) or the first dose
(Part B).
●For the derivation of treatment-related TEAE status: If the study treatment relationship
for a TEAE is missing, a TEAE will be assumed to be a treatment-related TEAE.
●For the derivation of onset time: If the start date/time of an AE is missing, onset time
will not be calculated. If the start date/time of an AE 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 dosing is 01MAY2019/08:00 and recorded start date/time
of an AE is 03MAY2019, then the minimum possible onset time will be calculated by
assuming the an AE 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).


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●For the derivation of duration: 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 the 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).
●For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE
will be counted under the maximum severity possible.
●For the calculation of 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.
8.7.2. 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 treatment and 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, calculation of summary statistics, 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. 
8.7.3. Vital Signs Parameters 
All vital signs parameters, with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged. 
Summary tables and boxplots by treatment and timepoint will be provided for all vital signs 
parameters with changes from baseline. 
8.7.4. 12-lead Electrocardiogram Parameters 
All 12-lead ECG parameters, with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged. 
Summary tables and boxplots by treatment and timepoint will be provided for all 12-lead 
ECG parameters, with changes from baseline. 
An outlier analysis will be performed for QT interval corrected for heart rate using Bazett’s 
formula (QTcB) and QT interval corrected for heart rate using Fridericia’s formula (QTcF). 
The analysis will include all individual original, repeat, and unscheduled postdose values. 


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The maximum postdose values will be summarized by treatment according to the following 
categories: 
●≤450 ms
●>450 and ≤480 ms (all instances flagged in the listing)
●>480 and ≤500 ms (all instances flagged in the listing)
●>500 ms (all instances flagged in the listing)
The maximum increases from baseline will be summarized by treatment according to the 
following categories: 
●≤30 ms
●>30 and ≤60 ms (all instances flagged in the listing)
●>60 ms (all instances flagged in the listing)
8.7.5. Heat Pain Threshold and Tolerance Tests 
Heat pain threshold and tolerance level tests will be conducted using a computer-controlled 
thermal sensory analyzer device on the subject’s thigh. 
For the heat pain threshold and heat pain tolerance tests, each test will be performed 3 times 
at each scheduled timepoint and the computer will record the mean time recording from the 
3 experiments for that timepoint. 
All heat pain threshold and tolerance tests data, with changes from baseline will be listed.
Summary tables by treatment and timepoint will be provided for heat pain threshold and 
tolerance tests data, with changes from baseline. 
8.7.6. Injection Site Assessments 
Injection site assessments will involve evaluation of the dosing site for the following criteria: 
•
Pain will be evaluated according to the following scale:
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Does not 
interfere with 
activity 
Interferes with 
activity or 
repeated use of 
non-narcotic 
pain reliever 
Prevents daily 
activity or 
repeated use of 
narcotic pain 
reliever 
Requires 
medical 
intervention 
greater than 
analgesia 
●Redness will be assessed by estimating the size of the red patch at the injection site
across its widest point, and will be evaluated according to the following scale:


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Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm
25-50 mm
51-100 mm
More than 
100 mm 
Requires 
medical 
intervention 
greater than 
analgesia 
●Swelling will be assessed by estimating the size of the raised area around the injection
site across its widest point, and will be evaluated according to the following scale:
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
0-24 mm
25-50 mm and
does not
interfere with
activity
51-100 mm or
interferes with
activity
More than 
100 mm and 
prevents daily 
activity 
Requires 
medical 
intervention 
greater than 
analgesia 
In addition, how the swelling affects the subject in their daily routing activities will be 
considered. 
●Tenderness will be evaluated using the following scale:
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
None 
Mild pain to 
touch 
Moderate Pain 
to touch 
Severe pain to 
touch 
Requires 
medical 
intervention 
greater than 
analgesia 
●Bruising and ulceration will be evaluated as being present or absent
Local tolerability ratings of ≥Grade 3 and the presence of ulceration will be recorded as an 
AE. 
All injection site assessment data will be listed.
Summary tables by treatment and timepoint will be provided for injection site assessment 
data. 
8.7.7. Other Assessments 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only. 
Medical history will not be listed. 
8.7.8. Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 


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9. INTERIM ANALYSES
In Part A, doses will be administered in an escalating manner following satisfactory review 
by the Sponsor and Investigator of the safety, and tolerability data up to Day 10 (216 hours 
postdose) from groups that received lower doses of OLP-1002. For escalation to doses 
≥12 µg, PK data up to Day 7 (144 hours postdose) will also be reviewed. All available safety, 
tolerability, and PK data from previous groups will be reviewed prior to dose escalation. 
In Part B, doses will be administered in an escalating manner following satisfactory review of 
safety, tolerability, and PK data up to Day 22 (216 hours post-final dose) from groups that 
received lower doses of OLP-1002. Doses may be reduced and may be lower than the starting 
dose. Available safety, tolerability, and PK data from all previous groups will be reviewed 
prior to dose escalation. 
Dose escalation in Part A will only occur if data from a minimum of 4 subjects (Groups A1, 
A3, A5, A7, and A8) or 6 subjects (Groups A2, A4, A6, A9, A10, and A11) have been 
reviewed from the previous lower dose group, such that data from a minimum of 3 or 
4 subjects, respectively, who have received OLP-1002 will be used to make the dose-
escalation decision. Dose escalation in Part B will only occur if data from a minimum of 
6 subjects have been reviewed from the previous lower dose group, such that data from a 
minimum of 4 subjects who have received OLP-1002 will be used to make the dose-
escalation decision. 
The justification for this is as follows: 
●The study drug is of a known pharmacological class for which the on-target effects in
humans are well characterized. Based upon nonclinical data, no clinically important
off-target effects are expected within the proposed dose range.
●A minimum of 3 subjects receiving the active drug is considered sufficient to
characterize the safety profile for OLP-1002.
Between each dose escalation, the Investigator will review all available blinded data to ensure 
it is safe to proceed with the planned dose escalation. An interim safety report, summarizing 
results from all available safety assessments, will be sent to the Sponsor and a dose-escalation 
meeting will occur prior to the start of each successive group. Any clinically significant 
results will be discussed with the Sponsor before dose escalation continues. Interim PD data 
may also be reviewed on an ongoing basis. In the event of a disagreement between Sponsor 
and Investigator on the dose-escalation decision, the decision of the Investigator will be 
upheld.
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES
There were no significant changes from the protocol-specified analyses. 
11. REFERENCES
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9).
5 February 1998.


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Version 1, Sponsor Final, 10 October 2019 
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2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports
(E3). 30 November 1995.


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12. APPENDICES
Appendix 1: 
Document History 
Version, Status 
Date of Change 
Summary/Reason for Change 
Version 1, Final 
NA 
NA; the first version. 
NA = not applicable