Clinical trial NCT04475198
Conditions: Acute, Post-operative Pain
Keywords: Pain
Sponsor: SiteOne Therapeutics, Inc.
Start date: 2021-03-04; Completion date: 2021-08-18
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, double-blind, placebo controlled, study will be conducted to evaluate the safety, tolerability, and pharmacokinetics of ST-2427. Subjects will be randomized to receive a single dose of ST-2427 or placebo in a Single Ascending Dose (SAD) design.

A total of 30 subjects will be enrolled. Subjects will be randomized in a 4:2 ratio of ST-2427 to placebo. Study drug will be blinded to all subjects and investigators.

Detailed description:
This is a Phase 1, randomized, double-blind, placebo-controlled study in healthy adult males and females of non-child-bearing potential to evaluate the safety, tolerability, and pharmacokinetics (PK) of ST-2427. This trial will include careful assessments of treatment effects on vital signs including cardiac and respiratory function and body temperature over a range of doses of ST-2427, administered as single doses. SiteOne Therapeutics, Inc. plans to use the safety, tolerability, and PK findings from this study to inform the doses and study design for Phase 2 clinical studies in subjects with acute post-operative pain.

Approximately 30 subjects, 6 subjects into each of 5 cohorts, will be enrolled in this study at a single clinical site.

Subjects will be randomized 4:2 to receive a single dose of ST-2427 or placebo in a Single Ascending Dose (SAD) design. The Study will evaluate 5 dose strengths of ST-2427, one dose level in each of 5 cohorts of subjects.

Arms: arm 1: 5 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. 2 sentinel subjects will receive dosing for review of safety data (ST-2427 n=1, placebo n=1) before remainder of cohort. arm 2: 10 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. arm 3: 15 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. arm 4: 22 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion. arm 5: 33 mg ST-2427 (n=4) or placebo (n=2) administered once over a 60-minute intravenous (IV) infusion.
Interventions: intervention 1: ST-2427 intervention 2: Placebo
Intervention descriptions: intervention 1: Investigational drug intervention 2: 5% Dextrose Injection

Protocol documents:
Prot_SAP_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single Ascending 
Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ST-
2427 Intravenous Infusion in Healthy Subjects/Development of a Potent and 
Highly Selective NaV1.7 Inhibitor for the Treatment of Acute Pain with the 
Goal of Reducing Opioid Use and Preventing Opioid Use Disorder 
 
PROTOCOL NUMBER: 
ST-2427-CS-001/
 5UG3 DA049599-01 
SPONSOR: 
SiteOne Therapeutics 
SPONSOR CONTACT: 
 
 
MEDICAL MONITOR: 
 
PROTOCOL DATE: 
10 July 2020  
AMENDMENT 1: 
 
23 November 2020 
 
AMENDMENT 2: 
18 December 2020 
AMENDMENT 3: 
25 June 2021 
 
 
STATEMENT OF COMPLIANCE 
This document contains confidential information.  It is intended solely for the use of the Principal 
Investigator, co-Investigators, staff, appropriate Institutional Review Boards or Ethical Committees, and 
other required regulatory bodies. 
 
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SITEONE 
THERAPEUTICS 
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INVESTIGATOR'S AGREEMENT 
I have received and read the Investigator's Brochure for ST-2427. I have read the protocol for 
ST-2427-CS-001/I
 5UG3 DA049599 01 and agree to conduct the study as outlined. I 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol. 
Signature of Investigator 
E-0 Jwr{ 9tJ:;)./ 
Date 
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PROCEDURES IN CASE OF EMERGENCY 
Role in Study 
Name 
Address and Telephone 
Number 
Clinical Study Leader 
 
 
 
 
Responsible Investigator 
 
Drug Safety Investigator 
 
24-Hour Emergency Contact 
 
 
 
 
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TABLE OF CONTENTS 
1. SYNOPSIS ..............................................................................................................................10 
2. INTRODUCTION..................................................................................................................16 
2.1. 
Indication .....................................................................................................................16 
 
 
2.3. 
Primary Objective ........................................................................................................23 
2.4. 
Secondary Objectives...................................................................................................23 
3. INVESTIGATIONAL PLAN ...............................................................................................24 
3.1. 
Overall Study Design ...................................................................................................24 
3.1.1. 
Single Ascending Dose Phase (SAD) .............................................................24 
3.1.2. 
General ..........................................................................................................24 
3.2. 
Number of Subjects......................................................................................................25 
3.3. 
Treatment Assignment .................................................................................................25 
3.4. 
Dose Adjustment Criteria ............................................................................................25 
3.4.1. 
Safety Criteria for Adjustment or Stopping Doses .........................................26 
3.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses .......................27 
3.5. 
Criteria for Study Termination.....................................................................................27 
4. SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................30 
4.1. 
Subject Inclusion Criteria ............................................................................................30 
4.2. 
Subject Exclusion Criteria ...........................................................................................31 
4.3. 
Subject Withdrawal Criteria ........................................................................................32 
5. TREATMENT OF SUBJECTS ............................................................................................34 
5.1. 
Description of Study Drug ...........................................................................................34 
5.2. 
Concomitant Medications ............................................................................................34 
5.3. 
Treatment Compliance .................................................................................................34 
5.4. 
Randomization and Blinding .......................................................................................35 
6. STUDY DRUG MATERIALS AND MANAGEMENT .....................................................36 
6.1. 
Study Drug ...................................................................................................................36 
6.2. 
Study Drug Packaging and Labeling ...........................................................................36 
6.3. 
Study Drug Storage ......................................................................................................36 
6.4. 
Study Drug Preparation................................................................................................36 
6.5. 
Administration .............................................................................................................36 
6.6. 
Study Drug Accountability ..........................................................................................37 
6.7. 
Study Drug Handling and Disposal .............................................................................37 
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7. PHARMACOKINETIC ASSESSMENTS...........................................................................38 
7.1. 
Blood Sample Collection .............................................................................................38 
7.2. 
Urine Sample Collection ..............................................................................................39 
7.3. 
Sample Analysis...........................................................................................................39 
8. ASSESSMENT OF SAFETY ................................................................................................40 
8.1. 
Safety Parameters.........................................................................................................40 
8.1.1. 
Demographic/Medical History ......................................................................40 
 
 
8.1.3. 
Weight, Height and Body Mass Index ............................................................40 
8.1.4. 
Physical Examination ....................................................................................41 
8.1.5. 
Local Injection Site Irritation ........................................................................41 
8.1.6. 
Electrocardiogram (ECG) .............................................................................41 
8.1.7. 
Laboratory Assessments .................................................................................41 
8.1.7.1. 
Hematology ....................................................................................41 
8.1.7.2. 
Blood Chemistry ............................................................................42 
8.1.7.3. 
Urinalysis .......................................................................................42 
8.1.7.4. 
Virus Serology ...............................................................................42 
8.1.7.5. 
Drug Screen ...................................................................................42 
8.1.7.6. 
Evaluation of Child-Bearing Potential ...........................................42 
8.2. 
Adverse and Serious Adverse Events ..........................................................................43 
8.2.1. 
Definition of Adverse Events ..........................................................................43 
8.2.1.1. 
Adverse Event (AE) .......................................................................43 
8.2.1.2. 
Serious Adverse Event (SAE) ........................................................43 
8.2.1.3. 
Other Adverse Events ....................................................................44 
8.3. 
Relationship to Study Drug ..........................................................................................44 
8.4. 
Recording Adverse Events ...........................................................................................45 
8.5. 
Reporting Adverse Events ...........................................................................................46 
9. STATISTICS ..........................................................................................................................47 
9.1. 
Statistical Methods .......................................................................................................47 
9.2. 
Pharmacokinetic Analyses ...........................................................................................47 
9.3. 
Analysis of ECGs .........................................................................................................47 
9.4. 
Analysis Populations ....................................................................................................48 
9.5. 
Handling of Missing Data ............................................................................................48 
9.6. 
Sample Size ..................................................................................................................48 
9.7. 
Data Monitoring Committee Reviews .........................................................................48 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................50 
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10.1. Study Monitoring .........................................................................................................50 
10.2. Audits and Inspections .................................................................................................50 
10.3. Institutional Review Board ..........................................................................................51 
11. QUALITY CONTROL AND QUALITY ASSURANCE ...................................................52 
12. ETHICS ..................................................................................................................................53 
12.1. Ethics Review ..............................................................................................................53 
12.2. Ethical Conduct of the Study .......................................................................................53 
12.3. Written Informed Consent ...........................................................................................53 
13. DATA HANDLING AND RECORDKEEPING .................................................................54 
13.1. Inspection of Records ..................................................................................................54 
13.2. Retention of Records....................................................................................................54 
14. PUBLICATION POLICY .....................................................................................................55 
15. LIST OF REFERENCES ......................................................................................................56 
APPENDIX A:  WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI ..............................................................................................................................58 
APPENDIX B:  CLINICAL LABORATORY TESTS .............................................................60 
APPENDIX C: BLOOD VOLUMES TO BE COLLECTED IN THIS STUDY ...................61 
APPENDIX D: TABLE FOR CLINICAL ABNORMALITIES ASSOCIATED WITH 
LOCAL REACTION TO INJECTABLE PRODUCT .......................................................62 
 
LIST OF TABLES 
 
 
 
 
 
 
 
 
 
 
 
 
 
LIST OF FIGURES 
 
 
 
 
 
 
 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialist Term 
Explanation 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Curve 
BID 
Twice Daily 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CL 
Clearance of drug from circulation 
Cmax 
Maximum drug concentration in circulation 
CNS 
Central Nervous System 
Ctrough 
Lowest drug concentration in circulation between repeat doses 
CRF 
Case Report Form 
DBP 
Diastolic Blood Pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
GCP 
Good Clinical Practice 
HBV, HCV 
Hepatitis B, Hepatitis C 
HIV 
Human Immune Deficiency 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
NOAEL 
No Observed Adverse Event Level 
OAE 
Other Significant Adverse Event 
PI 
Principal Investigator 
The investigator who leads the study conduct at an individual study 
center.  Every study center has a principal investigator. 
PK 
Pharmacokinetics 
Q12H 
Every 12 hours 
QT 
Cardiac QT interval 
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Abbreviation or 
Specialist Term 
Explanation 
QTcF 
QT interval corrected for heart rate using the Fredericia method 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
Vd 
Volume of distribution of drug 
Vss 
Volume of distribution of drug at steady state 
WBC 
White Blood Cell 
 
 
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1. 
SYNOPSIS 
Name of Sponsor/Company:  SiteOne Therapeutics, Inc. 
Name of Investigational Product:  ST-2427 for Intravenous (IV) Infusion 
Name of Active Ingredient:  ST-2427 
Protocol Number:  ST-2427-CS-
001/
 5UG3 DA049599-01 
Phase:  Phase 1 
Country:  USA 
Title of Study:  
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single Ascending Dose Study to Evaluate 
the Safety, Tolerability, and Pharmacokinetics of ST-2427 IV Infusion in Healthy 
Subjects/Development of a Potent and Highly Selective NaV1.7 Inhibitor for the Treatment of Acute 
Pain with the Goal of Reducing Opioid Use and Preventing Opioid Use Disorder 
Study Center(s):  
Altasciences Clinical Kansas, Inc., 10103 Metcalf Ave. Overland Park, KS, USA 66212  
Principal Investigator:  
 
Studied Period (years):  
Estimated date first patient enrolled:  April 2021  
Estimated date last patient completed:  December 2021 
Phase of development:  
Phase 1  
Objectives:  
Primary:  To evaluate the safety and tolerability of ST-2427 intravenous (IV) Infusion.   
Secondary:  To measure the pharmacokinetics (PK) of ST-2427 IV Infusion. 
Study Design: 
This randomized, double-blind, placebo controlled, study will be conducted to evaluate the safety, 
tolerability, and pharmacokinetics of ST-2427.  Subjects will be randomized to receive a single dose 
of ST-2427 or placebo in a Single Ascending Dose (SAD) design.   
A total of 30 subjects will be enrolled.  Subjects will be randomized in a 4:2 ratio of ST-2427 to 
placebo.  Study drug will be blinded to all subjects and Investigators.   
Methodology:  
Subjects will be enrolled into the following sequential cohorts and randomized 4:2 to receive ST-2427 
or placebo: 
 
Cohort 1:  6 subjects will receive a single administration of placebo or ST-2427 5 mg by IV 
infusion over approximately 1 hour. 
 
Cohort 2:  6 subjects will receive a single administration of placebo or ST-2427 10 mg by IV 
infusion over approximately 1 hour. 
 
Cohort 3:  6 subjects will receive a single administration of placebo or ST-2427 15 mg by IV 
infusion over approximately 1 hour. 
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 
Cohort 4:  6 subjects will receive a single administration of placebo or ST-2427 22 mg by IV 
infusion over approximately 1 hour. 
 
Cohort 5:  6 subjects will receive a single administration of placebo or ST-2427 33 mg by IV 
infusion over approximately 1 hour. 
Sentinel dosing will be used in Cohort 1 in the SAD wherein the first 2 subjects (one ST-2427, one 
placebo) will be randomly chosen to receive study drug and be followed for up to 2 days before any 
other subject is dosed in that cohort.  Dosing of the remaining 4 subjects (3 ST-2427, 1 placebo) in 
the cohort will commence after safety review by the Principal Investigator.  This method of sentinel 
dosing of 2 subjects on the first day, followed by dosing of all remaining subjects will be used for the 
assessment of safety and risk mitigation.  Subjects will return to the clinic for the Follow-Up visit on 
Day 8 ± 2 days.   
C.  General 
Blood samples will be collected at pre-defined time points for evaluation of clinical laboratory tests 
(Table 4), and the PK of ST-2427.  The total blood volume to be collected from each subject in this 
study is approximately 65.2 mL during participation in the SAD (Appendix C).   
Safety and tolerability of each regimen will be assessed by adverse event (AE) monitoring, clinical 
laboratory tests, vital signs, body weight, electrocardiograms (ECGs), and physical examinations.  
Enrollment into Cohorts 2 through 5 will commence after all subjects in the prior cohort have 
completed the Follow-Up Visit, and safety and PK data from all prior cohorts have been reviewed by 
a Data Monitoring Committee (DMC) consisting of the Principal Investigator, a medical 
representative from the Sponsor, and a PK expert, and no clinical concerns are identified from 
evaluation of safety.  The DMC will additionally examine all available clinical and PK data to 
determine the dose of ST-2427 to be administered in the next cohort.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
In addition to the above subject level stopping criteria, if 2 subjects randomized to ST-2427 in a given 
cohort experience any of the above drug-related events, will lead to stopping the study/cohort, will 
define the maximum tolerated dose, and will result in cessation of further subject exposures in that 
cohort, and prevent further dose escalation in a subsequent cohort.  
 
 
 
 
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Sample Size Justification: 
Descriptive, non-inferential statistics are planned for the primary endpoint analyses.  Based on 
clinical judgement, a sample size of 30 (20 randomized to ST-2427, and 10 randomized to placebo) is 
expected to be adequate to identify major treatment effects. 
Number of Patients (planned):  
Approximately 30 subjects 
Diagnosis and Main Criteria for Inclusion:  
Inclusion Criteria  
Only subjects who meet the following criteria will be eligible for inclusion: 
1. 
Healthy adult males and/or females (of non-childbearing potential), 18 to 55 years of age 
(inclusive) at the time of screening. 
2. 
Body mass index (BMI) within 18.0 to 35.0 kg/m2, inclusive (minimum weight of at least  
50.0 kg at Screening). 
3. 
Medically healthy without clinically significant abnormalities at the screening visit, including 
physical examination and vital signs within the following ranges: heart rate 50 to 100 bpm, 
systolic blood pressure 100 to 149 mmHg; diastolic 70 to 94 mmHg. 
4. 
The mean QTcF interval duration ≤450 msec for males and ≤470 msec for females measured 
from the triplicate ECGs taken at least 1 minute apart with QT wave corrected for heart rate (HR) 
using Frediricia’s method.  
5. 
Hemoglobin/hematocrit, white blood cell (WBC) count, and platelet count equal to or greater 
than the lower limit of normal range of the reference laboratory (may be confirmed upon repeat 
testing without Sponsor approval). 
6. 
Non-smokers (including tobacco, e-cigarettes, or marijuana), and no use of any tobacco product 
for at least 1 month prior to admission in the study. 
7. 
Willing and able to provide written informed consent. 
8. 
Willing and able to comply with all study assessments and adhere to the protocol schedule. 
9. 
Have suitable venous access for blood sampling, as determined by an Investigator at screening. 
10. 
If female, be of non-childbearing potential (e.g. post-menopausal as demonstrated by follicle 
stimulating hormone (>40 mIU/mL), amenorrhea for at least one year, or surgically sterilized by 
tubal ligation, hysterectomy, bilateral oophorectomy and/or salpingectomy). Site personnel’s 
review of the subject’s medical records, medical examination, or medical history interview is 
acceptable evidence of female sterilization, verbal confirmation is adequate. 
11. 
If male, willing not to donate sperm from the time of first study drug administration until 90 days 
after the final administration of study drug.  If male and not intending to engage in sexual 
intercourse over the duration of the study, willing to agree to abstinence at screening.  If male and 
engaging in sexual intercourse, willing to use a double barrier method of contraception (condom 
and spermicide).  The latter criterion applies to all males (and/or female partners) including males 
who are surgically sterile and must be followed from the time of first study drug administration 
until 90 days after the final administration of study drug. 
Exclusion Criteria 
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Subjects will be excluded from the study if they meet any of the following criteria: 
1. 
History or presence of significant cardiovascular (including arrhythmia and ventricular 
tachyphylaxis), pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, 
immunologic, dermatologic or neurological disease, including any acute illness or surgery within 
the past 3 months determined by an Investigator to be clinically relevant. 
2. 
Creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) equal to 1.5 × upper limit of normal for the reference laboratory (may be 
confirmed upon repeat testing). 
3. 
History of orthostatic reactions. 
4. 
Orthostatic reaction at screening defined as drop in systolic blood pressure by ≥20 mmHg or drop 
in systolic blood pressure to <90 mmHg on standing for 3 minutes from the supine position. 
5. 
History of seizure disorders, except for non-complex febrile seizures in childhood with absence 
of non-febrile seizures in parents and siblings. 
6. 
Positive urine drug/alcohol testing at Screening or Day –2. 
7. 
Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or 
Hepatitis C Antibody (HCVAb). 
8. 
Positive test results for COVID-19 (PCR or Antibodies) 
9. 
History of substance abuse or alcohol abuse (defined as greater than 2 standard drinks per day) 
within the previous 2 years. 
10. 
Use of any prescription medication or any over-the-counter medication, including herbal products 
and vitamins within 14 days or 5 half-lives (whichever is longer) prior to randomization. 
11. 
Documented hypersensitivity reaction or anaphylaxis to any medication. 
12. 
Blood donation (excluding plasma donation) of approximately 500 mL within 56 days prior to 
Screening, or receipt of a blood transfusion within 1 year of Screening. 
13.  Plasma donation within seven days prior to screening. 
14. 
Dosed in another investigational clinical trial within 30 days prior to Screening. 
15. 
Any condition or prior therapy, e.g., seizures, or head trauma, that may lead to CNS effects during 
the study. 
16. 
Documented or self-reported history of orthostatic hypotension or symptoms of hypotension such 
as dizziness, syncope, or blurred vision upon standing. 
17. 
Any condition which is associated with increased brain permeability, e.g., cerebral ischemia, 
brain trauma, multiple sclerosis, brain tumors, brain infection. 
Investigational Product, Dosage and Mode of Administration:  
In all cohorts, study drug (ST-2427 or placebo) will be infused via IV over 1 hour.  Subjects will be 
randomized 4:2 to receive a single dose of ST-2427 or placebo.   
Subjects randomized to ST-2427 in Cohort 1 will receive 5 mg ST-2427 as a single IV infusion over 
one hour.  The starting dose of 5 mg will be administered to all subjects in Cohort 1 regardless of 
body weight. 
The doses of ST-2427 to be administered in all cohorts after Cohort 1 will be approved by the DMC 
following examination of all available clinical and PK data.  In the SAD, the dose increase of 
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ST-2427 from Cohort 1 onwards is ≤2-fold from the prior cohort, 
 
 
 
In all cohorts, placebo will be administered as 1-hour IV infusions at matching volumes and times to 
those administered to subjects randomized to ST-2427 in the same cohort.   
Details of study drug preparation are provided in the Pharmacy Manual for this study.   
Duration of Treatment:  
Single 1-hour IV infusion 
Reference Therapy, Dosage, and Mode of Administration:  
Placebo (5% Dextrose Injection, USP) will be administered by 1-hour IV infusions at the same 
volume and rate as used for ST-2427 
Criteria for Evaluation: 
Safety: 
Safety measures include incidence and severity of AE’s, physical examination
 
 
body weight, ECG, clinical laboratory testing (chemistry, hematology, urinalysis), 
respiratory rate, body temperature, oxygen saturation, local (injection site) irritation, and QTcF 
measures. 
Pharmacokinetics: 
Blood and urine samples will be collected at specified times during the study for measurement of 
ST-2427 concentration using a validated analytical method.  The measured concentrations will be 
used for PK modeling. 
Statistical Methods: 
Treatment effects on safety and tolerability will be evaluated using descriptive statistics (mean, 
standard deviation, median, minimum, maximum) of the number and proportion of subject 
experiencing adverse events by system organ class, and preferred term.   
Prior to dosing on Day 1, three separate measurements of supine BP (including DBP, SBP) and HR 
will be recorded one minute apart after at least 5 minutes rest.  These repeat assessments will be used 
for analyses of change from baseline for these measures.   
Cardiodynamic evaluation will be performed to evaluate the treatment effects on heart rate-corrected 
QT interval using the Fridericia (QTcF) corrections, using concentration-QTc analysis, and on other 
ECG parameters (heart rate, PR and QRS interval and treatment emergent T and U-wave 
abnormalities).  The statistical analysis will be detailed in a separate SAP.  
For purposes of monitoring safety, treatment-emergent adverse events (AEs) will be graded using the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers (FDA 2007) which is 
appropriate for healthy subjects.  
Descriptive statistics will be used to evaluate the treatment effects on clinical laboratory assessments 
including clinical chemistry, hematology, and urinalysis.   
PK modeling will be performed using compartmental methods.  PK parameters such as, but not 
limited to Cmax, Tmax, Volume of distribution, Elimination half-life, and AUC after the ST-2427 
infusion in the SAD.  Descriptive statistics will be used to summarize PK parameters, and ST-2427 
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concentrations in the urine by cohort.  In addition, exploratory analyses of the effects of some 
baseline characteristics (e.g., sex, body weight) on PK parameters may be undertaken. 
 
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2.
INTRODUCTION
This is a Phase 1, randomized, double-blind, placebo-controlled study in healthy adult males and 
females of non-child-bearing potential to evaluate the safety, tolerability, and pharmacokinetics 
(PK) of ST-2427.  
 
 
  SiteOne Therapeutics, Inc. plans to use the safety, 
tolerability, and PK findings from this study to inform the doses and study design for Phase 2 
clinical studies in subjects with acute post-operative pain.   
Approximately 30 subjects, 6 subjects into each of 5 cohorts, will be enrolled in this study at a 
single clinical site.   
Subjects will be randomized 4:2 to receive a single dose of ST-2427 or placebo in a Single 
Ascending Dose (SAD) design.  The study will evaluate 5 dose strengths of ST-2427, infused 
intravenously (IV) over 1 hour; one dose level in each of 5 cohorts of subjects.   
2.1. 
Indication 
SiteOne Therapeutics, Inc. plans to develop ST-2427, a novel, selective, state-independent 
inhibitor of the voltage-gated sodium channel isoform NaV1.7, for treatment of acute 
postoperative pain and sparing of opioids.  Study ST-2427-CS-001 is the first-in-human study, 
and aims to evaluate the safety, tolerability, and PK of ST-2427 when administered at increasing 
dose strengths/durations to healthy volunteers. 
An estimated 80% of patients who undergo surgery experience acute postoperative pain that is 
typically moderate, severe or extreme in nature (Chou 2016), a majority of whom have 
inadequate pain control which negatively impacts quality of life, recovery of function, the risk of 
persistent postsurgical pain, and morbidity and mortality due to post-surgical complications 
(Apfelbaum 2003, Sharrock 1994, Katz 1996, Kehlet 2006).  Effective postoperative pain control 
is essential to enhance patient comfort, earlier mobilization, fewer pulmonary and cardiac 
complications, reduced risk of deep vein thrombosis, faster recovery, less likelihood of 
developing neuropathic pain and reduced cost of care (Ramsay 2000).   
The American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, 
and the American Society of Anesthesiologists (Chou 2016) recommends the use of opioids, 
non-steroidal anti-inflammatory drugs (NSAIDs) and/or acetaminophen, gabapentin or 
pregabalin, ketamine (IV) for management of postoperative pain in conjunction with appropriate 
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patient education, real-time pain evaluation/scoring, and other analgesia modalities including 
transcutaneous electrical nerve stimulation.   
Opioids in particular are associated with dose-limiting side effects, such as confusion, 
drowsiness, nausea, respiratory depression and the potential for dependence and abuse 
(Kelly 2008).  The alarming level of opioid abuse in the United States (US) has led some to focus 
on multimodal pain management approaches that decrease or eliminate the use of opioids 
altogether (Wardhan 2017).  Key to this approach is the need to develop new, effective non-
opioid analgesic therapies. 
Human and animal genetic and pharmacology data support Nav1.7 as a promising target for the 
development of non-opioid pain therapeutics.  Nav1.7 is preferentially expressed in peripheral 
somatic and visceral sensory neurons within the dorsal root ganglion, including nociceptors, 
olfactory sensory neurons, and sympathetic ganglion neurons (Dib-Hajj 2013, Dib-Hajj 2017).  
Conditional, or global deletion of Nav1.7 in mice led to reduction or loss of inflammatory pain 
responses induced by a range of stimuli (Nassar 2004, Yeomans 2005, Minett 2012, 
Gingras 2014).  Congenital insensitivity (indifference) to pain (CIP) in humans is linked to loss-
of-function mutations in both alleles of SCN9A, the gene encoding Nav1.7 (Cox 2006).  By 
contrast, dominantly inherited gain-of function missense mutations in SCN9A are found in 
patients with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD), 
who report flushing and severe, episodic pain triggered by mild warmth or exercise (in IEM) or 
bowel movement (in PEPD) (Yang 2004, Fertleman 2006).   
 
2.2. 
Nonclinical Experience with ST-2427  
ST-2427 is a highly selective, state-independent inhibitor of human voltage-gated Na+ ion 
channel 1.7 (NaV1.7) intended for the treatment of acute, postoperative pain. 
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2.3. 
Primary Objective 
The primary objectives of the study are to evaluate the safety and tolerability of ST-2427 IV 
Infusion.  
 
 
 
 
2.4. 
Secondary Objectives 
The secondary objective of the study is to measure the PK of ST-2427 IV infusion. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design 
Owing to its cationic nature, ST-2427 has low cellular permeability and is expected to have low 
bioavailability in humans if administered orally.  As such, ST-2427 will be administered via IV 
in this trial.  Furthermore, study drug will be administered slowly over a 1-hour infusion to 
mitigate/eliminate the number and severity of clinical observations which, in rats and monkeys, 
were generally observed at the time of highest drug concentration. 
Subjects will be enrolled into the following sequential cohorts and randomized 4:2 to receive 
ST-2427 or placebo: 
 
3.1.1. 
Single Ascending Dose Phase (SAD) 
Cohort 
Dose 
mg 
Fold Increase from 
Previous Cohort 
Predicted Peak 
Concentration ng/mL 
1 
5 
— 
200 
2 
10 
2 
375 
3 
15 
1.5 
565 
4 
22 
1.5 
820 
5 
33 
1.5 
1190 
 
Subjects will be asked to participate in this study for a period of approximately 5 weeks:  4 
weeks of Screening, 1 day of study treatment, 1 week of follow-up.   
Sentinel dosing will be used in Cohort 1 wherein the first 2 subjects (one ST-2427, one placebo) 
will be randomly chosen to receive study drug and be followed for up to 2 days before any other 
subject is dosed in that cohort.  Dosing of the remaining 4 subjects (3 ST-2427, 1 placebo) in the 
cohort will commence after safety review by the Principal Investigator and Sponsor.  Study 
assessments will be performed at the days/times defined in Table 4.  Subjects enrolled in the 
SAD will return to the clinic for additional assessments and sample collections at approximately 
8 days (± 2 days) after the start of infusion.   
 
3.1.2. 
General 
Eligible subjects will be scheduled to return to the clinic and be admitted for a confinement 
period of 3 days in the SAD.  The confinement period will begin the day before the start of study 
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drug administration to confirm eligibility for the study and for the completion of baseline 
assessments. 
Subjects will return to clinic on Day 8 ± 2 days for the Follow-Up visit. 
Safety and tolerability of each regimen will be assessed by adverse event (AE) monitoring, 
clinical laboratory tests, vital signs, body weight, electrocardiograms (ECGs), and physical 
examinations.  Enrollment into Cohorts 2 through 5 will commence after all subjects in the prior 
cohort have completed the Follow-Up visit, and safety and PK data from all prior cohorts have 
been reviewed by a Data Monitoring Committee (DMC) consisting of the Principal Investigator, 
a medical representative from the Sponsor, and a PK expert, and no clinical concerns are 
identified.   
 
3.2. 
Number of Subjects 
Approximately 30 subjects will be enrolled into this study, 6 subjects in each of the 5 cohorts.   
 
3.3. 
Treatment Assignment 
Subjects who meet all criteria for enrollment will be randomly assigned to 1 of 2 treatment 
groups, ST-2427 or placebo, following a 4:2 allocation.  A randomization schedule will be 
produced by an unblinded statistician using a validated computer program.  Once baseline data 
(Day –1) has been reviewed and subjects are determined to be eligible for the study, they will be 
assigned a unique randomization number.  Investigators and subjects will remain blinded to the 
study drug assignment and only certain designated staff (such as pharmacy personnel) will be 
unblinded to study treatment. 
Sealed code break envelopes will be provided by an unblinded statistician prior to the start of the 
study.  During the study, the blind is to be broken by an Investigator only when subject safety is 
at risk and unblinding must occur to determine effective medical intervention for the subject.  All 
unscheduled unblinding events must be reported to the medical monitor and SiteOne 
Therapeutics, Inc. as soon as possible. 
 
3.4. 
Dose Adjustment Criteria 
The dose levels have been selected to reach defined peak concentrations as predicted from PK 
parameters in animal studies.  If it is found in the initial study cohort that the achieved peak 
concentrations at a group level deviate from the predictions, doses will be adjusted accordingly 
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in subsequent cohorts to achieve the defined peak concentrations.  All subjects will receive the 
dose defined for the cohort to which they were randomized.   
 
3.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
The following stopping criteria will be used to inform decisions to continue drug infusion in any 
given subject: 
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3.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
If it is found in the initial study cohort that the achieved peak concentrations at a group level 
deviate from the predictions, doses will be adjusted accordingly in subsequent cohorts to achieve 
the defined peak concentrations. 
 
3.5. 
Criteria for Study Termination 
The study will run to completion unless the Sponsor decides to terminate it earlier, e.g., 
following a recommendation from the DMC based on review of all available PK and safety data.   
 
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Table 4: 
Schedule of Assessments in Part A (Single Ascending Dose)  
 
Screening 
CONFINEMENT 
Follow-
Up/EOS/ET 
Time (days) 
-28 to -2 
-1 
1 
2 
3 
8± 2 
Timea (hours) 
 
 
Pre-
dose 
0 
0.25 
0.5 
0.75 
1 
1.15 
1.3 
1.5 
2 
2.5 
3 
4 
6 
8 
10 
12 
24 
4
8 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication 
history 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x
b 
x 
Weight, height, BMI 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Local Irritation at the 
infusion site 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
HIV, hepatitis B, 
hepatitis C testing 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 testingf 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follicle stimulating 
hormoneg 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review 
inclusion/exclusion 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to clinic 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinementh 
 
x 
 
Discharge from clinic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Adverse events 
x 
Concomitant 
Medications 
x 
x 
Study drug 
administrationi 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY MEASURES 
Urine drug and alcohol 
tests 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical chemistry 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Hematology 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Coagulation tests 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Blood PK samplej 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
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Screening 
CONFINEMENT 
Follow-
Up/EOS/ET 
Time (days) 
-28 to -2 
-1 
1 
2 
3 
8± 2 
Timea (hours) 
 
 
Pre-
dose 
0 
0.25 
0.5 
0.75 
1 
1.15 
1.3 
1.5 
2 
2.5 
3 
4 
6 
8 
10 
12 
24 
4
8 
 
Urine PK samplek 
 
 
x 
x 
x 
x 
x 
x 
x 
 
a 
Time is defined relative to the start of the first infusion of study drug.  For example, an assessment scheduled to occur at time = 2 hour must be performed 2 hours after the start of study drug 
infusion, i.e., 1 hour after the end of the infusion.  
b 
A symptom-directed physical exam will be conducted prior to discharge. 
c 
 
  
 Orthostatic tests will be performed pre-dose (within 60 minutes prior to study drug administration), and at 0.5, 1, 1.5, 2, and 2.5 hours (± 10 minutes) after start of infusion.  For these tests, 
subjects should be standing for 3 minutes with measurements of heart rate and blood pressure (SBP, DBP) at 1, 2, and 3 minutes after standing 
d 
  
e 
 
 
 
f  
COVID-19 test will be performed after Screening is complete and subject is confirmed, but prior to check-in to the unit 
g 
A blood sample will be collected from women and tested for follicle stimulating hormone to confirm eligibility for this study unless documented evidence of surgical sterilization is available and 
reviewed by qualified study personnel. 
h 
Subjects will be confined at the clinic from the day before study drug infusion through at least 48 hours after the start of study drug infusion.  This is predicted to exceed the time necessary for the 
concentration of ST-2427 to decrease to <5% of the peak concentration.  During the study, the period of confinement may be extended if the drug elimination is found to be slower than predicted 
in the first cohort(s).  Subjects will be discharged only if clinically significant AEs, if any, are resolved.   
i 
Study drug is to be administered intravenously as a 1–hour infusion. A ±10-minute window is allowed for the duration of infusion, and a ±15-minute window is allowed for the start of infusion 
relative to the nominal time.   
j 
Whole blood samples collected for PK analysis should be collected at the specified time.  When blood sample collections coincide with other assessments, assessments should be conducted in the 
following order:
  Whole blood samples 
for PK will be collected at the following time points: 
 
Day 1: pre-dose, and 0.25, 0.5, 0.75, 1, 1.15, 1.3, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48  
 
Predose PK samples should be collected within approximately 60 minutes prior to dosing  
k 
A pre-dose urine sample will be collected at any time prior to dosing on Day 1 for analysis of pre-dose ST-2427 concentrations in the urine.  Subjects are to be instructed to empty their bladders 
prior to dosing on Day 1.  All urine will be collected for interval analysis of PK from the start of the first infusion until at least 48 hours later.  Urine will be pooled 0 hr – 4 hr, 4 hr – 8 hr,  
8 hr – 12 hr, 12 hr – 24 hr, and 24 hr – 48 hr collection windows and the collection time and volume for each collection recorded.  Pooled urine samples will be maintained refrigerated and 
processed at the end of each pooled collection.   
 
 
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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Subject Inclusion Criteria 
Only subjects who meet all of the following criteria will be eligible for inclusion: 
1. 
Healthy adult males and/or females (of non-childbearing potential), 18 to 55 years of age 
(inclusive) at the time of Screening. 
2. 
Body mass index (BMI) within 18.0 to 35.0 kg/m2, inclusive (minimum weight of at least 
50.0 kg at Screening). 
3. 
Medically healthy without clinically significant abnormalities at the screening visit, 
including physical examination and vital signs within the following ranges:  heart rate 50 to 
100 bpm, systolic blood pressure 100 to 149 mmHg; diastolic 70 to 94 mmHg. 
4. 
The mean QTcF interval duration ≤450 msec for males and ≤470 msec for females 
measured from triplicate ECGs taken at least 1 minute apart with QT wave corrected for 
heart rate (HR) using Fredericia’s method. 
5. 
Hemoglobin/hematocrit, white blood cell (WBC) count, and platelet count equal to or 
greater than the lower limit of normal range of the reference laboratory (may be confirmed 
upon repeat testing without Sponsor approval). 
6. 
Non-smokers (including tobacco, e-cigarettes, or marijuana), and no use of any tobacco 
product for at least 1 month prior to admission in the study. 
7. 
Willing and able to provide written informed consent. 
8. 
Willing and able to comply with all study assessments and adhere to the protocol schedule. 
9. 
Have suitable venous access for blood sampling, as determined by an Investigator at 
screening. 
10. If female, be of non-childbearing potential (e.g. post-menopausal as demonstrated by 
follicle stimulating hormone (>40 mIU/mL), amenorrhea for at least one year or surgically 
sterilized by tubal ligation, hysterectomy, bilateral oophorectomy and/or salpingectomy).  
Site personnel’s review of the subject’s medical records, medical examination, or medical 
history interview is acceptable evidence of female sterilization, verbal confirmation is 
adequate. 
 
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11. If male, willing not to donate sperm from the time of first study drug administration until 
90 days after the final administration of study drug.  If male and not intending to engage in 
sexual intercourse over the duration of the study, willing to agree to abstinence at 
screening.  If male and engaging in sexual intercourse, willing to use a double barrier 
method of contraception (condom and spermicide).  The latter criterion applies to all males 
(and/or female partners) including males who are surgically sterile and must be followed 
from the time of first study drug administration until 90 days after the final administration 
of study drug. 
 
4.2. 
Subject Exclusion Criteria 
Subjects will be excluded from the study if they meet any of the following criteria: 
1. 
History or presence of significant cardiovascular (including arrhythmia and ventricular 
tachyphylaxis), pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, 
immunologic, dermatologic, or neurological disease, including any acute illness or surgery 
within the past 3 months determined by an Investigator to be clinically relevant. 
2. 
Creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) equal to 1.5 × upper limit of normal for the reference laboratory 
(may be confirmed upon repeat testing). 
 
 
 
 
 
 
 
 
 
6. 
Positive urine drug/alcohol testing at Screening or Day –1. 
7. 
Positive test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or 
Hepatitis C Antibody (HCVAb). 
8. 
Positive test results for COVID-19 (PCR or Antibodies). 
9. 
History of substance abuse or alcohol abuse (defined as greater than 2 standard drinks per 
day) within the previous 2 years. 
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10. Use of any prescription medication or any over-the-counter medication, including herbal 
products and vitamins within 14 days or 5 half-lives (whichever is longer) prior to 
randomization. 
11. Documented hypersensitivity reaction or anaphylaxis to any medication. 
12. Blood donation (excluding plasma donation) of approximately 500 mL within 56 days prior 
to Screening, or receipt of a blood transfusion within 1 year of Screening. 
13. Plasma donation within seven days prior to screening 
14. Dosed in another investigational clinical trial within 30 days prior to Screening. 
15. Any condition or prior therapy, e.g., seizures, or head trauma, that may lead to CNS effects 
during the study. 
16. Documented or self-reported history of orthostatic hypotension or symptoms of 
hypotension such as dizziness, syncope, or blurred vision upon standing. 
17. Any condition which is associated with increased brain permeability, e.g., cerebral 
ischemia, brain trauma, multiple sclerosis, brain tumors, brain infection. 
 
4.3. 
Subject Withdrawal Criteria 
There are no protocol-defined withdrawal criteria.   
Subjects have the right to withdraw from the study at any time and for any reason without prejudice 
to their future medical care by the Investigator or at the institution.  Subjects may also be 
discontinued from the study by the Investigator or the Sponsor for reasons such as safety, non-
compliance, or ineligibility. 
The Investigator will make a reasonable effort to determine the reason for withdrawal while 
respecting the subject’s rights.   
Reasons for removal from investigational product or observation might include: 
 withdrawal of consent 
 administrative decision by the Investigator or Sponsor 
 hardship (e.g., move, family situation, change in job, etc.) 
 pregnancy  
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 ineligibility 
 major protocol deviation 
 subject noncompliance 
 AE 
 death 
 
Reasons for withdrawal will be reported in the corresponding CRF.  Withdrawal of consent should 
only be indicated if no more specific reason can be ascertained. 
For all subjects withdrawing from the study prior to the end of the study, a complete final evaluation 
including the assessments defined for the Follow-up visit should be made at the time of the subject’s 
withdrawal.   
 
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5. 
TREATMENT OF SUBJECTS 
5.1. 
Description of Study Drug 
 
Table 5: 
Investigational Product 
 
Investigational Product 
Product Name: 
ST-2427 for IV Infusion 
Placebo (5% Dextrose Injection, 
USP) 
Dosage Form: 
Sterile Solution 
Sterile Solution 
Unit Dose (by Cohort) 
250 mL total volume 
1:  5 mg ST-2427 
2:  10 mg ST-2427 
3:  15 mg ST-2427 
4:  22 mg ST-2427 
5:  33 mg ST-2427 
0 mg/mL 
Route of Administration 
Intravenous Infusion 
Intravenous Infusion 
Physical Description 
Clear, colorless solution 
Clear, colorless solution 
Manufacturer 
AMRI, Albany, NY 
Sterile solution will be prepared 
by Alta Sciences 
Sourced by Alta Sciences 
 
5.2. 
Concomitant Medications 
No concomitant therapy is allowed between the start of confinement through the completion of the 
Follow-up visit.  In addition, subjects are disqualified from participation in this study if they used 
any prescription medication or any over-the-counter medication, including herbal products and 
vitamins within 14 days or 5 half-lives (whichever is longer) prior to randomization.   
 
5.3. 
Treatment Compliance 
All study drug will be administered to all subjects by qualified site personnel during the confinement 
period.  As such, treatment compliance is not relevant to this study.  Missed doses will be assumed 
to be for reasons of subject safety, withdrawal, dosing error or other protocol deviation.   
 
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5.4. 
Randomization and Blinding 
Subjects who meet all criteria for enrollment will be randomly assigned to 1 of 2 treatment groups, 
ST-2427 or placebo, following a 4:2 allocation.  A randomization schedule will be produced by an 
unblinded statistician using a validated computer program.  Once baseline data has been reviewed 
and subjects are determined to be eligible for the study, they will be assigned a unique 
randomization number.  Investigators and subjects will remain blinded to the study drug assignment 
and only certain designated staff (such as pharmacy personnel) will be unblinded to study treatment. 
Sealed code break envelopes will be provided by an unblinded statistician prior to the start of the 
study.  During the study, the blind is to be broken by an investigator only when subject safety is at 
risk and unblinding must occur to determine effective medical intervention for the subject.  Any 
unblinding events must be reported to the medical monitor and SiteOne Therapeutics, Inc. as soon as 
possible. 
After all Follow-Up assessments are complete for subjects in a given cohort, safety and PK data will 
be reviewed by the DMC to determine whether to proceed to the next cohort, and the dose of 
ST-2427 to be administered in the next cohort.   
In the event a pre-defined protocol stopping criterion is met, or a serious adverse event is observed 
for which knowledge of the randomization code would guide treatment decisions, the Investigator 
may be unblinded.  In such cases, the Sponsor must be informed of the decision to unblind and 
provided all associated evidence within 24 hours.   
Subjects who are randomized but withdraw prior to participation in the study will be replaced.  
Subjects that withdraw consent prior to dosing or discontinue due to adverse events or stopping 
criteria may be replaced.   
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug 
The study drug substance (ST-2427) will be manufactured by AMRI, Albany, New York in 
accordance with current good manufacturing practices (GMPs).   
The placebo, Sterile 5% Dextrose Injection, USP (D5W) will be obtained commercially by the study 
site. 
 
6.2. 
Study Drug Packaging and Labeling 
Study drug substance (ST-2427) will be supplied to the pharmacy at the study site as non-sterile drug 
substance powder.  Study drugs will be labeled according to the local regulatory requirements.   
 
6.3. 
Study Drug Storage 
ST-2427 will be stored frozen at –20°C, protected from light. 
The D5W will be stored and handled according to the manufacturer label. 
 
6.4. 
Study Drug Preparation 
ST-2427 for IV infusion sterile solutions will be prepared by the clinical site pharmacy.  The drug 
substance will be reconstituted in sterile 5% dextrose injection, USP.  No other excipients will be 
added to the infusion solution.  The site pharmacy will prepare the infusion solutions in a sterile 
compounding area and follow the requirements in USP <797> Pharmaceutical Compounding – 
Sterile Preparations. 
Concentrations will be determined by the dose group and total volume of infusion.  Refer to the 
Study Pharmacy Manual for detailed instructions. 
 
6.5. 
Administration 
Four subjects in each cohort will be randomized to receive ST-2427.  ST-2427 will be administered 
via IV over 1 hour (± 10 minutes). 
Two subjects in each cohort will be randomized to receive placebo.  The placebo drug will be the 
matched volume of D5W administered via IV over 1 hour (± 10 minutes) to maintain the blind.   
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6.6. 
Study Drug Accountability 
Study drug will be stored, inventoried, reconciled, and destroyed according to applicable regulations.   
 
6.7. 
Study Drug Handling and Disposal 
Any remaining study drug will be returned to SiteOne Therapeutics, Inc. or its designee for 
destruction or destroyed by the site (if the site has appropriate facilities and written procedures to 
dispose of clinical trial materials).   
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7. 
PHARMACOKINETIC ASSESSMENTS
Blood samples will be collected at protocol-defined time points for analysis of ST-2427 
concentrations in whole blood using a validated analytical method.  In addition, urine samples will 
be collected for analysis of ST-2427 concentrations in urine using a validated analytical method. A 
PK manual will be provided. 
7.1. 
Blood Sample Collection 
Blood will be collected from an accessible vein at the protocol-defined time points. 
After each collection interval, primary samples will be shipped by overnight carrier to the address 
below.  Duplicate samples will be stored at the clinical site for shipment as and when requested.   
 
 
Alturas Technology Park 
1324 Alturas Drive 
Moscow, Idaho 83843 
UNITED STATES OF AMERICA 
Telephone No.: 208.883.3400 
E-mail:  
cc:  samplecustodian@alturasanalytics.com 
cc:  
 
Before shipping, the recipient (lhvozda@alturasanalytics.com, lmalsack@alturasanalytics.com, and 
samplecustodian@alturasanalytics.com), Study Director, Study Coordinator, and Study Monitor will 
be notified by e-mail as to the date and method of sample shipments. 
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7.2. 
Urine Sample Collection 
Urine samples will be collected at the protocol-defined intervals in the SAD.  
During each protocol-defined urine collection interval, urine will be pooled in 0hr - 4hr, 4hr – 8hr, 
8hr – 12hr, 12hr – 24hr and 24hr – 48hr collection windows and the collection time and volume for 
each collection recorded.  Pooled urine samples will be maintained refrigerated and processed at the 
end of each 4-hour pooled collection.  Approximately 200 µL of urine from each 4-hour pool will be 
added to a tube containing approximately 200 µL of ammonium acetate buffer (provided by Alturas 
Analytics as a 500 mM, pH 5.4 ammonium acetate buffer and stored at ambient conditions) and 
placed on wet ice or chilled cryoracks for up to 6 hours until stored in a freezer, set to maintain 
approximately –70°C.  This will be repeated 2 more times to create 3 samples of urine/ammonium 
acetate mixture for every 4-hour pool.  Any remaining urine will be discarded.   
Samples will be collected, stored, and shipped as described above for the whole blood samples.  
 
7.3. 
Sample Analysis 
Whole blood and urine analysis for ST-2427 will be conducted by Alturas Analytics using validated 
HPLC-MSMS methods (TM20-573, urine; TM20-574, whole blood:buffer), and in accordance with 
the guidelines indicated in Alturas Analytics’ SOPs. 
Incurred sample reproducibility will be conducted in accordance with Test Site standard operating 
procedures on whole blood and urine samples.  Results will be included in the analysis report. 
When requested, ST-2427 concentrations in blood and urine will be transferred to the Sponsor-
designated PK expert.  These data will be analyzed using standard compartmental models (described 
in Section 9) for determination of PK parameters in time for the DMC meetings at the end of each 
cohort.   
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8. 
ASSESSMENT OF SAFETY 
8.1. 
Safety Parameters 
8.1.1. 
Demographic/Medical History 
Demographics, including sex, age, race, ethnicity, and medical history including body weight, 
height, BMI, concomitant medications, and child-bearing potential (for women) will be recorded 
during Screening.  These data will be used to evaluate eligibility for the trial.  Demographics and 
medical history will be summarized as Baseline characteristics in the Clinical Study Report.   
In addition, exploratory analyses of the effects of Baseline parameters (e.g., sex, body weight) on 
ST-2427 PK may be undertaken (refer to Section 9.2).  
 
8.1.3. 
Weight, Height and Body Mass Index 
Body weight and height will be measured and recorded for all subjects in the SAD during screening 
and upon admission for the confinement (on Day –1).  BMI will be computed from body weight and 
height at all observation time points.   
 
 
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8.1.4. 
Physical Examination 
The Investigator will perform a physical examination on all subjects at Screening, upon admission 
for the confinement, at the Follow-Up visit and for Symptom directed Physical Examination at 
discharge.  Physical examinations will include assessments of possible medical signs or symptoms 
from clinical observation and subject interview per site SOPs.  All findings will be recorded on case 
report forms. 
8.1.5. 
Local Injection Site Irritation 
Consistent with Food and Drug Administration (FDA) guidance, Guidance for Industry Toxicity 
Graading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine 
Clinical Trials, (2007), the assessment of local irritation at the injection site will be performed at the 
visits noted in Table 4 and Appendix D.  The scale consists of 4 categories with each graded on a 
scale from 1 to 4 based on clinical abnormality.  The scale is provided in Appendix D.  
8.1.6. 
Electrocardiogram (ECG) 
At Screening, ECGs will be recorded from all subjects in the SAD to evaluate and confirm subject 
eligibility for the trial. 
Telemetry will be performed for detection of arrhythmias for 12 hours on Day 1 in SAD. 
ECGs will be extracted at time points detailed in Schedule of Events.  
8.1.7. 
Laboratory Assessments 
Blood samples will be collected at pre-defined time points for evaluation of clinical laboratory tests 
(Appendix B), and the PK of ST-2427.  The total blood volume to be collected from each subject in 
this study is approximately 65.2 mL during participation in the SAD (Appendix C).  All hematology 
and blood chemistry analyses will be conducted by a central laboratory.   
8.1.7.1. 
Hematology 
At Screening, at the protocol-defined time points during the confinement periods for the SAD, and at 
the Follow-Up visit, blood samples will be collected for analysis of hematology.  At each of these 
time points, approximately 4 mL of venous blood will be collected into potassium EDTA tubes.  
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8.1.7.2. 
Blood Chemistry 
At Screening, at the protocol-defined time points during the confinement periods for the SAD, and at 
the Follow-Up visit, blood samples will be collected for analysis of clinical chemistry.  At each of 
these time points, approximately 5 mL of venous blood will be collected in tubes without 
anticoagulant.  
An additional approximately 2.7 mL venous blood sample will be collected into a sodium citrate 
tube for coagulation tests at Screening.  
8.1.7.3. 
Urinalysis 
Urinalyses will be conducted using spot urine sample collections at Screening, Check-In (Day -1), 
24 hours, and at the Follow-up visit.   
In addition, separate spot urine samples will be collected at Screening for analysis of drugs of 
abuse (Section 8.1.7.5). 
8.1.7.4. 
Virus Serology 
A single, approximately 8.5-mL blood sample will be collected at Screening for testing for human 
immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies 
(HCV).  All tests will be conducted by a central laboratory.   
8.1.7.5. 
Drug Screen 
At Screening and upon admission for the confinement, a urine alcohol test will be conducted, and a 
urine sample will be collected for testing for drugs of abuse.  Urine drug tests will be conducted by a 
central laboratory and will screen for amphetamine, methamphetamine, benzodiazepines, 
barbiturates, cannabinoids, cocaine, cotinine, phencyclidine, methadone, and opioids.   
8.1.7.6. 
Evaluation of Child-Bearing Potential 
Women who enroll into this study must be of non-child-bearing potential, e.g., post-menopausal as 
demonstrated by follicle stimulating hormone, or surgically sterilized by tubal ligation, 
hysterectomy, bilateral oophorectomy and/or salpingectomy.  During Screening, a blood sample will 
be collected from women and tested for follicle stimulating hormone to confirm eligibility for this 
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study unless documented evidence of surgical sterilization is available and reviewed by qualified 
study personnel.   
 
8.2. 
Adverse and Serious Adverse Events 
8.2.1. 
Definition of Adverse Events 
8.2.1.1. 
Adverse Event (AE) 
An AE is the development of an undesirable sign (including an abnormal laboratory finding), 
symptom, medical condition or the deterioration of a pre-existing medical condition following or 
during exposure to a pharmaceutical product, whether or not considered casually related to the 
product.  In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
It is the responsibility of the investigator to document all AEs that occur during the study.  All AEs 
that occur after any patient/subject has been enrolled, before treatment, during treatment, or at any 
time up to the Follow-Up visit, whether or not they are related to the study, must be recorded on the 
appropriate case report forms (CRFs). 
 
8.2.1.2. 
Serious Adverse Event (SAE) 
A SAE is an AE occurring during any study phase (i.e., Baseline, treatment, washout, or Follow-
Up), and at any dose of the investigational product, comparator, or placebo, that fulfils one or more 
of the following: 
 Results in death 
 It is immediately life-threatening 
 It requires in-patient hospitalization or prolongation of existing hospitalization 
 It results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
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All SAEs that occur after any patient/subject has been enrolled, before treatment, during treatment, 
or at any time up to the Follow-Up visit, whether or not they are related to the study, must be 
recorded on the appropriate CRF. 
 
Definition of Terms 
Life-Threatening:  An AE is life-threatening if it places the subject at immediate risk of death from 
the event as it occurred (i.e., it does not include an event that, had it occurred in a more severe form, 
might have caused death).  For example, drug induce hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening, even though drug induced hepatitis can be 
fatal. 
Hospitalization:  An AE requiring hospitalization should be considered an SAE.  Hospitalization 
scheduled for an elective procedure or treatment of a pre-existing condition that has not worsened 
during the participation in the trial (e.g., elective surgery for a pre-existing condition that has not 
worsened), or for a routine clinical procedure that is not the result of an AE is not considered as an 
AE, either serious or non-serious, according to the defined criteria.   
In general, hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency department for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. 
Disability/Incapacity:  An AE is disabling or incapacitating if the event results in a substantial 
disruption of a subject’s ability to conduct normal life functions. 
 
8.2.1.3. 
Other Adverse Events  
Other AEs will be identified by the Drug Safety Investigator and if applicable also by the Clinical 
Study Team Investigator during the evaluation of safety data for the Clinical Study Report.  
Significant AEs of particular clinical importance, other than SAEs and those AEs leading to 
discontinuation of the patient/subject from the study, will be classified as other AEs.  For other AEs, 
a narrative may be written and included in the Clinical Study Report. 
 
8.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each AE (Unrelated, Possibly Related, or Probably Related).  The 
Investigator should decide whether, in his or her medical judgment, there is a reasonable possibility 
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that the event may have been caused by the investigational product.  If no valid reason exists for 
suggesting a relationship, then the AE should be classified as “unrelated.”  If there is any valid 
reason, even if undetermined, for suspecting a possible cause-and-effect relationship between the 
investigational product and the occurrence of the AE, then the AE should be considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined to be 
“possible” or “probable” the event will be considered related to the investigational product for the 
purposes of expedited regulatory reporting. 
 
8.4. 
Recording Adverse Events 
AEs spontaneously reported by the patient/subject and/or in response to an open question from the 
study personnel or revealed by observation will be recorded during the study at the investigational 
site.  Clinically significant changes in laboratory values, blood pressure, and pulse need not be 
reported as AEs.  However, abnormal values that constitute an SAE or lead to discontinuation of 
administration of study drug must be reported and recorded as an AE.  Information about AEs will 
be collected from the Screening at enrollment until the end of the study.  SAE information will be 
collected from the first administration of study drug until the Follow-up visit.  The AE term should 
be reported in standard medical terminology when possible.  For each AE, the investigator will 
evaluate and report the onset (date and time), resolution (date and time), intensity, causality, action 
taken, serious outcome (if applicable), and whether or not it caused the patient to discontinue the 
study. 
Intensity will be assessed according to the following scale: 
 Grade 1: Mild (awareness of sign or symptom, but easily tolerated) 
 Grade 2: Moderate (discomfort sufficient to cause interference with normal activities) 
 Grade 3: Severe (incapacitating, with inability to perform normal activities) 
 Grade 4: Potentially Life Threatening (emergency room visit or hospitalization) 
Should a pregnancy occur, it must be reported and recorded on the pregnancy reporting form.  
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the patient was discontinued 
from the study. 
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All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 
handled as AEs. 
 
8.5. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from the first administration of study drug until 
the Follow-Up visit.  All SAEs discovered by the Investigator at any time should be reported.  All 
SAEs must be reported to SiteOne Therapeutics, Inc. within one business day of the first awareness 
of the event.  The Investigator must complete, sign and date the SAE pages, verify the accuracy of 
the information recorded on the SAE pages with the corresponding source documents, and send a 
copy by telephone or email to SiteOne Therapeutics, Inc.   
Additional follow-up information, if required or available, should all be emailed to SiteOne 
Therapeutics, Inc. within one business day of receipt and this should be completed on a follow-up 
SAE form and placed with the original SAE information and kept with the appropriate section of the 
CRF and/or study file. 
SiteOne Therapeutics, Inc. is responsible for notifying the relevant regulatory authorities of certain 
events.  It is the Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that 
occur at his or her site.  Investigators will also be notified of all unexpected, serious, drug-related 
events (7/15 Day Safety Reports) that occur during the clinical trial.  Each site is responsible for 
notifying its IRB or IEC of these additional SAEs. 
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9. 
STATISTICS 
9.1. 
Statistical Methods 
Treatment effects on safety and tolerability will be evaluated using descriptive statistics (mean, 
standard deviation, median, minimum, maximum) of the number and proportion of subject 
experiencing adverse events by system organ class, and preferred term.   
Prior to dosing on Day 1, three separate measurements of supine blood pressure (BP; diastolic blood 
pressure [DBP], systolic blood pressure [SBP]) and heart rate (HR) will be recorded one minute 
apart.  These values will be averaged and used to establish the baseline from which analyses of 
change from baseline will be computed.   
For purposes of monitoring safety, AEs will be graded using the Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers (FDA, 2007) which is appropriate for healthy subjects.  
Descriptive statistics will be used to evaluate the treatment effects on clinical laboratory assessments 
including clinical chemistry, hematology, and urinalysis.   
 
9.2. 
Pharmacokinetic Analyses 
PK modeling will be performed using compartmental methods.  PK parameters including but not 
limited to Cmax, Tmax, Volume of distribution, Elimination half-life, and AUC after the ST-2427 
infusion in the SAD.   
Descriptive statistics will be used to summarize PK parameters, and ST-2427 concentrations in the 
urine by cohort. 
In addition, exploratory analyses of the effects of some baseline characteristics (e.g., sex, body 
weight) on ST-2427 PK parameters may be undertaken. 
 
9.3. 
Analysis of ECGs 
ECGs will be collected during SAD as indicated in the Schedule of Events.  Data from the ECGs 
will be used to determine cardiodynamic effects including concentration-QTc analysis.  Details of 
this analysis will be given in a separate SAP and will include change-from-baseline ECG parameters 
(heart rate (HR), PR, QTcF and QRS), categorical outliers for HR, QTcF, PR and QRS and 
frequency of treatment emergent T- and U-wave abnormalities.  For QTcF, the following categories 
will be used in the outlier analysis:  
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 Categorical analyses:   number and proportion of subjects meeting the following corrected QT 
categories:  >450 msec, >480 msec, and >500 msec, 
 
9.4. 
Analysis Populations 
The safety population will include all subjects who received at least one dose of study drug.  
Subjects will be analyzed as treated.  The safety population will be used for all analyses of safety 
endpoints.   
The PK population will include all subjects who received at least one dose of study drug, and who 
have sufficient data for evaluation of at least one PK parameter.  Subjects will be analyzed as 
treated.  Subjects randomized to placebo will not be included in the analysis. 
 
9.5. 
Handling of Missing Data 
Every effort will be made to query missing or spurious data prior to unblinding for DMC reviews 
and database lock.   
Missing safety or PK data will not be imputed.   
Deviations from the protocol will be recorded and assessed for potential to impact the trial outcomes.   
 
9.6. 
Sample Size 
Descriptive, non-inferential statistics are planned for the primary endpoint analyses.  Based on 
clinical judgement, a sample size of 30 (20 randomized to ST-2427, and 10 randomized to placebo) 
is expected to be adequate to identify major treatment effects.   
 
9.7. 
Data Monitoring Committee Reviews 
A DMC consisting of the Principal Investigator, a medical representative from the Sponsor, and a 
PK expert, will be appointed for this study.  Enrollment into Cohorts 2 through 5 will commence 
after all subjects in the prior cohort have completed the Follow-Up visit, and safety and PK data 
from all prior cohorts have been reviewed by the DMC, and no clinical concerns are identified.  The 
DMC will additionally examine all available clinical and PK data to determine the dose of ST-2427 
to be administered in the next cohort.   
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The study will run to completion unless the Sponsor decides to terminate it earlier, e.g., following a 
recommendation from the DMC following review of all available PK and safety data.   
 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
10.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of SiteOne 
Therapeutics, Inc. will: 
 Determine the adequacy of the facilities 
 Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of SiteOne Therapeutics, Inc. or its representatives.  
This will be documented in a Clinical Study Agreement between SiteOne Therapeutics, Inc. 
and the Investigator. 
During the study, a monitor will have regular contacts with the investigational site, for the following: 
 Provide information and support to the Investigator(s) 
 Confirm that facilities remain acceptable 
 Confirm that the investigational team is adhering to the protocol, that data are being accurately 
recorded in the CRFs, and that investigational product accountability checks are being 
performed 
 Perform source data verification.  This includes a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to the study.  
This will require direct access to all original records for each patient (e.g., clinic charts). 
 Record and report any protocol deviations not previously sent to SiteOne Therapeutics, Inc.. 
 Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs have 
been forwarded to SiteOne Therapeutics, Inc. and those SAEs that met criteria for reporting 
have been forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs information or 
advice. 
 
10.2. 
Audits and Inspections 
Authorized representatives of SiteOne Therapeutics, Inc., a regulatory authority, an Independent 
Ethics Committee (IEC), or an Institutional Review Board (IRB) may visit the site to perform audits 
or inspections, including source data verification.  The purpose of a SiteOne Therapeutics, Inc. audit 
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or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, analyzed, 
and accurately reported according to the protocol, Good Clinical Practice (GCP) guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.  The 
Investigator should contact SiteOne Therapeutics, Inc. immediately if contacted by a regulatory 
agency about an inspection. 
 
10.3. 
Institutional Review Board  
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, and 
all materials approved by the IRB for this study including the patient consent form and recruitment 
materials must be maintained by the Investigator and made available for inspection. 
 
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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCPs and all applicable regulatory requirements, SiteOne Therapeutics, 
Inc., or their representative may conduct a quality assurance audit. 
 
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12. 
ETHICS 
12.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved, or given a favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator 
must submit written approval to SiteOne Therapeutics, Inc. before he or she can enroll any 
patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit patients for the study.  The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any reportable 
serious adverse drug reactions from any other study conducted with the investigational product.  
SiteOne Therapeutics, Inc. will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB or 
IEC according to local regulations and guidelines. 
 
12.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (refer to Appendix A) and are consistent with ICH/GCP, and applicable 
regulatory requirements. 
 
12.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate oral 
and written information about the nature, purpose, possible risk, and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject should 
be given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy of 
the signed Informed Consent Form must be given to the subject. 
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14. 
PUBLICATION POLICY 
The publication policy is detailed in the Clinical Trial Agreement.   
The data generated in this clinical trial are the exclusive property of SiteOne Therapeutics, Inc. and 
are confidential.  Written approval from SiteOne Therapeutics, Inc. is required prior to disclosing 
any information related to this clinical trial.  Authorship on any publication of the results from this 
study will be at SiteOne Therapeutics, Inc. discretion based upon contributions to study enrollment, 
data analysis and interpretation of results as well as being consistent with the Uniform Requirements 
of the International Committee of Medical Journal Editors.   
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15. 
LIST OF REFERENCES 
Alexandrou, A. J. et al.Subtype-selective small molecule inhibitors reveal a fundamental role for 
Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release. PLoS One 2016;11. 
Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national 
survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003 
Aug;97(2):534-40. 
Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, et al.  
Management of postoperative pain: a clinical practice guideline from the American Pain Society, the 
American Society of Regional Anesthesia and Pain Medicine, and the American Society of 
Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative 
Council.  J Pain. 2016 Feb;17(2):131-57. 
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. 
Dib-Hajj SD, Yang Y, Black JA, Waxman SG.  The Na(V)1.7 sodium channel: from molecule to 
man. Nat Rev Neurosci. 2013 Jan;14(1):49-62.  
Dib-Hajj SD, Geha P, Waxman SG. Sodium channels in pain disorders: pathophysiology and 
prospects for treatment. Pain. 2017 Apr;158 Suppl 1: S97-S107. 
Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, et al. SCN9A 
mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and 
phenotypes. Neuron. 2006 Dec 7;52(5):767-74. 
Gingras J, Smith S, Matson DJ, Johnson D, Nye K, Couture L, et al. Global Nav1.7 knockout mice 
recapitulate the phenotype of human congenital indifference to pain. PLoS One. 2014 Sep 4;9(9): 
e105895.  
Jurcakova, D. et al.Voltage-gated sodium channels regulating action potential generation in itch-, 
nociceptive-, and low-threshold mechanosensitive cutaneous C-fibers. Mol. Pharmacol. 
2018;94:1047–1056. 
Katz J, Clairoux M, Redahan C, Kavanagh BP, Carroll S, Nierenberg H, et al. High dose alfentanil 
pre-empts pain after abdominal hysterectomy. Pain. 1996 Nov;68(1):109-18. 
Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 
2006 May 13;367(9522):1618-25. 
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Kelly JP, Cook SF, Kaufman DW, Anderson T, Rosenberg L, Mitchell AA. Prevalence and 
characteristics of opioid use in the US adult population. Pain. 2008;138(3):507-513.  
Minett MS, Nassar MA, Clark AK, Passmore G, Dickenson AH, Wang F, et al. Distinct Nav1.7-
dependent pain sensations require different sets of sensory and sympathetic neurons. Nat Commun. 
2012 Apr 24; 3:791. 
Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, et al. Nociceptor-
specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc 
Natl Acad Sci U S A. 2004 Aug 24;101(34):12706-11. 
Ramsay MA. Acute postoperative pain management. Proc (Bayl Univ Med Cent). 2000 
Jul;13(3):244-7. 
Sharrock NE, Urquhart BL, Ganz S, Williams-Russo PG. Epidural infusions of bupivacaine and 
fentanyl do not improve rehabilitation following one-stage bilateral total knee arthroplasty. Ann 
Acad Med Singapore. 1994 Nov;23(6 Suppl):3-9. 
Wardhan R, Chelly J. Recent advances in acute pain management: understanding the mechanisms of 
acute pain, the prescription of opioids, and the role of multimodal pain therapy. F1000Res. 2017 
Nov 29;6: 2065. 
World Medical Association.  Ethical Principles for Medical Research Involving Human Subjects.  
JAMA. 2013;310(20):2191-2194. 
Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, et al. Mutations in SCN9A, encoding a sodium channel 
alpha subunit, in patients with primary erythromalgia. J Med Genet. 2004;41(3):171-174. 
Yeomans DC, Levinson SR, Peters MC, Koszowski AG, Tzabazis AZ, Gilly WF, et al. Decrease in 
inflammatory hyperalgesia by herpes vector-mediated knockdown of Nav1.7 sodium channels in 
primary afferents. Hum Gene Ther. 2005 Feb;16(2):271-7. 
Yeomans DC, Lu Y, Laurito CE, Peters MC, Vota-Vellis G, Wilson SP, et al.  Recombinant herpes 
vector-mediated analgesia in a primate model of hyperalgesia.  Mol Ther. 2006 Mar;13(3):589-97. 
 
 
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APPENDIX A:  
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects (2013) 
JAMA. 2013;310(20):2191-2194.  
 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
2. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
3. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
Investigators.  The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles. 
 
General Principles 
4. 
The Declaration of Geneva of the WMA binds the Investigator with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A Investigator shall act in the patient's best interest when providing medical 
care.” 
5. 
It is the duty of the Investigator to promote and safeguard the health, well-being, and rights 
of patients, including those who are involved in medical research.  The Investigator's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
6. 
Medical progress is based on research that ultimately must include studies involving human 
subjects. 
7. 
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures, and treatments).  Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility. and quality. 
8. 
Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
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9. 
While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects. 
10. It is the duty of Investigators who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects.  The responsibility for the protection of research 
subjects must always rest with the Investigator or other health care professionals and never 
with the research subjects, even though they have given consent. 
11. Investigators must consider the ethical, legal, and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards.  No national or international ethical, legal, or regulatory requirement 
should reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. 
12. Medical research should be conducted in a manner that minimizes possible harm to the 
environment. 
13. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training, and qualifications.  Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified Investigator or other health care professional. 
14. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
15. Investigators who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the Investigator has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research subjects. 
16. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
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APPENDIX B:  
CLINICAL LABORATORY TESTS 
Clinical Chemistry: 
Fasting Lipid Profile: 
Urinalysis: 
Serum Concentrations of: 
Total cholesterol 
Protein 
Sodium 
Triglycerides 
Specific gravity 
Potassium 
Low Density Lipoprotein (LDL) 
pH 
Chloride 
High Density Lipoprotein (HDL) 
Glucose 
Total serum CO2 
Very Low Density Lipoprotein (VLDL) 
Ketones 
Blood urea nitrogen (BUN) 
 
Bilirubin 
Total Calcium 
 
Urobilinogen 
Phosphorus 
 
Blood 
Magnesium 
Hematology: 
Nitrite 
Glucose 
Hematocrit 
Leukocyte esterase 
Creatinine 
Hemoglobin 
Urine creatinine 
Albumin 
Erythrocyte count (RBC) 
Urine uric acid 
Pre-albumin 
Leukocytes (WBC) 
 
Total protein 
Absolute counts of: 
Other: 
Alkaline phosphatase 
Neutrophils, segmented 
Follicle stimulating hormonea 
Alanine aminotransferase (ALT) 
Neutrophils, juvenile (bands) 
Activated partial thromboplastin time (aPTT) 
Aspartate aminotransferase (AST) 
Lymphocytes 
Prothrombin time/International normalized ratio (PT/INR) 
Lactate dehydrogenase (LDH) 
Monocytes 
HIV-1/HIV-2 Antibodies 
Total bilirubin 
Eosinophils 
Hepatitis B surface Antigen (HBsAg) 
Direct bilirubin 
Basophils 
Hepatitis C Antibody (HCVAb) 
Urinary drug screen (UDS) 
Uric Acid 
Platelets 
 
Gamma-glutamyl transferase (GGT) 
 
 
Creatine phosphokinase (CPK) 
 
 
 
 
 
Abbreviations:  RBC = red blood cells; WBC = white blood cells. 
Note:  All labs will be assayed by central laboratory unless otherwise noted. 
a 
In women only for confirmation of non-child-bearing potential if documented evidence of surgical sterilization is not available 
  
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APPENDIX C: 
BLOOD VOLUMES TO BE COLLECTED IN THIS STUDY  
The tables below summarize the maximum volumes for all blood sampling during screening, standard laboratory, 
and monitoring tests during the study.  Fewer samples may actually be collected, but this will not require a 
protocol amendment.  Similarly, additional samples may be drawn if needed for safety assessments. 
 
Maximum Blood Volume To be Collected 
Blood volume per 
sample (mL) 
# Samples 
collected 
Total Blood 
Volume (mL) 
Total Blood 
Volume (pint) 
Clinical Chemistry 
5 
4 
25.5 
0.053 
Coagulation 
2.7 
1 
2.7 
0.006 
Hematology 
4 
4 
12 
0.032 
Pharmacokinetics 
1 
18 
16 
0.169 
Virus serology 
8.5 
1 
8.5 
0.011 
TOTAL 
24.7 
28 
65.2 
0.138 
 
 
 
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APPENDIX D: 
TABLE FOR CLINICAL ABNORMALITIES ASSOCIATED WITH LOCAL REACTION TO 
INJECTABLE PRODUCT 
 
  
 
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