Clinical trial NCT03852459
Conditions: Pain, Acute
Sponsor: Aponia Laboratories, Inc.
Start date: 2018-01-12; Completion date: 2019-04-11
Enrollment: 251 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 2 study designed to evaluated analgesic efficacy and safety of S-Ibuprofen Topical Gel 5%

Detailed description:
The purpose of this randomized, double-blind study is to evaluate the efficacy and safety of S-Ibuprofen Topical Gel 5% in reducing pain/soreness associated with delayed onset muscle soreness (DOMS).

Arms: arm 1: S-Ibuprofen Topical Gel 5% arm 2: Vehicle Topical Gel
Interventions: intervention 1: S-Ibuprofen intervention 2: Vehicle
Intervention descriptions: intervention 1: Topical Gel 5% intervention 2: Vehicle Gel

Protocol documents:
Prot_SAP_001.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title: A Phase 2/3, Randomized, Double-Blind, Vehicle-Controlled Study to Determine 
the Efficacy and Safety of AP0302 in the Treatment of Delayed Onset Muscle 
Soreness (DOMS) 
 
NCT Number: NCT03852459 
 
Applicant/IND: Aponia Laboratories, Inc. 
 
Version Date: 02-Jul-2018  
 
 
 
 
 
 






CONFIDENTIAL 
Aponia Laboratories, Inc. 
 
Protocol Amendment 3 AP-007 
Version: 02-Jul-2018 
3 
2 STUDY SYNOPSIS 
TITLE 
A Phase 2/3, Randomized, Double-Blind, Vehicle-Controlled Study to 
Determine the Efficacy and Safety of AP0302 in the Treatment of 
Delayed Onset Muscle Soreness (DOMS) 
PROTOCOL NUMBER 
AP-007 
INVESTIGATOR AND 
STUDY SITE 
, MD 
 
 
OBJECTIVE(S) 
Primary objective: 
• 
To evaluate the efficacy of AP0302 5% (
 
 in DOMS of the elbow flexors in generally healthy 
subjects 
Secondary objective: 
• 
To evaluate the safety of AP0302 
 in DOMS of the elbow 
flexors in generally healthy subjects 
STUDY DESIGN 
This is a Phase 2/3, randomized, single-center, double-blind, 
vehicle-controlled, parallel-group study designed to determine the 
efficacy and safety of AP0302 (
 
 for the treatment of muscle 
pain/soreness associated with DOMS.  Enough subjects will be 
screened to randomize 250 subjects. 
Subjects will be screened up to 28 days prior to Day 1.  After 
completing the informed consent and screening processes, the 
following procedures will be completed: physical examination, 
medical history and concomitant medications collections, 
inclusion/exclusion criteria review, baseline laboratory testing, 12-lead 
electrocardiogram (ECG), pregnancy testing (females of child-bearing 
potential), drug and alcohol testing, and vital sign measurements. 
Subjects who meet initial inclusion/exclusion criteria will be 
scheduled to return to the research center to undergo an exercise 
regimen
 
.   
Between 
 following the end of the exercise regimen, 
subjects will return to the clinic to be evaluated for eligibility into the 
active treatment phase of the study. 
To qualify for randomization, subjects must report a
 
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Aponia Laboratories, Inc. 
 
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STUDY POPULATION 
A sufficient number of generally healthy subjects of either gender will 
be enrolled to obtain 250 randomized subjects. 
DURATION OF 
TREATMENT AND 
STUDY 
PARTICIPATION 
TEST PRODUCT, DOSE, 
AND MODE OF 
ADMINISTRATION 
REFERENCE 
THERAPY, DOSE AND 
MODE OF 
ADMINISTRATION 
ELIGIBILITY 
CRITERIA 
Inclusion criteria 
1. Generally healthy subjects of either gender aged 18 to 55 years 
(inclusive) at the time of signing the study informed consent form 
(ICF).  The subject is in good health, with no clinically significant 
medical conditions, as determined by the investigator based on 
medical and exercise history, physical examination, ECG, and 
screening laboratory results.   
2. Female subjects of childbearing potential (women who have 
experienced menarche and are not postmenopausal or permanently 
sterilized [by tubal ligation, hysterectomy, or bilateral 
salpingectomy]) will agree to use medically acceptable methods of 
contraception including but not limited to abstinence, birth control 
pills or patches, vaginal rings, diaphragm with vaginal spermicide, 
condom with vaginal spermicide, intrauterine device, and 
progestin implant or injection (used consistently for 3 months prior 
to study dosing) throughout the study and for 30 days following 
the last dose of IP.  Male subjects will agree to use abstinence or 
condom throughout the study and for 30 days following the last 
dose of IP.  Male subjects will agree to refrain from sperm 
donation and female subjects from egg donation throughout the 
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study and for 30 days following the last dose.  
3. Subject has a history of experiencing muscle pain/soreness after 
moderately strenuous exercise. 
4. Subject has a body mass index between 18 and 30, inclusive. 
5. The subject has signed the ICF approved by the Institutional 
Review Board (IRB). 
6. Subject is willing and able to complete the standardized exercise 
regimen. 
Post-Exercise: 
7
Exclusion criteria 
1. 
Subjects who have regularly worked out or exercised the upper 
extremities with weights or gym equipment during the past 
3 months. 
2. 
Subjects who have a job or hobby that involves regular lifting or 
involvement of the upper extremities (eg, rock climbers, movers, 
construction workers). 
3. 
Subjects with a history of surgery, significant trauma, significant 
musculoskeletal pathology, or significant nervous system 
pathology in the neck or in the non-dominant arm or shoulder that 
is likely to be exacerbated by the exercise regimen, in the opinion 
of the investigator. 
4. 
Subjects with any condition, in the investigator’s judgment, that 
may interfere with local tolerability assessments in the area of 
study drug application, including recently applied tattoos. 
5. 
History of any muscle disorder (eg, statin myopathy or any 
muscular dystrophy), neuropathy, fibromyalgia, rhabdomyolysis, 
or chronic fatigue syndrome. 
6. 
Presence of another painful physical condition that, in the opinion 
of the investigator, may confound study assessments. 
7. 
Any contraindication to the use of ibuprofen, or any nonsteroidal 
anti-inflammatory drug (NSAID) or cyclooxygenase-2 inhibitor, 
or aspirin, including any history of asthma or recent history of 
gastritis or gastrointestinal bleeding. 
8. 
Presence of an allergy or intolerance to any NSAID or aspirin or 
any of the components of the study drug. 
9. 
Presence of a latex allergy (customized armband components 
contain latex). 
10. Any skin condition that could potentially interfere with 
absorption of drug (eg, keloid, rash, dermatitis). 
11. Have received chronic opioid therapy defined as greater than 
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15 morphine equivalents units per day for greater than 3 out of 
7 days per week in any 1-month period within 12 months prior to 
Day 1.   
12. Have received an opioid within 30 days prior to Day 1. 
13. Routine use (defined as 3 out of 7 days per week) of any 
analgesic drug (over-the-counter [OTC] or prescription).  
14. Consumption of any medication (prescription or OTC 
medications, vitamins, minerals, and dietary supplements) within 
2 weeks prior to Day 1.  Exception: continuing hormonal 
contraception and hormone replacement therapy is allowed.   
15. Any history of drug or alcohol abuse (according to the 
investigator’s judgment) in the prior 5 years. 
16. The subject has received an investigational drug or device within 
3 months prior to screening. 
17. The subject has participated previously in this trial or the subject 
has participated in another clinical trial involving exercise of the 
upper extremities within the last 6 months. 
18. The subject is an employee or relative of an employee of the 
study site directly involved with the study. 
19. Any medical or other condition that, in the opinion of the 
investigator, might affect the subject’s ability to safely complete 
all study procedures (including the exercise regimen) or might 
interfere with the efficacy results of the study. 
EFFICACY VARIABLES 
Primary Endpoint: Sum of the time-weighted pain intensity 
differences from baseline with movement (SPIDMOVE) over 0-24 hours 
post-T0 (SPIDMOVE 0-24 hr). 
Key Secondary Endpoints: 
1. SPIDMOVE over the following intervals: 0-6, 6-12, 0-12, 12-24, 
24-36, 0-36, 24-48, 36-48, and 0-48 hours post-T0. 
Other Secondary Endpoints: 
1. Sum of time-weighted differences from baseline in muscle 
stiffness with movement (SSIDMOVE) over the following 
intervals: 0-6, 6-12, 0-12, 12-24, 0-24, 0-36, 24-48, and 0-48 
hours post-T0. 
2. Total relief with movement (TOTPARMOVE) 0-6 hours post-T0. 
3. Subject’s global assessment of study medication assessed at 
approximately 48 hours post-T0 (or upon early termination, if 
applicable). 
SAFETY VARIABLES 
• 
AEs 
• 
Local tolerability assessments 
• 
Clinical laboratory assessments 
• 
Physical examination, including neuromuscular and strength 
assessment of upper extremities 
• 
Vital signs (blood pressure, heart rate, temperature, and 
respiratory rate) 
• 
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ANALYSIS 
POPULATIONS 
Three analysis populations will be used: 
Safety Population: all subjects who receive at least 1 dose of study 
drug.   
Full Analysis Set (FAS): all subjects who are randomized, receive at 
least 1 dose of study drug, and have at least 1 post-baseline efficacy 
assessment.  
Per Protocol Set (PPS): all subjects in the FAS without a major 
protocol deviation.  The sponsor will identify which protocol 
deviations are considered major before unblinding the study. 
PRIMARY ENDPOINT 
ANALYSIS  
The primary efficacy endpoint will be the SPIDMOVE for 0-24 hours 
post-T0.  The muscle pain/soreness intensity differences will be 
calculated by subtracting each post-T0 muscle pain/soreness intensity 
score from the baseline muscle pain/soreness intensity score.  The 
weight given to each pain intensity difference (PID) will be equal to 
the elapsed time since the previous evaluation. 
The mean SPIDMOVE for 0-24 hours post-T0 will be compared between 
treatments using an analysis of covariance model with baseline muscle 
pain/soreness score as a covariate. 
 
 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .......................................................................................................................... 1 
2 
STUDY SYNOPSIS ............................................................................................................... 3 
3 
TABLE OF CONTENTS ........................................................................................................ 9 
4 
LIST OF TABLES ................................................................................................................ 11 
5 
LIST OF ACRONYMS AND ABBREVIATIONS ............................................................. 12 
6 
INTRODUCTION ................................................................................................................ 14 
6.1 
Background .................................................................................................................... 14 
6.2 
Laboratory Abnormalities Specific to Exercise ............................................................. 15 
6.3 
Safety Data on AP0302 .................................................................................................. 16 
6.4 
Indication ....................................................................................................................... 16 
6.5 
Study Rationale .............................................................................................................. 16 
7 
STUDY OBJECTIVE ........................................................................................................... 17 
7.1 
Objectives ...................................................................................................................... 17 
8 
OVERVIEW OF STUDY DESIGN ..................................................................................... 17 
8.1 
SUBJECT SELECTION ................................................................................................ 19 
8.1.1 
Inclusion Criteria .................................................................................................. 19 
8.1.2 
Exclusion Criteria ................................................................................................. 20 
8.2 
Subject Identification ..................................................................................................... 21 
8.3 
Replacement of Subjects ................................................................................................ 21 
9 
STUDY TREATMENTS ...................................................................................................... 21 
9.1 
Identification and Description of Investigational Product ............................................. 21 
9.1.1 
Study Drug ............................................................................................................ 21 
9.2 
Storage and Accountability ............................................................................................ 22 
9.3 
Study Drug Administration ............................................................................................ 22 
9.4 
Blinding ......................................................................................................................... 23 
9.5 
Study Drug Randomization ............................................................................................ 24 
9.6 
Compliance .................................................................................................................... 24 
9.7 
Study Restrictions .......................................................................................................... 24 
9.7.1 
Prior/Concomitant Medications ............................................................................ 24 
9.7.2 
Non-medicinal Therapies ...................................................................................... 24 
9.7.3 
Activity Restriction ............................................................................................... 24 
10 STUDY ASSESSMENTS .................................................................................................... 25 
10.1 Subject Rating Scales ..................................................................................................... 25 
10.1.1 
Pain Intensity NRS ................................................................................................ 25 
10.1.2 
Categorical Pain Rating Scale for Eligibility ........................................................ 25 
10.1.3 
Muscle Stiffness NRS ........................................................................................... 25 
10.1.4 
Categorical Relief Rating Scale ............................................................................ 25 
10.1.5 
Subject Global Assessment ................................................................................... 26 
10.2 Efficacy Assessments/Endpoints ................................................................................... 26 
10.2.1 
Primary Endpoint .................................................................................................. 26 
10.2.2 
Key Secondary Endpoints: .................................................................................... 26 
10.2.3 
Other Secondary Endpoints: ................................................................................. 26 
10.3 Safety and Screening Assessments ................................................................................ 27 
10.3.1 
Medical History and Exercise History .................................................................. 27 
10.3.2 
Adverse Events ..................................................................................................... 27 


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10.3.3 
Local Tolerability Assessments ............................................................................ 27 
10.3.4 
Clinical Laboratory Tests ...................................................................................... 28 
10.3.5 
Physical Examination ............................................................................................ 29 
10.3.6 
Vital Signs ............................................................................................................. 30 
10.3.7 
Electrocardiograms ............................................................................................... 30 
11 STUDY PROCEDURES ...................................................................................................... 30 
11.1 Screening Visit (Day -28 to Day -3) .............................................................................. 30 
11.2 Exercise Visit (Day -1 or -2) .......................................................................................... 31 
11.3 Treatment Period Visit (Days 1 to 3) ............................................................................. 33 
11.4 Follow-up Telephone Call on Day 7 (±1 day) ............................................................... 37 
11.5 Order of Procedures ....................................................................................................... 37 
11.6 Allowable Windows ....................................................................................................... 38 
11.7 Early Termination Assessments ..................................................................................... 38 
11.8 Subject Withdrawal ........................................................................................................ 39 
11.9 Estimated Blood Loss .................................................................................................... 39 
12 ADVERSE EVENT REPORTING ....................................................................................... 40 
12.1 Adverse Event Definition .............................................................................................. 40 
12.2 Recording of Adverse Events ........................................................................................ 40 
12.3 DOMS-Specific Arm Pain and Muscle Related Laboratory Test Abnormalities .......... 41 
12.4 Causality Assessments ................................................................................................... 41 
12.5 Severity Assessments ..................................................................................................... 42 
12.6 Serious Adverse Events ................................................................................................. 42 
12.7 Pregnancy ....................................................................................................................... 43 
13 DATA HANDLING ............................................................................................................. 43 
13.1 Case Report Forms/Electronic Data Record .................................................................. 43 
13.2 Clinical Database ........................................................................................................... 44 
14 STATISTICS ........................................................................................................................ 44 
14.1 Analysis Populations ...................................................................................................... 44 
14.2 Randomization ............................................................................................................... 45 
14.3 Sample Size Determination ............................................................................................ 45 
14.4 Efficacy Analysis ........................................................................................................... 45 
14.4.1 
Primary Efficacy Endpoint and Analysis .............................................................. 45 
14.4.2 
Key Secondary Efficacy Endpoints and Analyses ................................................ 46 
14.4.3 
Other Secondary Analyses .................................................................................... 46 
14.5 Safety Analysis .............................................................................................................. 47 
14.5.1 
Local Tolerability Scores ...................................................................................... 48 
14.6 Demographics and Baseline Characteristics .................................................................. 48 
15 REGULATORY AND ETHICAL ISSUES ......................................................................... 49 
15.1 Institutional Review Board/Independent Ethics Committee .......................................... 49 
15.2 Ethical Conduct of the Study ......................................................................................... 49 
15.3 Informed Consent ........................................................................................................... 49 
15.4 Confidentiality ............................................................................................................... 50 
15.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCPs .......... 50 
15.6 Access to Records .......................................................................................................... 50 
15.7 Retention of Records ...................................................................................................... 50 
15.8 Monitoring, Quality Control and Quality Assurance ..................................................... 51 


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15.9 Sponsor Discontinuation Criteria ................................................................................... 51 
16 PUBLICATION OF STUDY RESULTS ............................................................................. 52 
17 REFERENCES ..................................................................................................................... 53 
Appendix 1 Schedule of Assessments .......................................................................................... 56 
Appendix 2 NRS and Categorical Rating Scales .......................................................................... 58 
Appendix 3 Standardized Exercise Regimen ................................................................................ 60 
 
4 LIST OF TABLES 
Table 10-1 
Dermal Response and Numerical Equivalent ....................................................... 27 
 


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5 LIST OF ACRONYMS AND ABBREVIATIONS 
1RM 
1 repetition maximum 
AE 
adverse events 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
CK 
creatine kinase 
CRF 
case report form 
DOMS 
delayed onset muscle soreness 
ECG 
electrocardiogram 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HEENT 
head, eyes, ears, nose, and throat 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical Rating Scale 
NSAID 
non-steroidal anti-inflammatory drug 
OTC 
over-the-counter 
PI-NRS 
Pain Intensity Numerical Rating Scale 
PID 
pain intensity difference 
PPS 
Per Protocol Set 
SAE 
serious adverse event 
SOC 
system organ class 
SPIDMOVE 
sum of the time-weighted pain intensity differences from baseline with 
movement  


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SSIDMOVE 
sum of the time-weighted differences from baseline in muscle stiffness with 
movement  
T0 
time zero, time of completion of first application of study drug 
TEAE 
treatment-emergent adverse event 
TOTPARMOVE 
total relief with movement 
US 
United States 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 


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6 INTRODUCTION 
 
 
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6.4 
Indication 
The proposed indication for AP0302 
 is for 
 
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7 STUDY OBJECTIVE 
7.1 
Objectives 
The primary objective of this study is to evaluate the efficacy of AP302 
topical gel) 
 in DOMS of the elbow flexors in generally healthy subjects. 
The secondary objective is to evaluate the safety of AP0302 
in DOMS of the elbow flexors 
in generally healthy subjects. 
8 OVERVIEW OF STUDY DESIGN 
This is a Phase 2/3, randomized, single-center, double-blind, vehicle-controlled, parallel-group 
study designed to determine the efficacy and safety of AP0302 (
 
) for the treatment of muscle pain/soreness associated 
with DOMS.  Enough subjects will be screened to randomize 250 subjects.  
Subjects will be screened up to 28 days prior to the Day 1.  After completing the informed 
consent process, the following procedures will be completed:  physical examination, medical 
history and concomitant medications collection, inclusion/exclusion criteria review, baseline 
laboratory testing, 12-lead electrocardiogram (ECG), pregnancy testing (females of child-bearing 
potential), drug and alcohol testing, and vital sign measurements. 
Subjects who meet initial inclusion/exclusion criteria will be scheduled to return to the research 
center to undergo an exercise regimen 
 
 
Between 
 hours following the end of the exercise regimen, subjects will return to the 
clinic to be evaluated for eligibility into the active treatment phase of the study. 
To qualify for randomization, subjects must report a
 
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Qualified subjects will be randomized to receive either AP0302 or vehicle control. 
 
  All doses and efficacy assessments will be completed while the 
subject is an inpatient at the study site. Subjects will be awakened for IP dosing and efficacy 
assessments as necessary.   
Subjects will complete the following assessments at baseline: 
• PI-NRS with movement 
• Categorical Pain Rating score with movement (baseline only) 
• Muscle Stiffness Numerical Rating Scale (NRS) with movement  
The following assessments will be completed at
, 
 hours post-initial IP dose and immediately prior to the 
subsequent doses of IP: 
• PI-NRS with movement 
• Muscle Stiffness NRS with movement  
The following assessment will be completed at 
 post-initial IP dose and 
immediately prior to a subsequent dose of IP if one occurs prior to 
: 
• Relief from starting pain with movement on the Categorical Relief Rating Scale.   
At
 post-initial dose (or prior to early termination, if applicable), the subject will 
complete a Subject Global Assessment to give their overall assessment of the IP. 
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Safety evaluations will include AE reports, physical examination, vital signs, ECG, application 
site assessments and laboratory testing.  The final safety assessments will be done approximately 
6 hours after the last dose, and subjects will be discharged from the site at that time.  There will 
be a safety Follow-up Telephone Call on Day 7 (±1 day). 
8.1 
SUBJECT SELECTION 
8.1.1 Inclusion Criteria 
1. Generally healthy subjects aged 18 to 55 years (inclusive) at the time of signing the study 
informed consent form (ICF).  The subject is in good health, with no clinically significant 
medical conditions, as determined by the investigator based on medical and exercise history, 
physical examination, ECG, and screening laboratory results.   
2. Female subjects of childbearing potential (women who have experienced menarche and are 
not postmenopausal or permanently sterilized [by tubal ligation, hysterectomy, or bilateral 
salpingectomy]) will agree to use medically acceptable methods of contraception including 
but not limited to abstinence, birth control pills or patches, vaginal rings, diaphragm with 
vaginal spermicide, condom with vaginal spermicide, intrauterine device, and progestin 
implant or injection (used consistently for 3 months prior to study dosing) throughout the 
study and for 30 days following the last dose of IP.  Male subjects will agree to use 
abstinence or condom throughout the study and for 30 days following the last dose of IP.  
Male subjects will agree to refrain from sperm donation and female subjects from egg 
donation throughout the study and for 30 days following the last dose.  
3. Subject has a history of experiencing muscle pain/soreness after moderately strenuous 
exercise. 
4. Subject has a body mass index between 18 and 30, inclusive. 
5. The subject has signed the ICF approved by the Institutional Review Board (IRB). 
6. Subject is willing and able to complete the standardized exercise regimen. 
Post-Exercise: 
7.
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“moderate” on a Categorical Pain Rating Scale using the words “none” “mild,” “moderate,” 
or “severe.”  
8.1.2 Exclusion Criteria 
1. Subjects who have regularly worked out or exercised the upper extremities with weights or 
gym equipment during the past 3 months. 
2. Subjects who have a job or hobby that involves regular lifting or involvement of the upper 
extremities (eg, rock climbers, movers, construction workers). 
3. Subjects with a history of surgery, significant trauma, significant musculoskeletal pathology, 
or significant nervous system pathology in the neck or in the non-dominant arm or shoulder 
that is likely to be exacerbated by the exercise regimen, in the opinion of the investigator. 
4. Subjects with any condition, in the investigator’s judgment, that may interfere with local 
tolerability assessments in the area of study drug application, including recently applied 
tattoos. 
5. History of any muscle disorder (eg, statin myopathy or any muscular dystrophy), 
neuropathy, fibromyalgia, rhabdomyolysis, or chronic fatigue syndrome. 
6. Presence of another painful physical condition that, in the opinion of the investigator, may 
confound study assessments. 
7. Any contraindication to the use of ibuprofen, or any nonsteroidal anti-inflammatory drug 
(NSAID) or cyclooxygenase-2 inhibitor, or aspirin, including any history of asthma or 
recent history of gastritis or gastrointestinal bleeding. 
8. Presence of an allergy or intolerance to any NSAID or aspirin or any of the components of 
the study drug. 
9. Presence of a latex allergy (customized armband components contain latex). 
10. Any skin condition that could potentially interfere with absorption of drug (eg, keloid, rash, 
dermatitis). 
11. Have received chronic opioid therapy defined as greater than 15 morphine equivalents units 
per day for greater than 3 out of 7 days per week in any 1-month period within 12 months 
prior to Day 1.   
12. Have received an opioid within 30 days prior to Day 1. 
13. Routine use (defined as 3 out of 7 days per week) of any analgesic drug (OTC or 
prescription).  


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14. Consumption of any medication (prescription or OTC medications, vitamins, minerals, and 
dietary supplements) within 2 weeks prior to Day 1.  Exception: continuing hormonal 
contraception and hormone replacement therapy is allowed.   
15. Any history of drug or alcohol abuse (according to the investigator’s judgment) in the prior 
5 years. 
16. The subject has received an investigational drug or device within 3 months prior to 
screening. 
17. The subject has participated previously in this trial or the subject has participated in another 
clinical trial involving exercise of the upper extremities within the last 6 months. 
18. The subject is an employee or relative of an employee of the study site directly involved 
with the study. 
19. Any medical or other condition that, in the opinion of the investigator, might affect the 
subject’s ability to safely complete all study procedures (including the exercise regimen) or 
might interfere with the efficacy results of the study. 
8.2 
Subject Identification 
Subjects will be identified by an assigned screening number and randomization number to 
maintain confidentiality.  
8.3 
Replacement of Subjects 
Subjects who discontinue prior to completion of the study may be replaced at the sponsor’s 
discretion. 
9 
STUDY TREATMENTS 
9.1 
Identification and Description of Investigational Product 
9.1.1 Study Drug 
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9.2 
Storage and Accountability 
9.3 
Study Drug Administration 
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9.4 
Blinding 
This is a double-blind, randomized study.  The sponsor, site staff and subjects will be blinded as 
to whether each tube of IP contains active treatment or vehicle.  The study blind may be broken 
for a specific subject only in the event of a medical emergency and when a decision regarding 
the subject’s condition requires knowledge of the treatment assignment.  Any such cases will be 
clearly justified and explained in a note to file.  The investigator will notify the Aponia medical 
monitor immediately in the event of the situation.   
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9.5 
Study Drug Randomization 
Subjects will be required to meet the eligibility for study drug application on Day 1 (see 
Section 11.3), prior to assignment of the study drug box.  Study drug boxes will be assigned by 
predetermined randomization and distributed sequentially starting with the lowest box number.   
9.6 
Compliance 
Study staff will observe and document each dose of study medication application.  The tubes will 
be weighed prior to the first dose and after the last dose. 
9.7 
Study Restrictions 
9.7.1 Prior/Concomitant Medications  
The following restrictions on prior/concomitant medications will apply: 
• May not have received chronic opioid therapy defined as greater than 15 morphine 
equivalents units per day for greater than 3 out of 7 days per week in any 1-month period 
within 12 months prior to Day 1.   
• May not have received an opioid within 30 days prior to Day 1. 
• Must not routinely use (defined as 3 out of 7 days per week) any analgesic drug (OTC or 
prescription).  
• Must not have consumed of any medication (prescription or OTC medications, vitamins, 
minerals, and dietary supplements) within 2 weeks prior to randomization.  Exception: 
continuing hormonal contraception and hormone replacement therapy is allowed.   
Any medication, including supplements, vitamins, and non-medicinal therapies taken by the 
subject from 30 days prior to the Screening Visit through the Follow-up Telephone Call will be 
recorded in the case report form (CRF). 
9.7.2 Non-medicinal Therapies 
Between the end of the exercise regimen and throughout the inpatient treatment phase, the 
application of heat, ice or other non-medicinal therapies involving the non-dominant arm are 
prohibited. 
9.7.3 Activity Restriction 
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10 STUDY ASSESSMENTS  
10.1 Subject Rating Scales 
Subjects will receive training on how to use rating scales to report muscle pain/soreness, muscle 
stiffness and relief from starting pain (see separate study reference document and subject rating 
scales presented in Appendix 2).
  
10.1.1 Pain Intensity NRS 
Subjects will rate muscle pain/soreness with movement 
 
10.1.2 Categorical Pain Rating Scale for Eligibility 
At baseline only, subjects will also report muscle pain/soreness with movement on the 
Categorical Pain Rating Scale: “none,” “mild,” “moderate” or “severe.” 
 
. 
10.1.3 Muscle Stiffness NRS  
Subjects will rate muscle stiffness with movement using an 11-point Muscle Stiffness NRS 
anchored at zero (0) for no stiffness and 10 for the worst possible stiffness. 
10.1.4 Categorical Relief Rating Scale 
Subjects will rate relief from starting pain with movement using a 5-point categorical relief scale: 
“no relief,” “a little relief,” “some relief,” “a lot of relief,” or “complete relief.” 
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10.1.5 Subject Global Assessment  
Subjects will rate their global assessment by answering the following question:   
Overall, how would you rate the investigational product you received? 
□ Poor (0) 
□ Fair (1) 
□ Good (2) 
□ Very Good (3) 
□ Excellent (4) 
10.2 Efficacy Assessments/Endpoints 
10.2.1 Primary Endpoint 
The primary endpoint is the sum of the time-weighted pain intensity differences (PIDs) from 
baseline with movement (SPIDMOVE) over 0-24 hours post-T0 (SPIDMOVE 0-24 hours). Muscle 
pain/soreness with movement will be scored using the PI-NRS described in Section 10.1.1 at the 
time points described in Section 11. The PIDs from 0-24 hours after T0 will be calculated by 
subtracting each post-T0 pain score from the baseline (prior to T0) pain score.  The weight given 
to each PID will be equal to the elapsed time since the previous evaluation.  
10.2.2 Key Secondary Endpoints: 
• SPIDMOVE over the following intervals: 0-6, 6-12, 0-12, 12-24, 24-36, 0-36, 24-48, 36-48, 
and 0-48 hours post-T0. 
10.2.3 Other Secondary Endpoints: 
• Sum of time-weighted differences from baseline in muscle stiffness with movement 
(SSIDMOVE) over the following intervals: 0-6, 6-12, 0-12, 12-24, 0-24, 0-36, 24-48, and 
0-48 hours post-T0. 
• Total relief with movement (TOTPARMOVE) over 0-6 hours post-T0. 
• Subject’s global assessment of study medication assessed at approximately 48 hours 
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10.3 Safety and Screening Assessments 
10.3.1 Medical History and Exercise History 
A complete medical history will be taken at the Screening Visit.  The medical history will 
include significant past medical or surgical procedures as well as previous and current 
co-existent diseases.  It should include relevant medical history for the following body systems: 
head, eyes, ears, nose, and throat (HEENT); respiratory; cardiovascular; gastrointestinal; 
endocrine; hematological; dermatological; genital-urinary (including reproductive history); 
neurological; musculoskeletal; psychological/psychiatric; and any other history of medical 
significance.  Changes in health occurring between the Screening Visit and the Treatment Period 
Visit, prior to the first dose of study medication, will be captured as medical history. 
At the Screening Visit and Exercise Visit, subjects will be questioned about their exercise history 
to verify continued eligibility.  Subjects who have worked out or exercised the upper extremities 
with weights or gym equipment during the past 3 months will not be eligible for the study. 
10.3.2 Adverse Events 
Adverse events will be defined, described, recorded, and reported according to Section 12. 
10.3.3 Local Tolerability Assessments 
 
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10.3.4 Clinical Laboratory Tests 
The subjects are not required to be in the fasted state for the clinical laboratory testing.  
Laboratory testing (multiphasic chemistry panel, hematology panel, coagulation, and urinalysis) 
will be performed at the Screening Visit and on Day 3 at 54 hours post T0.  Screening laboratory 
tests must be reviewed for clinical significance prior to exercise at the Exercise Visit on Day -1 
or 2. 
Urine drug screens and alcohol breath tests will be performed at the Screening Visit, at the 
Exercise Visit, and on Day 1 prior to the first dose.  Urine dipsticks will be used for the urine 
drug screens. 
In women of childbearing potential (WOCBP; women who have experienced menarche and are 
not postmenopausal or permanently sterilized [by tubal ligation, hysterectomy, or bilateral 
salpingectomy]), urine pregnancy tests will be performed at the Screening Visit, Exercise Visit 
and on Day 1 (pre-dose).  
: 
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 Physical Examination 
A complete physical examination will be conducted during the Screening Visit and on Day 3 at 
54 hours and will include assessment of the following: HEENT; neck (including an examination 
of the thyroid); heart; lungs; abdomen (including an examination of the liver and spleen); lymph 
nodes; extremities; nervous system; and skin.   
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An abbreviated, symptom-directed physical examination will be performed at the Exercise Visit 
on Day -1 or -2.  The abbreviated, symptom-directed physical examination is to be performed at 
the Exercise Visit to re-assess any abnormal clinically significant findings identified at the 
screening exam and/or to assess any current symptoms at the time of the symptom-directed 
exam.  If there are no abnormal clinically significant findings at the screening visit AND no 
current symptoms, a symptom-directed examination is not required. 
10.3.6 Vital Signs 
Vital signs (blood pressure, heart rate, temperature, and respiratory rate) will be recorded at the 
Screening Visit, at the Exercise Visit (Day -1 or 2), on Day 1 pre-dose, and Day 3 at 54 hours (or 
at early termination, if applicable).  Measurements are to be obtained after the subject has been 
seated and resting quietly for at least 5 minutes.   
Height and weight will be recorded at the Screening Visit. 
10.3.7 Electrocardiograms 
A 12-lead ECG will be recorded at the Screening Visit and on Day 3 after the subject has been in 
the supine position resting quietly for 10 minutes.  The results must be reviewed for clinically 
meaningful deviations from normal prior to exercise. 
11 STUDY PROCEDURES  
An overview of the study assessments and procedures is presented in the Schedule of 
Assessments, Appendix 1. 
11.1 Screening Visit (Day -28 to Day -3) 
The investigator or designated qualified study personnel will perform the following assessments 
at the Screening Visit:  
• Obtain written informed consent. 
• Verify eligibility via inclusion and exclusion criteria.  
• Record demographics. 
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• Obtain medical history and exercise history.  Subjects who have exercised the upper 
extremities with weights or gym equipment within the prior 3 months will not be eligible 
for the study. 
• Height and weight will be recorded. 
• Record prior/current medications and non-medicinal therapies. 
• Perform a physical examination, 
 
 (as described in Section 10.3.5). 
• Record vital sign measurements (blood pressure, heart rate, temperature, and respiratory 
rate) after subject has been in a seated position and resting quietly for at least 5 minutes.   
• Perform 12-lead ECG with the subject in a supine position after subject has been resting 
quietly for 10 minutes.  Results must be reviewed for clinically meaningful deviations 
from normal prior to exercise. 
• Obtain screening laboratory tests as follows: 
o Obtain blood and urine for screening laboratory tests (multiphasic chemistry, 
hematology, coagulation, and urinalysis).  
o Obtain urine for urine drug screen.  
o Perform alcohol breath test. 
o Obtain sample for urine pregnancy test for WOCBP. 
All information and clinical findings will be recorded in the appropriate sections of the CRFs.  
The investigator will make the final determination of whether a subject is eligible for the study.  
All subjects screened will be documented on the Screening Log.  Specific reasons for excluding 
any potential subject will be recorded. 
11.2 Exercise Visit (Day -1 or -2) 
Subjects will return to the research unit on the day of exercise.  
 
 
The following assessments and procedures will be performed prior to the exercise: 
• Eligibility will be re-assessed. 
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• Update medical history.  Changes in health between the Screening Visit and the Exercise 
Visit will be captured as medical history. 
• Record prior/current medications and non-medicinal therapies. 
• An abbreviated, symptom-directed physical examination will be performed, if indicated. 
• Vitals signs (blood pressure, heart rate, temperature, and respiratory rate) will be 
collected after the subject has been seated for at least 5 minutes. 
• Obtain urine and perform urine drug screen.  Results should be reviewed prior to 
exercise. 
• Obtain urine sample and perform urine pregnancy test in WOCBP.  Results should be 
reviewed prior to exercise. 
• Perform the alcohol breath test.  Results should be reviewed prior to exercise. 
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11.3 Treatment Period Visit (Days 1 to 3) 
 
.  The following assessments and procedures will be performed to determine 
eligibility: 
• Eligibility will be re-assessed. 
• Update medical history.  Changes in health between the Screening Visit until the 
Treatment Period Visit, prior to the first dose of study medication, will be captured as 
medical history. 
• Review prior/current medications and non-medicinal therapies. 
• Vitals signs (blood pressure, heart rate, temperature, and respiratory rate) will be 
collected after the subject has been seated for at least 5 minutes. 
• Obtain urine for a urine drug screen.  Results should be reviewed prior to treatment with 
IP. 
• Perform the alcohol breath test.  Results should be reviewed prior to treatment with IP. 
• Obtain sample for urine pregnancy test in WOCBP.  Results should be reviewed prior to 
treatment with IP. 
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• The following assessments are to be completed at 
, 
 post first dose of IP and immediately 
prior to the subsequent doses of IP: 
o Muscle pain/soreness with movement on the PI-NRS  
o Muscle Stiffness with movement on the Muscle Stiffness NRS  
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• The following assessment is to be completed at 
 post first dose of 
IP and immediately prior to a subsequent dose of IP, if one occurs prior to 
 
o Relief from starting pain with movement on the Categorical Relief Rating 
Scale 
• 
 
 
. 
• At approximately 
 post-T0, the Subject Global Assessment of IP will be recorded 
in addition to the
 NRS assessments. 
• 
 
• Record any AEs and any concomitant medications or non-medicinal therapies throughout 
the visit. 
On Day 3, at approximately 
 post-T0, the following assessments and procedures will be 
performed: 
• 
 
 
• Perform a physical examination,
 
). 
• Record vital sign measurements (blood pressure, heart rate, temperature, and respiratory 
rate) after subject has been in a seated position and resting quietly for at least 5 minutes.   
• Perform 12-lead ECG with the subject in a supine position after subject has been resting 
quietly for 10 minutes. 
• Obtain laboratory tests as follows: 
o Obtain blood and urine for laboratory tests (multiphasic chemistry, hematology, 
coagulation, and urinalysis).  
• Any AEs and concomitant medications or non-drug therapies will be recorded. 
After these final assessments have been performed, the subject can be discharged from the site. 
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11.4 Follow-up Telephone Call on Day 7 (±1 day) 
Subjects will be called on Day 7 (±1 day) and the following assessments will be performed: 
• Record prior/current medications and non-medicinal therapies. 
• Record any AEs. 
Each AE will be followed until it resolves, until the investigator assesses the subject’s status to 
have returned to baseline, or until the investigator feels that the event is stable and chronic. 
11.5 Order of Procedures 
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11.6 Allowable Windows 
11.7 Early Termination Assessments 
Subjects who discontinue early from the study after receiving IP, will undergo the following 
assessments and procedures: 
• The subject’s global assessment of IP will be recorded (if termination is prior to this 
48-hour assessment). 
• Perform a physical examination, including a neuromuscular and strength assessment of 
the upper extremities (as described in Section 10.3.5). 
• Record vital sign measurements (blood pressure, heart rate, temperature, and respiratory 
rate) after subject has been in a seated position and resting quietly for at least 5 minutes.   
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• Perform 12-lead ECG with the subject in a supine position after subject has been resting 
quietly for 10 minutes. 
• Obtain laboratory tests as follows: 
o Obtain blood and urine for laboratory tests (multiphasic chemistry, hematology, 
coagulation, and urinalysis).  
• Any AEs and concomitant medications or non-drug therapies will be recorded. 
11.8 Subject Withdrawal 
If a subject withdraws from the study after the receipt of IP, this will be considered an early 
withdrawal and the subject should undergo the assessments presented in Section 11.7. 
The sponsor should be notified of any withdrawals, and the investigator should record the reason 
for discontinuation in the CRF.  A subject may be removed from the study for medical or 
administrative reasons such as the following: 
• AE 
• Lack of efficacy 
• Noncompliance with study drug 
• Protocol deviation 
• Subject withdrawal 
• Lost to follow-up 
• Physician decision 
• Other reasons as determined by the investigator or the sponsor 
11.9 Estimated Blood Loss 
The amount of blood loss during this study per each subject is estimated to be as follows: 
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12 ADVERSE EVENT REPORTING 
12.1 Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not considered related to the 
medicinal (investigational) product. 
A TEAE is defined as an AE that is new or worsened in severity after the first dose of study 
drug. 
12.2 Recording of Adverse Events 
The investigator should record any AEs that occur from time of first dose of study medication to 
14 days after the last dose of study drug; the investigator should record any SAEs from the time 
of signing the ICF until 30 days after the last dose of study drug.  Adverse events will not be 
considered treatment-emergent unless they are new or worsened in severity after the first dose of 
study drug. 
At each contact with the subject, the investigator or designee must seek information on AEs by 
specific questioning and, as appropriate, by examination.  All observed or volunteered AEs, 
regardless of suspected causal relationship to study drug, must be recorded on the AE page of the 
CRF. 
Any events involving illnesses or injuries with onset during the study or any events involving 
exacerbations of pre-existing illnesses should be recorded.  All clearly related signs and 
symptoms should be grouped together and recorded as a single diagnosis in the CRF.  A 
pre-existing condition must not be reported as an AE unless the condition worsens during the 
trial.  The condition, however, must be reported in the Medical History section of the CRF. 
Scheduled or planned diagnostic and therapeutic procedures such as surgery must not be reported 
as AEs.  The scheduled procedure and medical condition for which the procedure was performed 
must be reported in the CRF. 
Each AE will be judged as to the relationship to study medication (as defined in Section 12.4), 
the severity (as defined in Section 12.5), and whether it meets the criteria for an SAE (as defined 
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Adverse events will be followed until resolution or until the investigator assesses the subject’s 
status to have returned to normal, or until the investigator feels that the event is stable and 
chronic.  
12.3 
 
12.4 Causality Assessments 
Each AE will be judged as to whether it is related, possibly related, or unrelated to the IP.  The 
following definitions will be used for these causality assessments. 
Related:  This causal relationship is assigned when the AE: 
• starts a reasonable time after study drug administration, 
• stops/improves when study drug has been stopped, 
• can reasonably be explained by known characteristics of the study drug, and 
• cannot be reasonably explained by the subject’s clinical state. 
Possibly Related:  This causal relationship is assigned when the AE: 
• starts a reasonable time after study drug administration, but 
• could have been produced by the subject’s clinical state or other modes of therapy 
administered to the subject. 
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A CRF is required and should be completed for each screened subject.  The completed original 
CRFs are the sole property of Aponia Laboratories, Inc. and should not be made available in any 
form to third parties, except for authorized representatives of Aponia Laboratories, Inc. or 
appropriate regulatory authorities, without written permission from Aponia Laboratories, Inc. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety 
and laboratory data entered on the CRFs and data collection forms (source documents) and 
ensuring that they are accurate, authentic / original, attributable, complete, consistent, legible, 
timely (contemporaneous), enduring and available when required.  The CRFs must be signed by 
the investigator to attest that the data contained on the CRFs are true.  Any corrections to entries 
made in the CRFs, source documents must be dated, initialed and explained (if necessary) and 
should not obscure the original entry.  
13.2 Clinical Database 
Creation and validation of the clinical database and entry and management of data will be 
conducted in accordance with Title 21 of the Code of Federal Regulations Part 11 and the 
guidance for industry on computerized systems used in clinical trials.  Methods used to ensure 
the quality and integrity of the data will be documented in the data management plan. 
14 STATISTICS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan, which will be signed off prior to the database lock.  
14.1 Analysis Populations 
The following populations will be utilized: 
• Safety Population: all subjects who receive at least 1 dose of study drug.  The 
demographic, baseline characteristics, and safety data summaries will be based on the 
Safety Population. 
• Full Analysis Set (FAS): all subjects who are randomized, receive at least 1 dose of 
study drug, and have at least 1 post-baseline efficacy assessment. 
• Per Protocol Set (PPS): all subjects in the FAS without a major protocol deviation.  The 
sponsor will identify which protocol deviations are considered major before unblinding 
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14.2 Randomization 
Study drug will be assigned by predetermined randomization and distributed sequentially starting 
with the lowest available randomization number.  Assignment to active and vehicle control will 
be in a 1:1 ratio. 
14.3 Sample Size Determination 
A sufficient number of generally healthy subjects of either gender will be enrolled to obtain 
250 randomized subjects.  The sample size of 250 subjects (125 for each of the treatment group) 
 
 
14.4 Efficacy Analysis 
All statistical testing will be performed with a 2-sided 0.05 level of significance.  For each of the 
time intervals analyzed, completion of administration of the first dose of study drug is considered 
time 0, T0.  Efficacy parameters will be analyzed using both the FAS and the PPS. 
14.4.1 Primary Efficacy Endpoint and Analysis 
The primary efficacy outcome is the sum of the time-weighted differences from baseline in 
muscle pain/soreness with movement (SPIDMOVE) over 0-24 hours post-T0 (SPIDMOVE 0-24h), that 
is the area under the differences from baseline pain/soreness intensity difference curve. 
The PIDs with movement from time point A to time point B will be calculated using the 
trapezoid rule by subtracting each post-T0 pain score with movement from the pain score with 
movement at time point Ti as follows: 
•
PID with movement at time point i (PIDMOVE i) = NRS score with movement at time point
i – NRS score with movement at baseline.
•
Mean of adjacent pain intensity differences MMOVEi = (PIDMOVEi  +  PIDMOVE i+1) / 2
•
The weight given to each MMOVE i score (Wi) = elapsed time to the next evaluation (ti+1 –
ti).
•
SPIDMOVE A-B hr = 
𝑊!
!!!
!!!
 𝑀!"#$%  where i refers to each NRS scheduled assessment 
time point between A and B (not including B). 
Thus, SPIDMOVE 0-24h =
𝑊!𝑀!"#$!
!"
!!!
, where i refers to each NRS scheduled assessment time 
point between baseline and 24 hours. 
 
 
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The general formula for computing SPID between any two time points a and b is as follows:  
𝑆𝑃𝐼𝐷!!! = 
𝑡!!! −𝑡!
𝑃𝐼𝐷!!! + 𝑃𝐼𝐷!
2
!!!
!!!
 
Where i refers to each scheduled assessment time point between a and b hours post 
baseline, ti is the ith time point and PIDi is the pain intensity difference at time i 
The mean SPIDMOVE for 0-24 hours post-T0 will be compared between the 2 treatment groups 
using an analysis of covariance (ANCOVA) model with baseline pain/soreness score as a 
covariate.  
14.4.2 Key Secondary Efficacy Endpoints and Analyses 
Following the similar formula mentioned in the previous section, the following SPIDMOVE for the 
different time intervals will be estimated and compared for the 2 treatment groups using the same 
ANCOVA model. 
• SPIDMOVE over the following intervals: 0-6, 6-12, 0-12, 12-24, 24-36, 0-36, 24-28, 36-48, 
and 0-48 hours post-T0.  The mean SPIDMOVE for 0-6, 6-12, 0-12, 12-24, 24-36, 0-36, 
24-28, 36-48, and 0-48 hours post-T0 will be compared between the 2 treatment groups 
(active versus vehicle) using an ANOCVA model with the baseline pain/soreness score as 
the covariate. 
14.4.3 Other Secondary Analyses 
The following other secondary endpoints for different time intervals will be compared between 
the 2 treatment groups using an ANCOVA model with the baseline pain/soreness score as the 
covariate. 
• 
SSIDMOVE over the following intervals: 0-6, 6-12, 0-12, 12-24, 0-24, 0-36, 24-48, and 
0-48 hours post-T0. The mean SSIDMOVE for 0-6, 6-12, 0-12, 12-24, 0-24, 0-36, 24-28, 
and 0-48 hours post-T0 will be compared between the 2 treatment groups (active versus 
vehicle) using an ANOCVA model with the baseline muscle stiffness score as the 
covariate. 
• TOTPARMOVE over 0-6 hours post-T0.  An ANOVA model will be used for these efficacy 
endpoints. 
TOTPARMOVE A-B hr = 
𝑷𝑹𝒊
𝑩!𝟏
𝒊!𝑨
 𝑯    where i refers to each pain relief scheduled 
assessment time point between A and B (not including B).  
 
  
 
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The TOPAR endpoints will be compared between the 2 treatment groups using an 
ANOVA model.  
The subject’s global assessment of efficacy will be assessed at approximately 48 hours post-T0 
(or upon early termination if the subject withdraws prior to the 48-hour assessment).  The 
distribution of 5 categories (poor, fair, good, very good, or excellent) will be compared between 
the 2 treatments (active versus vehicle) using the Chi-Squared test.  In addition, the 5 categories 
will be dichotomized into 2 categories (good/very good/excellent versus poor/fair).  The 
proportion of good, very good, and excellent ratings will be calculated for each treatment.  This 
proportion will be compared between the 2 treatments (active versus vehicle) using the Fisher’s 
Exact test. 
14.5 Safety Analysis 
For the safety analysis, descriptive statistics such as mean, median, minimum, maximum, and 
standard deviation will be summarized for continuous variables.  Frequency distributions will be 
summarized for categorical variables.  Since all subjects will receive vehicle on the dominant 
arm in addition to blinded study drug on the non-dominant arm, some subjects will receive both 
active and vehicle treatments. All safety-related data will be summarized as an overall group 
except AEs related to the area of application. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.1 (or higher).  For summary tables, AEs coded to the same preferred term will be 
counted only once within a given subject.  If an AE was recorded on multiple occasions in the 
same treatment period, only the highest severity and the highest degree of relationship to the 
study drug will be presented.  If 2 or more clinical events are reported within a single AE entry, 
then the corresponding individual preferred terms will be coded separately.   
All AEs, including those that are not treatment-emergent, will be listed.  All summaries of AEs 
will be of TEAEs.  A TEAE is defined as an AE that is new or worsened in severity after the first 
dose of study drug.  Adverse events will be summarized by system organ class (SOC), and 
preferred term.  Summaries will be prepared for all AEs, treatment-related AEs, and SAEs.  The 
AE summary will also be presented with a breakdown by severity.  Adverse events that are 
specific to the arm, such as application site reactions, will be summarized by treatment (active 
versus vehicle).  
Changes from baseline in chemistry, hematology, coagulation, and urinalysis parameters will be 
summarized descriptively.  Laboratory results will be classified as low, normal, or high according 
to the laboratory-supplied reference ranges.  Shift tables describing out-of-range shifts from 


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baseline (in frequency counts) will be created and presented by treatment.  All laboratory results 
will be listed. 
The results of physical examinations will be summarized by body categories with frequency and 
percentages of normal versus abnormal, and if abnormal whether it is clinically significant or 
non-clinically significant.  A listing of physical examination results will be presented by subject and 
assessment time point. 
Results of the ECGs will be presented as normal, abnormal (clinically significant), and abnormal 
(not clinically significant).  These results will be listed by subject and summarized descriptively.  
Vital signs will be listed by subject and summarized descriptively by time point. 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary and summarized descriptively.  Prior medications are defined as any medications 
started prior to the day of the first dose of study drug.  Concomitant medications are defined as any 
medications taken on the day of or after the first dose of study drug.  Prior and concomitant 
medications will be coded using the WHO Drug Dictionary version of September 2014.  A 
by-subject listing will be generated that contains both prior and concomitant treatments.  
Medications will be classified according to primary 4th level Anatomical Therapeutic Chemical 
codes and WHO Drug preferred terms in the listing.  Subjects may have more than 1 concomitant 
treatment per drug class and per preferred term.  Summary tables will be generated by treatment for 
both prior and concomitant treatments.  In these summary tables, a subject will be counted only 
once for a given prior or concomitant treatment.  Prior and concomitant non-medicinal therapies 
(non-drug treatments) will be coded using MedDRA and then summarized in a similar manner as 
prior and concomitant medications. 
 
14.6 Demographics and Baseline Characteristics 
Demographic characteristics will be listed by subject and will be summarized descriptively.  
Medical history will be coded using MedDRA and summarized by SOC and preferred term.   
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15 REGULATORY AND ETHICAL ISSUES 
15.1 Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Aponia Laboratories, Inc. 
Any changes to the protocol will require approval of the sponsor, in writing, and the IRB/IEC 
prior to implementation.  The only circumstance in which an amendment may be initiated prior 
to IRB/IEC approval is where the change is necessary to eliminate apparent immediate hazards 
to the subjects.  In that event, the investigator must notify the IRB/IEC and Aponia Laboratories, 
Inc. in writing immediately after the implementation. 
15.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, the FDA, applicable local 
regulatory requirements and laws, as well as the general principles set forth in the International 
Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for 
International Organizations of Medical Sciences 2002), Guidelines for Good Clinical Practices 
(GCPs) (International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use [ICH] 1996), and the Declaration of Helsinki (World Medical 
Association 2008).  The rights, safety, and well-being of the study subjects are the most 
important consideration and prevail over the interests of science and society.  All personnel 
involved in the conduct of this study must be qualified by education, training, and experience to 
perform their assigned responsibilities.  
15.3 Informed Consent 
The investigator, or a person designated by the investigator, will obtain voluntary written 
informed consent from each subject or the subject's legal representative before any study-specific 
activity is performed.  The investigator must ensure that each study subject, or his/her legal 
representative, is fully informed about the nature and objectives of the study and possible risks 
associated with participation.  The subject will be given ample time to review the ICF and the 
opportunity to discuss any questions before making a decision about participation in this study.  
The process of informed consent will be documented in the subject’s source data.  The 
investigator will retain the original of each subject's signed consent document and a signed copy 
will be provided to the subject. 


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The informed consent document must be in compliance with ICH guideline on GCPs, the FDA, 
local regulatory requirements, and legal requirements. 
The informed consent document used in this study, and any changes made during the course of 
the study, must be approved by both the IRB/IEC and Aponia Laboratories, Inc. before use. 
15.4 Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
law.  
Subject names, addresses, birth dates, and other identifiable data will be replaced by a numerical 
code consisting of a numbering system provided by Aponia Laboratories, Inc. in order to 
de-identify the subjects.  In case of data transfer, Aponia Laboratories, Inc. will maintain high 
standards of confidentiality and protection of subject personal data. 
15.5 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCPs 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
product, Aponia Laboratories, Inc. should be informed immediately.   
In addition, the investigator will inform Aponia Laboratories, Inc. immediately of any urgent 
safety measures taken by the investigator to protect the study subjects against any immediate 
hazard, and of any serious breaches of this protocol or of ICH GCPs that the investigator 
becomes aware of. 
15.6 Access to Records 
The investigator and study personnel will permit study-related monitoring, audits, IRB/IEC 
review, and regulatory inspections by providing direct access to source data and documents. 
15.7 Retention of Records 
To enable evaluations and/or audits from regulatory authorities or Aponia Laboratories, Inc., the 
investigator agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed consent 
documents, copies of all CRFs, safety reporting forms, source documents, and detailed records of 
treatment disposition, and adequate documentation of relevant correspondence (eg, letters, 
meeting minutes, telephone calls reports).   


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The investigator must arrange for retention of study records at the site for 2 years after the 
AP0302 5% New Drug Application is approved or the Investigational New Drug application is 
withdrawn, as required by FDA regulations.  If the investigator becomes unable for any reason to 
continue to retain study records for the required period (eg, retirement, relocation), Aponia 
Laboratories, Inc. should be immediately notified.  The study records must be transferred to a 
designee acceptable to Aponia Laboratories, Inc., such as another investigator, another 
institution, or to an independent third party arranged by Aponia Laboratories, Inc.     
The investigator must obtain Aponia's written permission before disposing of any records, even 
if retention requirements have been met. 
15.8 Monitoring, Quality Control and Quality Assurance  
During study conduct, Aponia Laboratories, Inc., or its agent will conduct periodic monitoring 
visits to ensure that the protocol and GCPs are being followed.  The monitor will ensure there are 
no deviations to the informed consent process for all screened subjects.  Source data will be 
reviewed to confirm that there are no deviations to the study protocol and data recorded on CRFs 
are accurate.  The monitor will ensure the following:  that essential documents are maintained 
and IRB approval current; that the study drug is stored appropriately; that drug accountability 
records are complete and accurate; and that the site’s resources remain adequate for the conduct 
of the trial.  The investigator and institution will allow Aponia Laboratories, Inc. monitors or its 
agents and appropriate regulatory authorities direct access to source documents and all study 
records to perform this verification. 
The study site may be subject to review by the IRB/IEC, to quality assurance audits performed 
by Aponia Laboratories, Inc., or companies working with or on behalf of Aponia Laboratories, 
Inc., and/or to inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
15.9 Sponsor Discontinuation Criteria 
Premature termination of this study may occur because of a regulatory authority decision, change 
in opinion of the IRB/IEC, drug safety problems, or at the discretion of Aponia Laboratories, Inc.  
In addition, Aponia Laboratories, Inc. retains the right to discontinue development of 
AP0302 5% at any time. 
If a study is prematurely terminated or discontinued, Aponia Laboratories, Inc. will promptly 
notify the investigator.  After notification, the investigator must contact all participating subjects 


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and the pharmacy (if applicable) within 14 days.  As directed by Aponia Laboratories, Inc., all 
study materials must be collected and all CRFs completed to the greatest extent possible. 
16 PUBLICATION OF STUDY RESULTS 
Please refer to the Clinical Study Agreement for the details and requirements for investigators 
interested in publishing the results of this study.   


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17 REFERENCES 
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Appendix 1 
Schedule of Assessments 
 
Screening Visit 
Exercise Visit 
Treatment Period 
Follow-up 
Phone Call 
 
 
 
 
Day-28 to  
Day -3 
Day -2 or -1 
Day 7 
±1 day 
Informed consent 
X 
 
 
 
 
 
 
Verify/re-assess eligibility 
X 
X 
X 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
 
Exercise history 
X 
X 
 
 
 
 
 
Record height and weight 
X 
 
 
 
 
 
 
Record prior/current medications and non-medicinal 
therapies 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
X 
 
Physical examination – abbreviated/symptom directed 
only based on Screening1 
 
X 
 
 
 
 
 
Vital signs (BP, HR, temperature, and RR) 
X 
X 
X 
 
 
X 
 
12-lead ECG 
X 
 
 
 
 
X 
 
Clinical laboratory tests (chemistry, hematology, 
coagulation, and urinalysis) 
X 
 
 
 
 
X 
 
Urine drug screen/ Alcohol breath test 
X 
X 
X 
 
 
 
 
Pregnancy test (WOCBP) 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Exercise regimen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Muscle pain/soreness with movement Categorical Pain 
Rating Scale3 
 
 
 
PI-NRS, Muscle stiffness with movement NRS 4  
 
 
 
Relief from starting pain with movement Categorical 
Relief Rating Scale5 
 
 
 
X 
 
 
 
Subject’s global assessment of study medication6 
 
 
 
 
 
X 
 
Adverse events 
 
 
 
X 
X 
X 
X 
CBI
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CBI
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Abbreviations: BP = blood pressure; ECG = electrocardiogram; HR = heart rate; NRS = numerical rating scale; PI-NRS =Pain Intensity Numerical Rating Scale; RR = respiratory rate; T0 = time of first 
application of study drug; WOCBP = women of childbearing potential. 
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Appendix 2 
NRS and Categorical Rating Scales  
 PAIN INTENSITY NUMERICAL RATING SCALE 
What number represents your muscle pain/soreness with movement? 
 
No Pain     0     1     2     3     4     5     6     7     8     9     10    Worst Possible Pain 
 
CATEGORICAL PAIN RATING SCALE 
What word best describes your muscle pain/soreness with movement? 
□  None (0) 
□  Slight (1) 
□  Moderate (2) 
□  Severe (3)  
MUSCLE STIFFNESS NUMERICAL RATING SCALE  
Stiffness refers to how hard it is to flex and extend your arm. 
What number represents your muscle stiffness with movement? 
 
     No Stiffness      0     1     2     3     4     5     6     7     8     9     10     Worst Possible Stiffness 
  
CATEGORICAL RELIEF RATING SCALE 
What word best describes your relief from starting pain? 
□  No relief (0) 
□  A little relief (1) 
□  Some relief (2) 
□  A lot of relief (3)  
□  Complete relief (4)  
 
 


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SUBJECT GLOBAL ASSESSMENT 
Overall, how would you rate the investigational product you received? 
□ Poor (0) 
□ Fair (1) 
□ Good (2) 
□ Very Good (3) 
□ Excellent (4) 
 
 


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