Clinical trial NCT04484428
Conditions: Acute Pain
Sponsor: Kowa Research Institute, Inc.
Start date: 2020-08-15; Completion date: 2021-03-19
Enrollment: 126 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study to evaluate the efficacy and safety of K-285 compared with menthol gel for the treatment of delayed onset muscle soreness (DOMS) in the lower extremity.

Detailed description:

Arms: arm 1: K-285 arm 2: Menthol
Interventions: intervention 1: K-285 intervention 2: Menthol
Intervention descriptions: intervention 1: 88 subjects are to be assigned to 1 week dosing, four times a day (QID) (Period 1), and 32 are to be assigned to 3 weeks dosing (Period 1 and Period 2) with 16 subjects each in the two times a day (BID) and QID dosing regimens. intervention 2: 88 subjects are to be assigned to 1 week dosing, four times a day (QID) (Period 1), and 32 are to be assigned to 3 weeks dosing (Period 1 and Period 2) with 16 subjects each in the two times a day (BID) and QID dosing regimens.

Protocol documents:
SAP_002.pdf: 
Kowa Research Institute, Inc.
Interim Statistical Analysis Plan
Protocol Number K-285-201
22JAN2021 
CONFIDENTIAL 
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STATISTICAL ANALYSIS PLAN 
INTERIM ANALYSIS 
A Phase II, Randomized, Double-blind, Active Comparator, Parallel Group Study to 
Evaluate the Efficacy and Safety of K-285 Compared with Menthol Gel for the Treatment 
of Delayed Onset Muscle Soreness (DOMS) in the Lower Extremity 
PROTOCOL NUMBER: K-285-201 
Protocol Version 2.0 (28MAY2020) 
SPONSORED BY 
PREPARED BY 
This document is confidential and proprietary to Kowa Research Institute, Inc. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be reproduced, published, or otherwise 
disclosed without the prior written approval of Kowa Research Institute, Inc., except that this document may be disclosed 
to appropriate Institutional Review Boards under the condition that they keep the information confidential. 
ClinicalTrials.gov  NCT04484428


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DOCUMENT VERSION CONTROL 
Version Number 
Date 
Comments/Changes 
V1.0 
22JAN2021 
Initial Version 
 
 
 
 
 
 
 


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APPROVALS  
 
Author: 
 
 
Reviewed: 
 
 
Approved: 
 
 
Approved: 
 


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Approved: 
 
 
 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
1 
PURPOSE OF THE ANALYSES ..................................................................................... 8 
2 
PROTOCOL SUMMARY ................................................................................................. 8 
2.1 
Study Objectives .................................................................................................. 8 
2.1.1 
Primary Objective ................................................................................................. 8 
2.1.2 
Secondary Objectives .......................................................................................... 8 
2.2 
Overall Study Design and Plan ............................................................................ 9 
2.2.1 
Study Design ....................................................................................................... 9 
2.2.2 
Study Population ................................................................................................ 12 
2.2.3 
Treatment Regimens ......................................................................................... 12 
2.2.4 
Treatment Group Assignments or Randomization .............................................. 12 
2.2.5 
Sample Size Determination ................................................................................ 13 
2.2.6 
Interim Analysis for Futility Assessment ............................................................. 13 
3 
GENERAL ANALYSIS AND REPORTING CONVENTIONS FOR INTERIM 
ANALYSES ........................................................................................................ 13 
4 
STUDY ASSESSMENTS............................................................................................... 14 
4.1 
Efficacy Evaluations ........................................................................................... 14 
4.1.1 
Pain Intensity ..................................................................................................... 14 
4.1.2 
Visual Analogue Scale ....................................................................................... 15 
4.1.3 
Categorical Pain Scale ....................................................................................... 15 
4.1.4 
Rescue Medication Use ..................................................................................... 15 
4.2 
Safety Evaluations ............................................................................................. 16 
5 
SUBJECT SUMMARIES................................................................................................ 16 
5.1 
Analysis Populations .......................................................................................... 16 
5.2 
Disposition of Subjects ....................................................................................... 16 
6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................. 16 
6.1 
Demographics and Baseline Characteristics ...................................................... 16 
7 
STUDY DRUG EXPOSURE .......................................................................................... 17 


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8 
Details of each gel application will be displayed in data listings. EFFICACY 
EVALUATION .................................................................................................... 17 
8.1 
Efficacy Endpoints ............................................................................................. 17 
8.1.1 
Primary Efficacy Endpoint .................................................................................. 17 
8.2 
Handling of Dropouts or Missing data ................................................................ 17 
8.2.1 
Assessment Time Windows ............................................................................... 18 
8.3 
Analysis Method for the Primary Efficacy Endpoint ............................................ 18 
9 
SAFETY EVALUATION ................................................................................................. 19 
10 
PHARMACOKINETIC EVALUATION ............................................................................ 19 
11 
INTERIM ANALYSES .................................................................................................... 19 
12 
REFERENCES .............................................................................................................. 20 
13 
APPENDICES ............................................................................................................... 22 
13.1 
Example of SPID Calculation ............................................................................. 22 
13.2 
Planned Tables, Figures and Listings for Interim Analysis ................................. 23 
13.2.1 Tables ................................................................................................................ 23 
13.2.2 Listings .............................................................................................................. 23 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
API 
active pharmaceutical ingredients 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CRF 
case report/record form 
CRO 
Contract Research Organization 
DOMS 
delayed onset muscle soreness 
ECG 
electrocardiogram 
eCRF 
electronic Case Report/Record Form 
e-diary 
electronic diary device 
eVAS 
electronic visual analog scale 
ET 
early termination 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LOCF 
last observation carried forward 
LOE 
lack of efficacy 
OTC 
Over the counter 
PPS 
per protocol set 
 
 
 


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1 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number K-285-201 from Kowa Research 
Institute Inc. This SAP will focus on analyses that will be performed for the unblinded interim 
analysis after a total of 120 subjects are enrolled and have completed the 24-hour assessment or 
are discontinued from the study. A final SAP will be created and signed off before the final 
database lock that will describe the full description of the analyses that will be performed for the 
final clinical study report (CSR).  
The SAP contains detailed information to aid in the performance of the interim statistical analysis 
and is not a complete description of all analyses that will be performed at the end of the study. 
This interim SAP is being written with due consideration of the recommendations outlined in the 
most recent International Council on Harmonization (ICH) E9 Guideline entitled Guidance for 
Industry: Statistical Principles for Clinical Trials, the ICH E9 (R1) Addendum, the most recent ICH 
E3 Guideline and the Guidance for Industry:  Structure and Content of Clinical Study, and the 
most recent FDA draft Guidance for Industry  Analgesic Indications: Developing Drug and 
Biological Products, dated February 2014. 
This SAP describes the data that will be analyzed and the futility assessments that will be 
evaluated for the interim analysis. This SAP provides details of the specific statistical methods 
that will be used for that analysis.  
2 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
2.1.1 Primary Objective 
To evaluate the efficacy of K-285 compared with menthol gel between 0 to 24 hours after the first 
gel application for the treatment of delayed onset muscle soreness (DOMS). 
2.1.2 Secondary Objectives 
Secondary objectives of this study are to determine: 
 To evaluate the efficacy of K-285 compared with menthol gel after the first gel application 
for the treatment of DOMS 
 To evaluate the safety and tolerability of K-285 compared with menthol gel after the first 
gel application for the treatment of DOMS 
 
 
 


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2.2 
Overall Study Design and Plan 
2.2.1 Study Design 
This is a phase II, randomized, double-blind, active comparator, parallel group study to evaluate 
the efficacy and safety of K-285 compared with menthol gel for the treatment of DOMS in the 
lower extremity. The study will consist of screening, an exercise visit (DOMS induction), in-patient 
and out-patient periods up to 3 weeks, and a follow-up telephone call.  
During the Screening Visit, subjects will provide informed consent and complete screening 
assessments including medical history, identification of the dominant leg, physical and skin 
examinations, blood and urine tests, vital signs measurements, electrocardiogram (ECG), and 
other screening procedures. Subjects who are able to participate in the study (Period 1 and 2) and 
who meet the pre-exercise inclusion and exclusion criteria will be enrolled into the study and 
return to the clinic on Day -1.  
Eligibility will be confirmed, and enrolled subjects will perform a standardized repetitive quadriceps 
muscle exercise to create DOMS to both legs (Day -1). The exercise regimen will consist of a 
warm-up, determination of maximum tolerated weight, and timed and untimed workout phases. 
Within 24 to 30 hours after the exercise session (Day 1), subjects will rate the pain of both legs 
using a categorical pain scale and record pain intensity of both legs at rest and while standing 
using a 0-100 point electronic visual analog scale (eVAS) (a capture program will linearly convert 
the pixel touched to an integer between 0 and 100) to determine eligibility for randomization. The 
specific post-exercise 
 inclusion criterion will be masked to subjects. 
 
 
 If both legs 
meet post-exercise inclusion criteria, the study leg will be the dominant leg, based on hand 
dominance. Subjects not qualifying for randomization will be given appropriate standard of care. 
A total of 240 subjects who meet post-exercise inclusion criteria will be randomly assigned in a 
1:1 ratio to Treatment Arm A (K-285 gel) or Treatment Arm B (Menthol gel). 
 
 
 
 
 
 
 
 
 
 
 


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In period 1 (
 study gels will be applied to randomized subjects on a 
 
 on the study leg as follows: 
 Treatment Arm A: Each subject will apply K-285 to the study leg 
 Treatment Arm B: Each subject will apply menthol gel to the study leg 
The first study gel application to the study leg will be applied by the subject with investigator (or 
designee) oversight to ensure proper application at the clinic on Day 1 within 24 to 30 hours after 
DOMS induction. Subsequent study gel applications at the clinic will be applied to the study leg by 
the subject with investigator (or designee) oversight to ensure proper application. On Day 2, 
photographic and residue evaluation of the application site will be performed prior to the 
 
study gel application. Subjects will remain in the clinic until they are discharged following 
completion of study assessments on Day 2.  
Pain intensity assessments will be performed for the study leg and non-study leg at rest and while 
standing using a 0-100 point eVAS on Day 1 at Baseline (0 hours) and at 
 
 after the first 
study gel application. Pain assessments scheduled between midnight and 6 am may be skipped if 
subjects are asleep but subjects may not skip more than two sequential assessments. A time 
window of +30 minutes will be allowed between qualifying pain assessments and first study gel 
application (0 hours).The following time windows will be allowed for each pain assessment (eVAS, 
Perceptible Pain Relief, and Meaningful Pain Relief) time point: 
 
 
  
Following discharge from the clinic on Day 2, subsequent study gel applications and pain intensity 
assessments will be performed by the subject on an out-patient basis (Day 2 through Day 8). 
Subjects will be instructed not to shower or bathe for at least 30 minutes before and at least 1 
hour after gel application. 


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All pain intensity assessments including eVAS, Perceptible Pain Relief, and Meaningful pain relief 
will be recorded in e-diaries through Day 8 (Period 1), and all study gel applications and rescue 
medications will be recorded in the e-diary by the subject through Day 22 (Period 1 and 2). 
Perceptible Pain Relief and Meaningful Pain Relief will be recorded in the e-diary until achieved in 
Period 1. Due to unexpected problems that occurred after 20 subjects randomized, the e-diary 
vendor was switched from ERT to 
.  Newly enrolled subjects will utilize the 
 e-
diary system.  A telephone call will be conducted by study staff on Day 5 (±1 day) to assess 
safety. Subjects will return to the clinic for assessments on Day 8 (±1 day). For subjects who are 
assigned to receive study gel for 1 week, Day 8 (+1 day) will be an end of study (EOS) clinic visit 
and a follow-up telephone call to assess safety will be conducted by study staff on Day 15 (±1 
day). Subjects who are assigned to receive study gel for 3 weeks will continue to apply study gel 
on an out-patient basis from Day 8 to Day 22 (Period 2) according to their assigned dosing 
regimen (
) (Table 1: Treatment Assignment). For subjects who are dosing in Period 2, 
telephone calls to assess safety will be conducted by study staff on Day 11 (±1 day) and Day 18 
(±1 day), study gel applications and use of any rescue medications will be recorded in e-diaries by 
the subjects through Day 22, and an end of study (EOS) clinic visit will occur on Day 22 (+1 day). 
A follow-up telephone call to assess safety will be conducted by study staff on Day 29 (±1 day).  
 
 


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2.2.2 Study Population 
The study population will be adult male and female subjects aged 18 to 35 years, inclusive, with a 
body mass index (BMI) between 18 and 32 kg/m2, inclusive.  
2.2.3 Treatment Regimens 
A description of each regimen is provided below: 
 
K-285: 
  
 
Menthol gel: 
 
2.2.4 Treatment Group Assignments or Randomization 
The study will be double-blind. The investigator, subjects, and sponsor personnel involved in the 
monitoring or conduct of the study will be blinded to the identity of the treatment from the time of 
randomization until the time of unblinding.  
Subjects will be assigned to study treatment via appropriate randomization methods, in 
accordance with the randomization schedule generated by the allocation vendor 
 
), prior to the start of the study, using validated internal software.  Once a 


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randomization number has been assigned to a subject, it must not be re-assigned to a different 
subject. 
) will prepare the randomization schedule before the 
study. Enrolled, eligible subjects will receive a kit containing study gels according to an allocation 
table that randomly assigns subjects by order of enrollment to receive study gel for 
 
) in 1 of 2 treatment arms (A or B). Separate allocation tables will be 
prepared for 120 male and 120 female subjects. Male or female enrollment may exceed the target 
sample size (n=120 each gender) by ±10%. If the target sample size is exceeded in one gender, 
the next available kit number in the other gender will be assigned. 
2.2.5 Sample Size Determination 
The parameters are conservatively estimated based on the DOMS study with 
 gel. The 
between-group difference in the mean 
 (using NPRS: numerical pain rating scale from 0 
to 10) is 11.07 with a SD of 25.62. To have statistical power of 90%, 113 subjects per group are 
required. Taking into account information loss caused by missing data, it is estimated that 120 
subjects need to be treated with each study gel. 
2.2.6 Interim Analysis for Futility Assessment 
 
 
. The interim analysis will assess the futility of the trial (conditional power <0.05) based on 
efficacy of K-285 to menthol gel using the FAS. That is, if the conditional power is less than 0.05 
(i.e., < 5%), the study would have met the stopping rule/decision criteria to stop for futility. The 
conditional power will be calculated under the assumption that the effect size estimate at the 
interim analysis is true. See Section 11 of SAP for more details.  
An independent team of biostatisticians and statistical programmers will perform the interim 
analysis within a folder that has restricted access to only the independent team members to 
maintain the blinding of the study.  
3 
GENERAL ANALYSIS AND REPORTING CONVENTIONS FOR INTERIM ANALYSES 
To maintain the blinding of the study, all outputs for interim analysis will be presented in blinded 
format (e.g., data will be summarized overall (not by treatment group) and treatment group will not 
be displayed in data listings). Data captured from both eDiary vendors (ERT for the first 20 
randomized patients and Trialogics for the remaining patients) will be included for analyses as 
appropriate.  
All continuous study assessments will be summarized overall and by time point (as applicable) 
using the descriptive statistics n, mean, SD, median, and range (minimum, and maximum). All of 
the categorical study assessments will be summarized overall and by time point (as applicable) 
using frequency counts and rates of occurrence (%). Changes from baseline for continuous 


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outcomes will be presented as their corresponding continuous measures for post-baseline visits. 
All study data will be listed by subject, and time point (as applicable).  
No preliminary rounding will be performed; rounding will only occur after the analysis. To round, 
up. Means and medians will be presented with one more decimal place than the precision of the 
data. Standard deviations will be presented with two more decimal places than the precision of 
the data. Percentages will be presented with one decimal place. A percentage of 100% will be 
reported as 100%. Minimums and maximums will be presented with the same precision as the 
original data. 
All analyses will be performed using the SAS System® version 9.4 or higher. The domain (Study 
data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets will be taken 
as input to the SAS programs that generate the report-ready tables, figures and listings. The 
submission ready SDTM and ADaM datasets will be provided to the sponsor along with display 
deliveries.  
The following conventions will be used throughout the study analysis: 
 Time T0 is the time of first treatment (first gel application) with study drug.  
 The date of first treatment with study drug is Day 1.  
 Assessment visit times are defined by time of treatment administration. 
 Baseline value is defined as the last valid measurement prior to the dosing of study 
treatment. 
 The change from baseline will be calculated as post-baseline value minus baseline 
value.  If either the baseline or post baseline value is missing, the change from 
baseline is set to missing as well. 
 Pain intensity difference (PID) is to be calculated by subtracting the pain intensity at 
each time point from the pain intensity at time 0 
PIDt = PIt  PI0 
 The number of days in the study is computed as: [Date of study completion or 
withdrawal minus the date of first study drug administration] + 1.  
4 
STUDY ASSESSMENTS  
4.1 
Efficacy Evaluations 
4.1.1 Pain Intensity 
Prior to exercise to induce DOMS, pain will be assessed for both legs at rest and while standing 
using a 0-100 point paper VAS to exclude subjects with other pain.  
Following exercise to induce DOMS, pain at rest and while standing will be assessed for both legs 
using a 0-100 point eVAS and a categorical pain scale to determine qualification for 


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randomization and to identify the study leg (baseline assessment). All pain assessments will be 
recorded in the e-diary.  
After randomization, pain at rest and while standing will be assessed for the study leg and the 
non-study leg using a 0-100 point eVAS at all post-study gel application time points in Period 1 
(see Table 2 of Protocol). When study gel application and pain assessment occur at the same 
time point, pain assessments will be performed before study gel application.  
The subject will rest quietly for at least 5 minutes before assessing pain at rest for the study leg 
and non-study leg (the study leg will be assessed first). The subject will sit for at least 5 minutes, 
then stand up and rate the worst pain caused by standing (the act of moving from a sitting to 
standing position) for the study leg and non-study leg (the study leg will be assessed first). 
4.1.2 Visual Analogue Scale 
The pain VAS, a unidimensional measure of pain intensity, is a continuous scale from 0 to 100 
used for pre-exercise pain assessments (see Appendix 1 of Protocol).  
The pain eVAS is electronically displayed and is completed by the subject for baseline and each 
post-randomization pain intensity assessment by touching the point on the eVAS that represents 
their pain intensity. (A capture program will linearly convert the pixel touched to an integer 
between 0 and 100). The integers of the eVAS will be referred to as points. The assessment date 
and time for the study leg and for the non-study leg is recorded in the e-diary (see Appendix 1 of 
Protocol).   
4.1.3 Categorical Pain Scale 
A 4-point categorical pain scale (none, mild, moderate, severe) at rest will be used to assess pain 
intensity following the exercise session. A categorical pain scale is provided in Appendix 2 of 
Protocol. 
4.1.4 Rescue Medication Use 
Use of any rescue medication for DOMS is strongly discouraged until 168 hours after the first 
study gel application, at which time over the counter (OTC) acetaminophen (one 500 mg 
acetaminophen tablet twice daily, not more than every 6 hours) as rescue medication is permitted 
if required.  Subjects experiencing severe pain, or inability to move or walk due to pain, may be 
permitted to use rescue medication (one 500 mg OTC acetaminophen tablet twice daily, not more 
than every 6 hours) prior to 168 hours after the first study gel application. If subjects take rescue 
medication within the first 168 hours after the first study gel application, it will be recorded in the e-
diary as rescue medication and entered into the eCRF as a concomitant medication, and will be 
programmatically categorized as a concomitant medication. Subjects will record their pain 


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intensity in the e-diary before taking the rescue medication. The number of tablets taken and the 
date and time will be recorded in the e-diary. 
4.2 
Safety Evaluations 
No safety analyses will be performed for interim analysis. 
 
5 
SUBJECT SUMMARIES 
5.1 
Analysis Populations 
Analysis populations are defined as follows:  
 Full Analysis Set (FAS) will include all randomized subjects who have a baseline pain 
score and at least 1 study gel applied. Subjects will be analyzed according to the 
treatment they are randomized to. 
 The per-protocol set (PPS) will include all randomized subjects who have a baseline 
pain score, at least 1 study gel applied, and no major protocol violations. Subjects will 
treat
 
 Safety set will include all subjects who have at least 1 study gel applied. Subjects will 
 
Analysis populations will be determined before final data base lock and study unblinding.  
The primary and secondary efficacy analyses will be performed using FAS population. Efficacy 
analyses will also be carried out using PPS populations for selected endpoints as appropriate. 
Baseline characteristics will be summarized using FAS population and safety endpoints will be 
summarized using Safety population.  
5.2 
Disposition of Subjects 
The number of subjects screened, randomized, and treated will be summarized. The number of 
subjects discontinuing treatment/withdrawing from the study will be summarized along with the 
reasons for discontinuation/withdrawal. Subjects who are screen failures along with the 
inclusion/exclusion criteria violation will also be summarized. 
A listing of randomized and subject disposition will also be produced. 
6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographics and Baseline Characteristics 


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Demographic variables include age, sex, race, and ethnicity. Baseline characteristics include 
height, weight (kg), and body mass index (BMI; kg/m2). Demographics and baseline 
characteristics will be presented in a by-subject listing and summarized overall and by treatment 
group using FAS population.  
For quantitative data, means, medians, standard deviations, minimum and maximum values will 
be determined. For qualitative data, counts and percentages will be calculated. 
7 
STUDY DRUG EXPOSURE  
Gel application information is captured on eDiary. Subjects who use eDiary from ERT are not 
allowed to enter prior missed gel application. However, for subjects who use eDiary from 
Trialogics, if subjects who miss the previous gel application entry (and only the previous one) will 
be allowed to enter  the missed gel application when they login in prior to the next scheduled gel 
application diary. Since the actual gel application time for the missing gel 
captured at the next entry, the date/time for the missing gel application will be imputed with the 
previous scheduled gel application time.  
8 
Details of each gel application will be displayed in data listings. EFFICACY 
EVALUATION 
8.1 
Efficacy Endpoints 
8.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the sum of PID between 0 (baseline) to 24 hours 
(SPID0-24) for the study leg after the first study gel application while standing using a 0-100 point 
eVAS. 
8.2 
Handling of Dropouts or Missing data 
Missing VAS values caused by early withdrawal from the study due to events which are not 
preferable to subjects such as an adverse event (AE) and/or lack of efficacy (LOE) will be imputed 
by last observation carried forward (LOCF).  
If missing VAS values caused by withdrawal other than AE and/or LOE will be imputed under the 
missing at random (MAR) assumption with the multiple imputation (MI) technique. The imputation 
will be carried out in SAS version 9.4 or later, using the full conditional specification method (FCS) 
with a regression model approach (Carpenter and Kenward, 2013). By using the MI technique, 
100 datasets will be generated. After calculating the SPID, an analysis of covariance (ANCOVA) 
model will be applied for the primary endpoint with gender and treatment as fixed effects and 
(Little and Rubin, 1987), and will be done in SAS using PROC MIANALYZE. A significance test of 
the treatment difference at the two-sided 0.05 level and corresponding 95% confidence intervals 


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will be calculated. However, the multiple imputation is used for subjects that have some baseline 
and post baseline data, i.e., if a subject is missing all pre and post data, no data will be imputed. 
If there exist missing VAS values to be imputed, any such values will be imputed before 
calculating the SPID. Intermediate missing VAS values due to an omission of recording pain 
 after the 
missing measurement will be directly connected in order to calculate the SPID. If subjects need to 
take the rescue medication, they will record their pain intensity in the eDiary before taking the 
rescue medication. If the rescue medication is taken within 6 hours of a nominal pain intensity 
assessment time point, the pain intensity score that was recorded before taking the rescue 
medication will be carried forward to the next pain intensity assessment time point.  
8.2.1 Assessment Time Windows 
Data are generally reported according to the nominal time of clinic visits and assessments as 
specified in the protocol. Refer Section 2.2.1 of this SAP (study design) for time windows for 
different assessments. 
8.3 
Analysis Method for the Primary Efficacy Endpoint  
The primary efficacy endpoint for this study is the sum of PID between 
 
) for the study leg after the first study gel application while standing using a 0-100 point 
eVAS. The primary analysis of the primary endpoint will be based on the FAS.  
   
 
 
  
 
  
The durations between nominal time points will be calculated using the actual times of the pain 
score measurement. If the actual time is missing the nominal planned time will be used. 
The primary endpoint will be analyzed using an ANCOVA model, which will include treatment and 
gender as fixed effects and baseline eVAS score as a covariate. The least square (LS) mean, 
standard error (SE) and associated 95% confidence interval (CI) for each treatment group will be 
estimated. In addition, the LS mean difference between each treatment group, SE, p-value and 
the associated 95% CI will also be computed. Descriptive summaries (including mean, SD, 
median, minimum and maximum) will also be presented. Missing data imputation methodology is 
described in Section 8.2 in this SAP. 
Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. 


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checking the normality assumption and constant variance assumption of the model respectively) 
to gain confidence that the model assumptions are reasonable. 
To explore the impact of collecting e-diary data from  different vendors, a sensitivity analysis by 
including both baseline eVAS score and the e-diary vendor with and without the interaction term 
of treatment and the e-diary vendor  in the model will be performed. 
9 
SAFETY EVALUATION 
Not applicable for interim analysis. 
10 PHARMACOKINETIC EVALUATION 
Not applicable for this study.  
11 INTERIM ANALYSES  
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 


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12 REFERENCES 
US Federal Register. (1998) International Council on Harmonization; Guidance for Industry:  
Statistical Principles for Clinical Trials. Department of Health and Human Services:  Food and 
Drug Administration. Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. 
US Federal Register (2017) International Council on Harmonization E9(R1) Addendum: Statistical 
Principles for Clinical Trials: Estimands and Sensitivity Analysis in Clinical Trials (DRAFT) 
US Federal Register. (1996) International Council on Harmonization; Guidance for Industry:  
Structure and Content of Clinical Study Reports. Department of Health and Human Services:  
Food and Drug Administration. Federal Register Vol. 61, July 17, 1996, page 37320.  
Multiple Imputations and its Application- By James Carpenter, Michael Kenward 
Little, R.J.A. and Rubin, D.B. (1987) Statistical Analysis with Missing Data. John Wiley & Sons, 
New York. 
Chen, Y. H. J., D. L. DeMets, and K. K. G. Lan. 2004. Increasing the samples size when the 
unblinded interim result is promising. Statistics in Medicine 


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Jennison, C., and Turnbull, B.W. 2000.  Group Sequential Methods with Applications to Clinical 
Trials.  Chapman & Hall/CRF. New York. 
 
 
 


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13 APPENDICES 
13.1 Example of SPID Calculation 
Following provide an example of SPID using the trapezoidal rule described in Section 8.3 
in this SAP: 
 
PID 
0
-4
-14
-15
-13
-20
-13
-27
-21
-16
-16
-12
-21
-29
 
 
 


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13.2 Planned Tables, Figures and Listings for Interim Analysis 
13.2.1 Tables 
Table 14.1.1 
All Subjects 
Summary of Subject Disposition 
Table 14.1.2.1 Full Analysis Set 
Summary of Demographic and Baseline Characteristics 
 
13.2.2 Listings 
Listing 16.2.1 All Randomized Subjects Randomization and Analysis Population Inclusion 
Listing 16.2.2 All Randomized Subjects Informed Consent and Re-Consent 
Listing 16.2.3 All Randomized Subjects Eligibility 
Listing 16.2.3.1Screen Failure Subjects 
Eligibility 
Listing 16.2.4 All Randomized Subjects Subject Completion/Early Termination 
Listing 16.2.5 All Subjects 
Demographics and Baseline Characteristics 
Listing 16.2.6 All Randomized Subjects Study Drug Administration 
Listing 16.2.7 All Subjects 
Rescue Medications 
 











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STATISTICAL ANALYSIS PLAN 
 
A Phase II, Randomized, Double-blind, Active Comparator, Parallel Group Study to 
Evaluate the Efficacy and Safety of K-285 Compared with Menthol Gel for the Treatment 
of Delayed Onset Muscle Soreness (DOMS) in the Lower Extremity 
 
PROTOCOL NUMBER: K-285-201 
Protocol Version 2.0 (28MAY2020) 
 
SPONSORED BY 
Kowa Research Institute, Inc 
 
 
 
PREPARED BY 
 
 
 
 
 
 
This document is confidential and proprietary to Kowa Research Institute, Inc. Acceptance of this document constitutes 
agreement by the recipient that no unpublished information contained herein will be reproduced, published, or otherwise 
disclosed without the prior written approval of Kowa Research Institute, Inc., except that this document may be disclosed 
to appropriate Institutional Review Boards under the condition that they keep the information confidential. 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ............................................................................................................ 6 
1 
PURPOSE OF THE ANALYSES ........................................................................................ 7 
2 
PROTOCOL SUMMARY .................................................................................................... 7 
2.1 
Study Objectives ..................................................................................................... 7 
2.1.1 
Primary Objective .................................................................................................... 7 
2.1.2 
Secondary Objectives ............................................................................................. 7 
2.2 
Overall Study Design and Plan ............................................................................... 7 
2.2.1 
Study Design ........................................................................................................... 7 
2.2.2 
Study Population ................................................................................................... 10 
2.2.3 
Treatment Regimens ............................................................................................ 10 
2.2.4 
Treatment Group Assignments or Randomization ............................................... 10 
2.2.5 
Sample Size Determination .................................................................................. 11 
2.2.6 
Interim Analysis for Futility Assessment ............................................................... 11 
3 
GENERAL ANALYSIS AND REPORTING CONVENTIONS FOR 
ANALYSES ........................................................................................................... 11 
4 
STUDY ASSESSMENTS .................................................................................................. 12 
4.1 
Efficacy Evaluations .............................................................................................. 12 
4.1.1 
Pain Intensity......................................................................................................... 12 
4.1.2 
Visual Analogue Scale .......................................................................................... 13 
4.1.3 
Categorical Pain Scale ......................................................................................... 13 
4.1.4 
Rescue Medication Use ........................................................................................ 13 
4.2 
Safety Evaluations ................................................................................................ 14 
5 
SUBJECT SUMMARIES ................................................................................................... 14 
5.1 
Analysis Populations ............................................................................................. 14 
5.2 
Disposition of Subjects ......................................................................................... 15 
5.3 
Protocol Deviations ............................................................................................... 15 
6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................. 15 
6.1 
Demographics and Baseline Characteristics ....................................................... 15 
6.2 
Medical History ..................................................................................................... 15 


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6.3 
Concomitant Medication ....................................................................................... 15 
7 
STUDY DRUG EXPOSURE ............................................................................................. 16 
8 
EFFICACY EVALUATION ................................................................................................ 16 
8.1 
Efficacy Endpoints ................................................................................................ 16 
8.1.1 
Primary Efficacy Endpoint..................................................................................... 16 
8.2 
Handling of Dropouts or Missing data .................................................................. 16 
8.2.1 
Assessment Time Windows.................................................................................. 17 
8.3 
Analysis Method for the Primary Efficacy Endpoint ............................................. 17 
8.4 
Analysis Method for the Secondary Efficacy Endpoints ...................................... 18 
8.5 
Other Exploratory Analyses .................................................................................. 20 
9 
SAFETY EVALUATION .................................................................................................... 20 
9.1  
Overview of Safety Analysis Methods .................................................................. 20 
9.2  
Adverse Events ..................................................................................................... 21 
9.3  
Deaths, Serious Adverse events, and Other Significant Adverse 
Events ................................................................................................................... 22 
9.4  
Clinical Laboratory Evaluation .............................................................................. 23 
9.5  
Vital Signs, Physical Measurements, and Physical Examinations ...................... 23 
9.5.1.  Vital Signs and Physical Measurements .............................................................. 23 
9.6 
Physical and Skin Examinations........................................................................... 24 
9.7  
12-Lead Electrocardiogram (ECG) ....................................................................... 25 
9.8 Residue Evaluation ..................................................................................................... 25 
10 
PHARMACOKINETIC EVALUATION ............................................................................... 26 
11 
INTERIM ANALYSES ....................................................................................................... 26 
12 
REFERENCES ................................................................................................................. 27 
13 
APPENDICES ................................................................................................................... 28 
13.1 
Planned Tables, Figures and Listings for Analysis .............................................. 28 
13.1.1 Tables.................................................................................................................... 28 
13.1.2 Listings .................................................................................................................. 31 
13.1.3 Figures .................................................................................................................. 32 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse event 
API 
active pharmaceutical ingredients 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CRF 
case report/record form 
CRO 
Contract Research Organization 
DOMS 
delayed onset muscle soreness 
ECG 
electrocardiogram 
EOS 
End of Study 
eCRF 
electronic Case Report/Record Form 
e-diary 
electronic diary device 
eVAS 
electronic visual analog scale 
ET 
early termination 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LOCF 
last observation carried forward 
LOE 
lack of efficacy 
OTC 
Over the counter 
PPS 
per protocol set 
 


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1 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) is based on protocol number K-285-201, Version 2.0 (May 
28th, 2020) from Kowa Research Institute Inc. The SAP contains detailed information to guide the 
performance of the statistical analysis and reporting of the study data for use in the final clinical 
study report (CSR).  
This SAP is being written with due consideration of the recommendations outlined in the most 
recent International Council on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: 
Statistical Principles for Clinical Trials, the ICH E9 (R1) Addendum, the most recent ICH E3 
Guideline and the Guidance for Industry:  Structure and Content of Clinical Study, and the most 
recent FDA draft Guidance for Industry – Analgesic Indications: Developing Drug and Biological 
Products, dated February 2014. 
This SAP describes the data sets that will be analyzed and the subject characteristics, efficacy, 
and safety assessments that will be evaluated. This SAP provides details of the specific statistical 
methods that will be used. If additional analyses are required to supplement the planned analyses 
described in this SAP, they may be completed and will be identified as post hoc in the CSR.  
2 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
2.1.1 Primary Objective 
To evaluate the efficacy of K-285 compared with menthol gel between 0 to 24 hours after the first 
gel application for the treatment of delayed onset muscle soreness (DOMS). 
2.1.2 Secondary Objectives 
Secondary objectives of this study are to determine: 
● To evaluate the efficacy of K-285 compared with menthol gel after the first gel application 
for the treatment of DOMS 
● To evaluate the safety and tolerability of K-285 compared with menthol gel after the first 
gel application for the treatment of DOMS 
2.2 
Overall Study Design and Plan 
2.2.1 Study Design 
This is a phase II, randomized, double-blind, active comparator, parallel group study to evaluate 
the efficacy and safety of K-285 compared with menthol gel for the treatment of DOMS in the 
lower extremity. The study will consist of screening, an exercise visit (DOMS induction), in-patient 
and out-patient periods up to 3 weeks, and a follow-up telephone call.  
During the Screening Visit, subjects will provide informed consent and complete screening 
assessments including medical history, identification of the dominant leg, physical and skin 


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examinations, blood and urine tests, vital signs measurements, electrocardiogram (ECG), and 
other screening procedures. Subjects who are able to participate in the study (Period 1 and 2) and 
who meet the pre-exercise inclusion and exclusion criteria will be enrolled into the study and 
return to the clinic on Day -1.  
Eligibility will be confirmed, and enrolled subjects will perform a standardized repetitive quadriceps 
muscle exercise to create DOMS to both legs (Day -1). The exercise regimen will consist of a 
warm-up, determination of maximum tolerated weight, and timed and untimed workout phases. 
Within 24 to 30 hours after the exercise session (Day 1), subjects will rate the pain of both legs 
using a categorical pain scale and record pain intensity of both legs at rest and while standing 
using a 0-100 point electronic visual analog scale (eVAS) (a capture program will linearly convert 
the pixel touched to an integer between 0 and 100) to determine eligibility for randomization. The 
specific post-exercise 
 inclusion criterion will be masked to subjects. 
 
 If both legs 
meet post-exercise inclusion criteria, the study leg will be the dominant leg, based on hand 
dominance. Subjects not qualifying for randomization will be given appropriate standard of care. 
A total of 240 subjects who meet post-exercise inclusion criteria will be randomly assigned in a 
1:1 ratio to Treatment Arm A (K-285 gel) or Treatment Arm B (Menthol gel). 
 
 
 
 
 
 
 
In period 1 
 study gels will be applied to randomized subjects on a 
 
 on the study leg as follows: 
● Treatment Arm A: Each subject will apply K-285 to the study leg 
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● Treatment Arm B: Each subject will apply menthol gel to the study leg 
The first study gel application to the study leg will be applied by the subject with investigator (or 
designee) oversight to ensure proper application at the clinic on Day 1 within 24 to 30 hours after 
DOMS induction. Subsequent study gel applications at the clinic will be applied to the study leg by 
the subject with investigator (or designee) oversight to ensure proper application. On Day 2, 
photographic and residue evaluation of the application site will be performed prior to the 
 
 gel application. Subjects will remain in the clinic until they are discharged following 
completion of study assessments on Day 2.  
Pain intensity assessments will be performed for the study leg and non-study leg at rest and while 
standing using a 0-100 point eVAS on Day 1 at Baseline (0 hours) and at
 
) after the first 
study gel application. Pain assessments scheduled between midnight and 6 am may be skipped if 
subjects are asleep but subjects may not skip more than two sequential assessments. A time 
window of +30 minutes will be allowed between qualifying pain assessments and first study gel 
application (0 hours).The following time windows will be allowed for each pain assessment (eVAS, 
Perceptible Pain Relief, and Meaningful Pain Relief) time point:
 
 
 
Following discharge from the clinic on Day 2, subsequent study gel applications and pain intensity 
assessments will be performed by the subject on an out-patient basis (Day 2 through Day 8). 
Subjects will be instructed not to shower or bathe for at least 30 minutes before and at least 1 
hour after gel application. 
All pain intensity assessments including eVAS, Perceptible Pain Relief, and Meaningful pain relief 
will be recorded in e-diaries through Day 8 (Period 1), and all study gel applications and rescue 
medications will be recorded in the e-diary by the subject through Day 22 (Period 1 and 2). 
Perceptible Pain Relief and Meaningful Pain Relief will be recorded in the e-diary until achieved in 
Period 1. Due to unexpected problems that occurred after 20 subjects randomized, the e-diary 
vendor was switched from ERT to 
.  Newly enrolled subjects will utilize the 
 e-
diary system.  A telephone call will be conducted by study staff on Day 5 (±1 day) to assess 
safety. Subjects will return to the clinic for assessments on Day 8 (±1 day). For subjects who are 
assigned to receive study gel for 1 week, Day 8 (+1 day) will be an end of study (EOS) clinic visit 
and a follow-up telephone call to assess safety will be conducted by study staff on Day 15 (±1 
day). Subjects who are assigned to receive study gel for 3 weeks will continue to apply study gel 
on an out-patient basis from Day 8 to Day 22 (Period 2) according to their assigned dosing 
regimen 
) (Table 1: Treatment Assignment). For subjects who are dosing in Period 2, 
telephone calls to assess safety will be conducted by study staff on Day 11 (±1 day) and Day 18 
(±1 day), study gel applications and use of any rescue medications will be recorded in e-diaries by 
the subjects through Day 22, and an end of study (EOS) clinic visit will occur on Day 22 (+1 day). 
A follow-up telephone call to assess safety will be conducted by study staff on Day 29 (±1 day).  
 
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2.2.2 Study Population 
The study population will be adult male and female subjects aged 18 to 35 years, inclusive, with a 
body mass index (BMI) between 18 and 32 kg/m2, inclusive.  
2.2.3 Treatment Regimens 
A description of each regimen is provided below: 
● 
K-285: 
  
● 
Menthol gel: 
 
2.2.4 Treatment Group Assignments or Randomization 
The study will be double-blind. The investigator, subjects, and sponsor personnel involved in the 
monitoring or conduct of the study will be blinded to the identity of the treatment from the time of 
randomization until the time of unblinding.  
Subjects will be assigned to study treatment via appropriate randomization methods, in 
accordance with the randomization schedule generated by the allocation vendor (
 
), prior to the start of the study, using validated internal software.  Once a 
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randomization number has been assigned to a subject, it must not be re-assigned to a different 
subject. 
) will prepare the randomization schedule before the 
study. Enrolled, eligible subjects will receive a kit containing study gels according to an allocation 
table that randomly assigns subjects by order of enrollment to receive study gel for 
 
 in 1 of 2 treatment arms (A or B). Separate allocation tables will be 
prepared for 120 male and 120 female subjects. Male or female enrollment may exceed the target 
sample size (n=120 each gender) by ±10%. If the target sample size is exceeded in one gender, 
the next available kit number in the other gender will be assigned. 
2.2.5 Sample Size Determination 
The parameters are conservatively estimated based on the DOMS study with 
 gel. The 
between-group difference in the mean 
 is 11.07 with a SD of 25.62. To have statistical 
power of 90%, 
 Taking into account information loss caused 
by missing data, it is estimated that 120 subjects need to be treated with each study gel. 
2.2.6 Interim Analysis for Futility Assessment 
 
. The interim analysis will assess the futility of the trial (conditional power <0.05) based on 
efficacy of K-285 to menthol gel using the FAS. That is, if the conditional power is less than 0.05 
(i.e., < 5%), the study would have met the stopping rule/decision criteria to stop for futility. The 
conditional power will be calculated under the assumption that the effect size estimate at the 
interim analysis is true. See Section 11 of SAP for more details.  
An independent team of biostatisticians and statistical programmers will perform the interim 
analysis within a folder that has restricted access to only the independent team members to 
maintain the blinding of the study.  
Interim analysis was conducted using 120 randomized subject data on Feb 26, 2021. The study 
has met the stopping rule to stop for futility because the conditional power is less than 0.05. As a 
result, 126 subjects randomized before the interim analysis will be included in final analysis, rather 
than the planned 240 subjects.  
3 
GENERAL ANALYSIS AND REPORTING CONVENTIONS FOR ANALYSES 
This section discusses general policies to be employed in the analysis and reporting of the data 
from the study. Departures from these general policies are provided in the specific detailed 
sections of this SAP. When this situation occurs, the rules set forth in the specific section take 
precedence over the general policies 
All continuous study assessments will be summarized overall and by time point (as applicable) 
using the descriptive statistics n, mean, SD, median, and range (minimum, and maximum). All of 
the categorical study assessments will be summarized overall and by time point (as applicable) 
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using frequency counts and rates of occurrence (%). Changes from baseline for continuous 
outcomes will be presented as their corresponding continuous measures for post-baseline visits. 
All study data will be listed by subject, and time point (as applicable).  
No preliminary rounding will be performed; rounding will only occur after the analysis. To round, 
consider the digit to the right of the last significant digit:  if <5, then round down; if ≥5, then round 
up. Means and medians will be presented with one more decimal place than the precision of the 
data. Standard deviations will be presented with two more decimal places than the precision of 
the data. Percentages will be presented with one decimal place. A percentage of 100% will be 
reported as 100%. Minimums and maximums will be presented with the same precision as the 
original data. 
All analyses will be performed using the SAS System® version 9.4 or higher. The domain (Study 
data tabulation Model [SDTM]) and analysis (Analysis Data Model [ADaM]) data sets will be taken 
as input to the SAS programs that generate the report-ready tables, figures, and listings. The 
submission ready SDTM and ADaM datasets will be provided to the sponsor along with display 
deliveries.  
The following conventions will be used throughout the study analysis: 
● Time T0 is the time of first treatment (first gel application) with study drug.  
● The date of first treatment with study drug is Day 1.  
● Assessment visit times are defined by time of treatment administration. 
● Baseline value is defined as the last valid measurement prior to the dosing of study 
treatment. 
● The change from baseline will be calculated as post-baseline value minus baseline 
value.  If either the baseline or post baseline value is missing, the change from 
baseline is set to missing as well. 
● Pain intensity difference (PID) is to be calculated by subtracting the pain intensity at 
each time point from the pain intensity at time 0 
PIDt = PIt – PI0 
● The number of days in the study is computed as: [Date of study completion or 
withdrawal minus the date of first study drug administration] + 1.  
4 
STUDY ASSESSMENTS  
4.1 
Efficacy Evaluations 
4.1.1 Pain Intensity 
Prior to exercise to induce DOMS, pain will be assessed for both legs at rest and while standing 
using a 0-100 point paper VAS to exclude subjects with other pain.  
Following exercise to induce DOMS, pain at rest and while standing will be assessed for both legs 
using a 0-100 point eVAS and a categorical pain scale to determine qualification for 


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randomization and to identify the study leg (baseline assessment). All pain assessments will be 
recorded in the e-diary.  
After randomization, pain at rest and while standing will be assessed for the study leg and the 
non-study leg using a 0-100 point eVAS at all post-study gel application time points in Period 1 
(see Table 2 of Protocol). When study gel application and pain assessment occur at the same 
time point, pain assessments will be performed before study gel application.  
The subject will rest quietly for at least 5 minutes before assessing pain at rest for the study leg 
and non-study leg (the study leg will be assessed first). The subject will sit for at least 5 minutes, 
then stand up and rate the worst pain caused by standing (the act of moving from a sitting to 
standing position) for the study leg and non-study leg (the study leg will be assessed first). 
4.1.2 Visual Analogue Scale 
The pain VAS, a unidimensional measure of pain intensity, is a continuous scale from 0 to 100 
comprised of a horizontal line anchored by 2 descriptors, one for each symptom extreme: “no 
pain” (score of 0) and “worst possible pain” (score of 100). A paper version of the pain VAS will be 
used for pre-exercise pain assessments (see Appendix 1 of Protocol).  
The pain eVAS is electronically displayed and is completed by the subject for baseline and each 
post-randomization pain intensity assessment by touching the point on the eVAS that represents 
their pain intensity. (A capture program will linearly convert the pixel touched to an integer 
between 0 and 100). The integers of the eVAS will be referred to as points. The assessment date 
and time for the study leg and for the non-study leg is recorded in the e-diary (see Appendix 1 of 
Protocol).   
4.1.3 Categorical Pain Scale 
A 4-point categorical pain scale (none, mild, moderate, severe) at rest will be used to assess pain 
intensity following the exercise session. A categorical pain scale is provided in Appendix 2 of 
Protocol. 
4.1.4 Rescue Medication Use 
Use of any rescue medication for DOMS is strongly discouraged until 168 hours after the first 
study gel application, at which time over the counter (OTC) acetaminophen (one 500 mg 
acetaminophen tablet twice daily, not more than every 6 hours) as rescue medication is permitted 
if required.  Subjects experiencing severe pain, or inability to move or walk due to pain, may be 
permitted to use rescue medication (one 500 mg OTC acetaminophen tablet twice daily, not more 
than every 6 hours) prior to 168 hours after the first study gel application. If subjects take rescue 
medication within the first 168 hours after the first study gel application, it will be recorded in the e-
diary as rescue medication and entered into the eCRF as a concomitant medication and will be 
programmatically categorized as a concomitant medication. Subjects will record their pain 
intensity in the e-diary before taking the rescue medication. The number of tablets taken, and the 
date and time will be recorded in the e-diary. 


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4.2 
Safety Evaluations 
Following safety evaluations will be performed. Refer section 9 of this SAP. 
• 
Treatment emergent adverse event (TEAE) reports, 
• 
Laboratory test results,  
• 
Vital signs,  
• 
Physical examinations,  
• 
ECG findings 
• 
Skin Examination (Study gel application site reaction) 
• 
Residue Evaluation 
5 
SUBJECT SUMMARIES 
5.1 
Analysis Populations 
Analysis populations are defined as follows:  
● Full Analysis Set (FAS) will include all randomized subjects who have a baseline pain 
score and at least 1 study gel applied. Subjects will be analyzed according to the 
treatment they are randomized to. 
● The per-protocol set (PPS) will include all randomized subjects who have a baseline 
pain score, at least 1 study gel applied, and no major protocol violations. Subjects will 
be analyzed by treatment group according to the actual treatment received, i.e., “as 
treated”. 
● Safety set will include all subjects who have at least 1 study gel applied. Subjects will 
be analyzed by treatment group according to the actual treatment received, i.e., “as 
treated”. 
Analysis populations will be determined before final data base lock and study unblinding.  
The primary and secondary efficacy analyses will be performed using FAS population. Efficacy 
analyses will also be carried out using PPS populations for selected endpoints as appropriate. 
Baseline characteristics will be summarized using FAS population and safety endpoints will be 
summarized using Safety population. All baseline characteristics and safety summaries will be 
presented by Treatment Arm and/or by Treatment assignment as specified below. 
• 
Treatment Arm 
o K-285 
o Menthol 
• 
Treatment Assignment 
o K-285 1-week 
(K-285 1w) 
o K-285 3-week 
(K-285 3w 
) 
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o K-285 3-week 
 (K-285 3w 
) 
o Menthol 1- week 
(Menthol 1w) 
o Menthol 3-week 
(Menthol 3w 
 
o Menthol 3-week 
(Menthol 3w 
) 
5.2 
Disposition of Subjects 
The number of subjects screened, randomized, and treated will be summarized. The number of 
subjects discontinuing treatment/withdrawing from the study will be summarized along with the 
reasons for discontinuation/withdrawal. Subjects who are screen failures along with the 
inclusion/exclusion criteria and post-exercise inclusion criteria violation will also be summarized. 
A listing of randomized and subject disposition will also be produced. 
5.3 
Protocol Deviations 
Protocol deviations will be summarized, and all protocol deviations will be listed. 
6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
6.1 
Demographics and Baseline Characteristics 
Demographic variables include age, sex, race, and ethnicity. Baseline characteristics include 
height, weight (kg), and body mass index (BMI; kg/m2). Demographics and baseline 
characteristics including identification of the study leg and baseline pain intensity of the study leg 
will be presented in a by-subject listing and summarized overall and by treatment group using 
FAS population.  
For quantitative data, means, medians, standard deviations, minimum and maximum values will 
be determined. For qualitative data, counts and percentages will be calculated. 
6.2 
Medical History 
Medical history including skin condition (history of rash, allergy, eczema, etc.) and any allergy 
history (including fragrance, jewelry, dust, clothing, house dust, animal, metal, rubber, nylon, food, 
pollen allergy, etc.), as collected at screening, will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 21.0 and summarized by system organ class (SOC) and 
preferred term (PT) in a frequency table based on the safety population. The SOC and PT will 
each be sorted in descending order by overall frequency. Medical histories will also be presented 
in a by-subject listing using the coded and verbatim history terms.  
AEs that occur prior to treatment or that are related to a medical history event will be captured as 
medical history prior to database lock. 
6.3 
Concomitant Medication 
All medications and other treatments taken by subjects within 30 days before dosing and during 
the study will be recorded in the eCRF. Any medication/therapy that stops at or after the date and 
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time of start of treatment or those with missing stop dates are considered concomitant 
medication/therapy.  
Concomitant medications will be coded using the March 1, 2018 version of the WHODrug. 
Subjects who take concomitant medications will be presented in a by-subject listing of verbatim 
and coded terms and summarized by drug class and preferred name, overall and by treatment 
group, for the safety population.  
A by-subject listing of all concomitant medications will be presented. Additionally, a summary and 
by-subject listing of concomitant medications that were prescribed or modified at or after the time 
of discharge on study day will also be presented. 
7 
STUDY DRUG EXPOSURE  
Gel application information is captured on eDiary. Subjects who miss the previous gel application 
entry (and only the previous one) will be allowed to enter the missed gel application when they 
login in prior to the next scheduled gel application diary. Since the actual gel application time for 
the missing gel application will not be captured at the next entry, the date/time for the missing gel 
application will be imputed with the previous scheduled gel application time. Details of each gel 
application will be displayed in data listings.  
The study gel will be applied at the clinic on Days 1 and 2. The study gel for application on Day 1 
will be dispensed by the site pharmacy, and for Days 2-8 will be dispensed to the subjects prior to 
discharge on Day 2. For subjects assigned to Period 2, study gel for application by subjects will 
be dispensed at the Day 8 and Day 15 Safety visits. Study gel tubes will be weighed, in grams, 
and the total weight for all tubes recorded prior to dispensing to subjects. Study gel will be 
collected on Day 8 (for Period 1 subjects) and Day 22 (for Period 2 subjects), weighed and the 
final weight recorded. Compliance will be determined from the final weight of the tubes compared 
to the expected decrease from the starting weight, based on the assigned dosing schedule (2.8 
grams per dose × the number of doses). 
The compliance will be measured by the ratio between actual weight decreased and the expected 
decrease from starting weight of a study gel tube. It will be summarized in a table by treatment 
group as well as displayed in a data listing for the safety population. 
8 
EFFICACY EVALUATION 
8.1 
Efficacy Endpoints 
8.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint for this study is the sum of PID between 0 (baseline) to 24 hours 
(
) for the study leg after the first study gel application while standing using a 0-100 point 
eVAS. 
8.2 
Handling of Dropouts or Missing data 
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Missing VAS values up to 168 hours caused by early withdrawal from the study due to events 
which are not preferable to subjects such as an adverse event (AE) and/or lack of efficacy (LOE) 
will be imputed by last observation carried forward (LOCF).  
If missing VAS values caused by withdrawal other than AE and/or LOE will be imputed for each 
treatment group separately under the missing at random (MAR) assumption with the multiple 
imputation (MI) technique. The imputation will be carried out in SAS version 9.4 or later, using the 
full conditional specification method (FCS) with a regression model approach (Carpenter and 
Kenward, 2013). By using the MI technique, 100 datasets will be generated. After calculating the 
SPID, an analysis of covariance (ANCOVA) model will be applied for the primary endpoint with 
gender and treatment as fixed effects and baseline pain as a covariate in each dataset. Multiple 
results will be combined using Rubin’s rule (Little and Rubin, 1987), and will be done in SAS using 
PROC MIANALYZE. A significance test of the treatment difference at the two-sided 0.05 level and 
corresponding 95% confidence intervals will be calculated. However, the multiple imputation is 
used only for subjects that have a baseline. 
If there exist missing VAS values to be imputed, any such values will be imputed before 
calculating the SPID. Intermediate missing VAS values due to an omission of recording pain 
intensity or subject’s sleep will not be imputed, therefore, the observed values before and after the 
missing measurement will be directly connected in order to calculate the SPID. If subjects need to 
take the rescue medication, they will record their pain intensity in the eDiary before taking the 
rescue medication. If the rescue medication is taken within 6 hours of a nominal pain intensity 
assessment time point, the pain intensity score that was recorded before taking the rescue 
medication will be carried forward to the next pain intensity assessment time point.  
8.2.1 Assessment Time Windows 
Data are generally reported according to the nominal time of clinic visits and assessments as 
specified in the protocol. Refer Section 2.2.1 of this SAP (study design) for time windows for 
different assessments. 
8.3 
Analysis Method for the Primary Efficacy Endpoint  
The primary efficacy endpoint for this study is the sum of PID between 
 
(
) for the study leg after the first study gel application while standing using a 0-100 point 
eVAS. The primary analysis of the primary endpoint will be based on the FAS.  
   
 
 
 
 
 
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The durations between nominal time points will be calculated using the actual times of the pain 
score measurement. If the actual time is missing the nominal planned time will be used. 
The primary endpoint will be analyzed using an ANCOVA model, which will include treatment and 
gender as fixed effects and baseline eVAS score as a covariate. The least square (LS) mean, 
standard error (SE) and associated 95% confidence interval (CI) for each treatment group will be 
estimated. In addition, the LS mean difference between each treatment group, SE, p-value and 
the associated 95% CI will also be computed. Descriptive summaries (including mean, SD, 
median, minimum, and maximum) will also be presented. Missing data imputation methodology is 
described in Section 8.2 in this SAP. 
Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e., 
checking the normality assumption and constant variance assumption of the model respectively) 
to gain confidence that the model assumptions are reasonable. A nonparametric test may be 
conducted if the normality assumption is violated. An ANCOVA with unequal variances may be 
conducted if the constant variance assumption is violated. 
To explore the impact of collecting e-diary data from different vendors, a sensitivity analysis by 
including both baseline eVAS score and the e-diary vendor in the model will be performed. Since 
majority of the eVAS data are collected by the second vendor, an analysis based on the second 
vendor’s data only will be performed also. 
8.4 
 Analysis Method for the Secondary Efficacy Endpoints  
SPID Outcomes 
For non-study leg, 
 after the first study gel application while standing using a 0-100 
point eVAS, will be calculated, summarized, and analyzed similarly to primary endpoint. 
The following secondary efficacy SPID outcomes are calculated and analyzed similarly to primary 
endpoint of sum of PID between 
 for the study leg after the 
first study gel application while standing using a 0-100 point eVAS, adjusting for the respective 
time periods: 
• 
SPID0-24 hours after the first study gel application at rest using a 0-100 point eVAS  
• 
SPID between 0 (Baseline) to 12 hours (SPID0-12) after the first study gel application 
while standing using a 0-100 point eVAS 
• 
SPID0-12 hours after the first study gel application at rest using a 0-100 point eVAS 
• 
SPID between 0 (Baseline) to 48 hours (SPID0-48) after the first study gel application 
while standing using a 0-100 point eVAS 
• 
SPID0-48 hours after the first study gel application at rest using a 0-100 point eVAS 
• 
SPID between 0 (Baseline) to 72 hours (SPID0-72) after the first study gel application 
while standing using a 0-100 point eVAS 
• 
SPID0-72 hours after the first study gel application at rest using a 0-100 point eVAS 
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Change from Baseline in PID 
The Mean change from Baseline in pain intensity difference (PID) while standing and rest at 
different time points, after the first study gel application using a 0-100 point eVAS, will be 
summarized descriptively. 
Time-specific mean change from baseline in PID will be assessed using a mixed model repeated 
measures (MMRM) with PID as the dependent variable. Fixed effects of the model include 
treatment arm, time, the treatment arm by time interaction, baseline eVAS, and gender. Subject is 
a random effect. A completely general (unstructured) covariance matrix will be used. A first-order 
autoregressive covariance matrix will be used if the model with an unstructured covariance matrix 
does not converge. Pairwise comparisons at each time point will be determined from the MMRM, 
and model-based means (LS means) and standard errors will be plotted for visual comparison of 
the treatment group outcomes. Only scheduled measurements will be included in the MMRM.  
Perceptible and Meaningful Pain Relief 
Pain assessments of time to first perceptible pain relief and time to meaningful pain relief for both 
legs at rest and while standing will be recorded by subjects using their e-diary. At the time of first 
perceptible pain relief and at the time of meaningful pain relief, subjects will use their e-diary to 
record the time the events are experienced. Since these assessments will be captured in the e-
diary, the electronic database will be the direct point of data capture and will serve as source for 
this variable. 
Both time to perceptible and meaningful pain relief will be analyzed using Kaplan-Meier curves 
with the log-rank test. Subjects will be censored at the time of safety visit on Day 8 or at the time 
of dropout. Estimated median time to perceptible/meaningful pain relief as well as their 95% 
confidence intervals will be tabulated by treatment group along with the number and percent of 
subjects censored. 
The proportion of subjects with perceptible pain relief and meaningful pain relief at rest and while 
standing, both at, between 
, will be 
summarized descriptively by treatment group, using counts and percentages, along with 95% 
confidence intervals and CMH chi-square or Fisher exact p-values. This will also be analyzed 
using logistic regression model with treatment as an explanatory variable with gender and 
baseline eVAS (<median, >=median) as covariates. For treatment comparison, the odds ratio, 95 
% CI and p-value will be presented. 
Rescue Medication Usage 
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The proportion of subjects receiving rescue medication will be summarized descriptively by 
treatment group, using counts and percentages, along with 95% confidence intervals and CMH 
chi-square or Fisher exact p-values.  
Time to first administration of rescue medication is the date/time of the earliest rescue medication 
use minus the date/time of administration of study drug.  If the subject receives no rescue 
medication, then the value will be censored at 168 hours or at dropout.  
Time to rescue medication will be analyzed using Kaplan-Meier curves with the log-rank test.  
Estimated median time to first use of rescue as well as its 95% confidence interval will be 
tabulated by treatment group along with the number and percent of subjects censored. 
Total (mg) rescue medication used will be summarized descriptively. For each summary period 
 
 
, the mean number of rescue medication per day and the percentage 
of rescue-free days will be calculated. For each period and overall, cumulative rescue medication 
use will be displayed. Any data recorded after 168 hours, will not be included in any summaries. 
8.5 
Other Exploratory Analyses  
SPID0-24, SPID0-48, SPID0-72, 
 at rest and while standing will be compared 
between study leg and non-study leg conditional on each of treatment groups based on a mixed 
model. The model will include treatment, type of leg, treatment by type of leg interaction, and 
gender as fixed effects and baseline eVAS score as a covariate. A compound symmetry 
covariance structure will be used to account for correlation between study leg and non-study leg 
within same subject. The LS mean difference between study leg and non-study leg, SE, p-value 
and the associated 95% CI will be computed for each of the treatment group.  
If any other exploratory analyses or any subgroup analyses are performed after the SAP finalized, 
they will be documented in Clinical Study Report (CSR). 
9 
SAFETY EVALUATION 
9.1  
Overview of Safety Analysis Methods 
All safety outcomes will be summarized using the safety population. Safety outcomes include: 
• 
Incidence of treatment-emergent AEs (TEAEs) 
• 
Changes from baseline in clinical laboratory test results 
• 
Changes from baseline in vital sign measurements 
• 
Changes from baseline in physical examinations 
• 
Changes from baseline in ECG findings  
• 
Skin Examination (Study gel application site reaction) 
• 
Residue Evaluation 
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9.2  
Adverse Events 
Treatment-emergent AE is defined as an AE that begins after the start of study gel or an event 
that begins before the start of the study gel and worsens in intensity after starting treatment. 
Verbatim terms used by investigators to identify AEs in the CRFs will be mapped to the 
appropriate preferred (PT) and system organ class (SOC) using a standardized coding dictionary 
(MedDRA Version 21.0 or higher). All coding will be reviewed prior to database lock. All recorded 
AEs/SAEs and TEAEs will be summarized and listed for each treatment group.  
In addition to a listing of all TEAEs, separate listings of subjects with SAEs and listings of subjects 
with severe, treatment related, and AEs leading to premature discontinuation will be provided.  
An overall summary will be produced for each treatment group of both the number of events and 
the number of subjects with TEAEs, SAEs, TEAEs by severity, TEAEs by relationship to 
treatment, and TEAEs leading to premature discontinuation.  
The incidence of TEAEs will be summarized for each treatment group by SOC and PT within SOC 
(sorted in descending order by overall frequency). These summaries will be given in separate 
tables for the following categories of TEAEs: 
• 
All TEAEs 
• 
TEAEs leading to premature discontinuation 
• 
SAEs 
Also summarized will be TEAEs by maximum severity and by maximum relatedness to treatment. 
Adverse events will be deemed treatment related if they were recorded as probably, possibly, or 
definitely related.  
If a given subject experiences a TEAE that maps to the same PT more than once, the subject will 
be counted once for the PT at its greatest severity (i.e., mild, moderate, or severe) and causality 
(i.e., attribution to study medication).  
Duration of an AE will be computed in days (or in hours when duration of the AE is less than 1 
day) as the stop date/time of the event minus the start date/time plus 1. If reported as ongoing at 
the time of database lock, the stop date/time is defined as the date/time of the last visit or the last 
date/time of any AE for the subject in the database, whichever is later. If an AE is considered 
resolved, but the stop date is missing, the last day of the month will be imputed if the month and 
year are available. If only the year is available, and the year is the same as the year of the last 
visit, the stop date will be the latest of the last visit date or latest AE for the subject in the 
database. If the year of the AE is prior to the year of the last treatment, the end day and month will 
be set to 31 December. 
For missing or partial start dates, it is most conservative to impute them as temporally related to 
the first dose of study medication. The following chart will be used to impute start date: 


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Missing Portion 
Prior to 
Treatment 
Same as 
Treatment Start 
Date 
After Treatment Start 
Date 
Day 
Month and Year < Month 
and Year of first 
treatment: 
 
Start Day = first day of 
the month 
Stop Day = last day of 
the month 
Month and Year = 
Month and Year of 
first treatment: 
 
Start Day = Day of 
first treatment 
Stop Day= last 
day of the month 
Month and Year > 
Month and Year of First 
Treatment: 
 
Start Day = first day of 
the month 
Stop Day= last day of 
the month 
Day and Month 
Define Day as 
above, then: 
Year < Year of first 
treatment: 
 
Start Month = July 
Stop Month = Dec 
Year = Year of 
first treatment: 
 
Start Month = 
Month of first 
treatment 
Stop Month = Dec 
Year > Year of first 
treatment: 
 
Month = January 
Stop Month = Dec 
Day, Month, and 
Year 
 
To be conservative, completely missing start dates will be set to the date 
of first treatment, completely missing end dates will be set to the date of 
last contact. 
Time 
Missing start times will be imputed as 00:01 (or the start time of the first 
dose administration if AE occurred on the date of first dose 
administration) 
Missing stop times will be imputed as 23:59  
 
After following these imputation rules, if the start date is imputed as a date after the end date, the 
start date will be set to the end date to provide a positive duration for the AE.  
Missing assessments for AE study medication relationship, or severity will be analyzed as related, 
severe, and associated, respectively. No other imputation is planned for safety data unless 
otherwise specified below 
 
9.3  
Deaths, Serious Adverse events, and Other Significant Adverse Events 
A serious adverse event (SAE) is defined as an event that may constitute a significant medical 


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hazard or side effect, regardless of the investigator or sponsor’s opinion about its relationship to 
study material. Serious events include, but may not be limited to, any event that: 
• 
Is fatal 
• 
Is life-threatening (places the subject at immediate risk of death while the event is 
occurring) 
• 
Requires inpatient hospitalization or prolongs hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Important medical event 
Significant untoward medical events that may not be life-threatening or result in death or 
hospitalization, or events that require intervention to prevent one of the outcomes listed above or 
that result in urgent investigation, may be considered serious. Elective hospitalizations for 
conditions that existed before administration of study material are not to be considered SAEs. 
Serious adverse events and deaths will be listed and summarized separately for the safety 
population. 
9.4  
Clinical Laboratory Evaluation 
Clinical laboratory samples will be collected at screening, and EOS (as applicable). For 
continuous laboratory parameters, the observed values and changes from baseline will be 
summarized for each treatment group. For categorical laboratory parameters, frequency counts 
and percentages of subjects in each category will be provided.  
Laboratory test results will be displayed in by-subject listings, and values outside of the normal 
reference range will be flagged. 
Drug and alcohol screening and pregnancy results will be displayed in by-subject listings. 
9.5  
Vital Signs, Physical Measurements, and Physical Examinations 
9.5.1.  Vital Signs and Physical Measurements 
Vital signs will be collected at screening, Day 1 prior to study gel administration (Day -1), Day 1, 2 
(period 1), Day 8, 15 (period 2), and at the end of study visit on Day 8 or 22 (± 1 day).   
Observed values and changes from baseline will be summarized using mean and change-from-
baseline descriptive statistics for each treatment group, for the following measurements: systolic 
blood pressure (mmHg), diastolic blood pressure (mmHg), pulse rate (beats/minute), and oral 
body temperature. Blood pressure and pulse rate will be measured after the subject has been 
resting in the supine position for at least 5 minutes. 


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Body weight and height will be measured, and BMI will be calculated during the screening visit 
only.  These values will be summarized along with other baseline characteristics for each 
treatment group. The number and percentage of subjects with potential clinically significant 
findings listed in Table 2 will be summarized for each treatment group. Vital signs will be 
displayed in a by-subject listing. 
Table 2. 
List of Potential Clinically Significant Ranges for Vital Sign Parameters  
Variable Name 
Low 
High 
Systolic blood 
pressure 
≤86 mm Hg OR a decrease of ≥25 
mm Hg from baseline 
≥200 mm Hg OR an increase of ≥25 
mm Hg from baseline 
Diastolic blood 
pressure 
≤48 mm Hg OR a decrease of ≥20 
mm Hg from baseline 
≥110 mm Hg OR an increase of ≥20 
mm Hg from baseline 
Pulse 
<45 bmp1 OR a decrease of ≥25 
bpm from baseline  
>105 bpm and increase ≥25 bpm 
from baseline OR >125 bpm 
 
9.6 
Physical and Skin Examinations  
Physical examinations are performed at screening, Day 1 prior to study gel administration (Day -
1), Day 1, 2 (period 1), Day 8, 15 (period 2), and at the end of study visit on Day 8 or 22 (± 1 day). 
Findings are recorded as normal or abnormal. Physical exam results will be displayed in a by-
subject listing. 
Skin examination will be performed according to the schedule in Table 2 of the protocol. Dermal 
responses collected from skin examination CRF will be displayed in a by-subject listing using 
following rating scales.  
Subjects who choose to discontinue from participating in the study will rate their dermal response 
in the e-diary. Dermal Responses scored by subjects will not be recorded in the eCRF. 
 


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Dermal Responses  
0 = no evidence of irritation  
1 = minimal erythema, barely perceptible  
2 = definite erythema, readily visible; minimal edema or minimal papular response  
3 = erythema and papules  
4 = definite edema  
5 = erythema, edema, and papules  
6 = vesicular eruption  
7 = strong reaction spreading beyond application site  
Notes: Papules are defined as solid, circumscribed skin elevations up to the size of a split 
pea (5 mm). Vesicles are defined as small blisters.  
 
Other Effects (With Corresponding Numeric Score)  
None (0) = no change in appearance  
A (0) = slightly glazed appearance  
B (1) = marked glazed appearance  
C (2) = glazing with peeling and cracking  
F (3) = glazing with fissures  
G (4) = film of dried serous exudates covering all or part of the application site  
H (5) = small petechial erosions and/or scabs  
9.7  
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG will be performed at screening, Day 1 prior to study gel application, as well as at 
the end of study visit on Day 8 or 22 (± 1 day).   
The findings (i.e., classification as “normal,” “abnormal not clinically significant,” or “abnormal 
clinically significant”) will be recorded in the subject’s eCRF. ECG results will be summarized for 
each treatment group and displayed in a by-subject listing. 
9.8 Residue Evaluation  
To evaluate the subject’s impression of the dried white gel residue, the following rating scale will 
be assessed before the fifth and sixth study gel applications on Day 2 and will be recorded on the 
appropriate form. Subjects must not shower, bathe, or wash the treated area until after discharge 
on Day 2.  
 
The following rating scale will be used:  


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0 = No dried white residue was observed  
1 = Dried white residue was observed but no discomfort.  
2 = Dried white residue was observed and slight discomfort (between 1 and 3)  
3 = Dried white residue was observed and uncomfortable 
10 PHARMACOKINETIC EVALUATION 
Not applicable for this study.  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
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12 REFERENCES 
US Federal Register. (1998) International Council on Harmonization; Guidance for Industry:  
Statistical Principles for Clinical Trials. Department of Health and Human Services:  Food and 
Drug Administration. Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. 
US Federal Register (2017) International Council on Harmonization E9(R1) Addendum: Statistical 
Principles for Clinical Trials: Estimands and Sensitivity Analysis in Clinical Trials (DRAFT) 
US Federal Register. (1996) International Council on Harmonization; Guidance for Industry:  
Structure and Content of Clinical Study Reports. Department of Health and Human Services:  
Food and Drug Administration. Federal Register Vol. 61, July 17, 1996, page 37320.  
Multiple Imputations and its Application- By James Carpenter, Michael Kenward 
Little, R.J.A. and Rubin, D.B. (1987) Statistical Analysis with Missing Data. John Wiley & Sons, 
New York. 
Chen, Y. H. J., D. L. DeMets, and K. K. G. Lan. 2004. Increasing the samples size when the 
unblinded interim result is promising. Statistics in Medicine 
Jennison, C., and Turnbull, B.W. 2000.  Group Sequential Methods with Applications to Clinical 
Trials.  Chapman & Hall/CRF. New York. 
 
 
 
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13 APPENDICES 
13.1 Planned Tables, Figures and Listings for Analysis 
13.1.1 Tables 
Table Number 
Table Title 
Population 
Subject disposition and baseline characteristics 
Table 14.1.1.1 
Summary of Subject Disposition (by Treatment Arm) 
All Subjects Screened 
Table 14.1.1.2 
Summary of Subject Disposition (by Treatment 
Assignment) 
All Subjects Screened 
Table 14.1.2 
Summary of Protocol Deviations (by Treatment Arm) 
Randomized Subjects 
Table 14.1.3.1.1 
Summary of Demographics and Baseline Characteristics 
(by Treatment Arm) 
Full Analysis Set 
Table 14.1.3.1.2 
Summary of Demographics and Baseline Characteristics 
(by Treatment Assignment) 
Full Analysis Set 
Table 14.1.3.2.1 
Summary of Demographics and Baseline Characteristics 
(by Treatment Arm) 
Per Protocol Set 
Table 14.1.3.2.2 
Summary of Demographics and Baseline Characteristics 
(by Treatment Assignment) 
Per Protocol Set 
Table 14.1.4 
Summary of Medical History by System Organ Class and 
Preferred Term (by Treatment Arm) 
Full Analysis Set 
Table 14.1.5 
Summary of Concomitant Medications, by ATC Class and 
Preferred Term (by Treatment Arm) 
Full Analysis Set 
Efficacy Evaluations 
Table 14.2.1.1 
Primary Endpoint: ANCOVA Results of Summed Pain 
Intensity Difference from T0 to T24 (SPID0-24) for the 
study leg while standing (by Treatment Arm) 
Full Analysis Set 
Table 14.2.1.2 
Primary Endpoint: ANCOVA Results of Summed Pain 
Intensity Difference from T0 to T24 (SPID0-24) for the 
study leg while standing (by Treatment Arm) 
Per Protocol Set 
Table 14.2.2.1 
ANCOVA Results of Sum of Pain Intensity Difference 
(SPID) 0-12, 0-24, 0-48, 0-72, 
 
 
Full Analysis Set 
Table 14.2.2.2 
ANCOVA Results of Sum of Pain Intensity Difference 
(SPID) 0-12, 0-24, 0-48, 0-72, 
 
Full Analysis Set 
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Table 14.2.2.3 
Repeated Measures Analysis Results of Sum of Pain 
Intensity Difference (SPID) 0-12, 0-24, 0-48, 0-72,
 
 for K-
285 Group 
Full Analysis Set 
Table 14.2.2.4 
Repeated Measures Analysis Results of Sum of Pain 
Intensity Difference (SPID) 0-12, 0-24, 0-48, 0-72, 
 
for K-285 
Group 
Full Analysis Set 
Table 14.2.2.5 
Repeated Measures Analysis Results of Sum of Pain 
Intensity Difference (SPID) 0-12, 0-24, 0-48, 0-72,
 
 for 
Menthol Group 
Full Analysis Set 
Table 14.2.2.6 
Repeated Measures Analysis Results of Sum of Pain 
Intensity Difference (SPID) 0-12, 0-24, 0-48, 0-72, 
 
for Menthol 
Group 
Full Analysis Set 
Table 14.2.2.8 
Primary Endpoint: ANCOVA Results of Summed Pain 
Intensity Difference from T0 to T24 (SPID0-24) for the 
Study Leg while Standing (by Treatment Arm) – Each 
Multiple Imputed Dataset 
Full Analysis Set 
Table 14.2.3.1 
 
 
Full Analysis Set 
Table 14.2.3.2 
 
 
 
Full Analysis Set 
Table 14.2.4.1 
 
 
 
Full Analysis Set 
Table 14.2.4.2 
 
  
Full Analysis Set 
Table 14.2.5.1 
 
Full Analysis Set 
Table 14.2.5.2 
 
 
Full Analysis Set 
Table 14.2.8.1 
 
 
  
Full Analysis Set 
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Final Statistical Analysis Plan 
Protocol Number K-285-201 
 
13APR2021  
 
CONFIDENTIAL 
 
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Table 14.2.9.1 
Proportion of subjects with onset of perceptible pain relief 
between 0 to 6 hours, 0 to 24 hours for study leg while 
standing and at rest (by Treatment Arm) 
Full Analysis Set 
Table 14.2.9.2 
Proportion of subjects with onset of meaningful pain relief 
between 0 to 6 hours, 0 to 24 hours for study leg while 
standing and at rest (by Treatment Arm) 
Full Analysis Set 
Table 14.2.10 
Summary of Rescue Medication (by Treatment Arm) 
 
Full Analysis Set 
Safety Evaluations 
Table 14.3.1.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
(by Treatment Arm) 
Safety Population 
Table 14.3.1.1.2 
Overall Summary of Treatment-Emergent Adverse Events 
(by Treatment Assignment) 
Safety Population 
Table 14.3.1.2.1 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (by Treatment 
Arm) 
Safety Population 
Table 14.3.1.2.2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term (by Treatment 
Assignment) 
Safety Population 
Table 14.3.1.4.1 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Severity (by 
Treatment Arm) 
Safety Population 
Table 14.3.1.4.2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Severity (by 
Treatment Assignment) 
Safety Population 
Table 14.3.1.5.1 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Relationship to 
Study Drug (by Treatment Arm) 
Safety Population 
Table 14.3.1.5.2 
Summary of Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Relationship to 
Study Drug (by Treatment Assignment) 
Safety Population 
Table 14.5.1.1 
Summary of Chemistry Results and Change from Baseline 
by Time Point (by Treatment Arm) 
Safety Population 
Table 14.5.1.2 
Summary of Hematology Results and Change from 
Baseline by Time Point (by Treatment Arm) 
Safety Population 
Table 14.5.1.3 
Summary of Continuous Urinalysis Results and Change 
from Baseline by Time Point (by Treatment Arm) 
Safety Population 
Table 14.5.1.4 
Summary of Categorical Urinalysis Results by Time Point 
(by Treatment Arm) 
Safety Population 


Kowa Research Institute, Inc. 
 
Final Statistical Analysis Plan 
Protocol Number K-285-201 
 
13APR2021  
 
CONFIDENTIAL 
 
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Table 14.6.1 
Summary of Vital Signs: Results and Change from Baseline 
by Time Point (by Treatment Arm) 
Safety Population 
Table 14.6.2 
Summary of Potential Clinically Significant Vital Sign 
Parameters (by Treatment Arm) 
Safety Population 
Table 14.7.1 
Summary of Physical Examination Results (by Treatment 
Arm) 
Safety Population 
Table 14.8.1 
Summary of ECG Results (by Treatment Arm) 
Safety Population 
Table 14.9.1 
Summary of Skin Examination (Dermal Responses and 
Other Effects) (by Treatment Arm) 
Safety Population 
Table 14.9.2 
Summary of Skin Examination (Dermal Responses and 
Other Effects) (by Treatment Assignment) 
Safety Population 
Table 14.10.1 
Summary of Study Drug Compliance (by Treatment Arm) 
Safety Population 
Table 14.11.1 
Subject’s Impression of Dried White Gel Residue (by 
Treatment Arm) 
Safety Population 
13.1.2 Listings 
Listing Number 
Listing Title 
Population 
Listing 16.2.1.1 
Randomization and Study Population  
All Patients Screened 
Listing 16.2.1.2 
Informed Consent and Re-Consent  
All Patients 
Randomized 
Listing 16.2.1.3 
Screen Failure  
All Patients Screened 
Listing 16.2.1.4 
Subject Populations and Reasons Excluded from Analysis Sets 
All Patients Screened 
Listing 16.2.1.5 
Subject Completion / Early Termination 
All Patients 
Randomized 
Listing 16.2.2 
Protocol Deviations  
All Patients 
Randomized 
Listing 16.2.3.1 
Demographics and Baseline Characteristics  
Full Analysis Set 
Listing 16.2.3.2 
Medical / Surgical History  
Full Analysis Set 
Listing 16.2.3.3 
Concomitant Medications 
Full Analysis Set 
Listing 16.2.3.4 
Rescue Medication Administration 
Full Analysis Set 
Listing 16.2.3.5 
eVAS Record 
Full Analysis Set 
Listing 16.2.3.6.1 
Sum of Pain Intensity Difference (SPID) in eVAS scores  
Full Analysis Set 
Listing 16.2.3.6.2 
eVAS Scores and Sum of Pain Intensity Difference (SPID) for 
Study Leg While Standing (0-24 Hours) - Imputed 
Full Analysis Set 
Listing 16.2.3.7 
Time to Pain Relief 
Full Analysis Set 
Listing 16.2.4.1 
Study Drug Administration, Pain Assessment Training, and 
Discharge   
Safety Population 
Listing 16.2.4.2 
Study Drug Compliance 
Safety Population 
Listing 16.2.5.1   
Adverse Events   
Safety Population 


Kowa Research Institute, Inc. 
 
Final Statistical Analysis Plan 
Protocol Number K-285-201 
 
13APR2021  
 
CONFIDENTIAL 
 
 Page 32 of 33 
 
 
Listing 16.2.5.2   
Serious Adverse Events   
Safety Population 
Listing 16.2.5.3   
Treatment Related Adverse Events  
Safety Population 
Listing 16.2.5.4   
Adverse Events Leading to Study Discontinuation  
Safety Population 
Listing 16.2.5.5   
Adverse Events Leading to Death 
Safety Population 
Listing 16.2.6.1 
Chemistry Laboratory Test Results  
Safety Population 
Listing 16.2.6.2 
Coagulation Laboratory Test Results  
Safety Population 
Listing 16.2.6.3 
Hematology Laboratory Test Results  
Safety Population 
Listing 16.2.6.4 
Urinalysis Laboratory Test Results  
Safety Population 
Listing 16.2.6.5 
Alcohol and Urine Drug Screen Tests  
Safety Population 
Listing 16.2.6.6 
Pregnancy Test  
Safety Population 
Listing 16.2.7.1   
12-Lead Electrocardiogram   
Safety Population 
Listing 16.2.7.2 
Vital Signs   
Safety Population 
Listing 16.2.7.3   
Dermal Responses and Other Effects 
Safety Population 
Listing 16.2.7.4 
Residue Evaluation 
Safety Population 
13.1.3 Figures 
Figures Number 
Figure Title 
Population 
Figure 14.2.1 
Mean (SE) of VAS Change from Baseline for the Study Leg 
while Standing (by Treatment Arm) 
Full Analysis Set 
Figure 14.2.2 
Mean (SE) of VAS Change from Baseline for the Study Leg 
at Rest (by Treatment Arm) 
Full Analysis Set 
Figure 14.2.3 
Mean (SE) of VAS Change from Baseline While Standing 
by Study and Non-Study Leg for K-285 Group  
Full Analysis Set 
Figure 14.2.4 
Mean (SE) of VAS Change from Baseline While Standing 
by Study and Non-Study Leg for Menthol Group 
Full Analysis Set 
Figure 14.2.5 
Mean (SE) of VAS Change from Baseline at Rest by Study 
and Non-Study Leg for K-285 Group 
Full Analysis Set 
Figure 14.2.6 
Mean (SE) of VAS Change from Baseline at Rest by Study 
and Non-Study Leg for Menthol Group 
Full Analysis Set 
Figure 14.3.1 
Mean (SE) of VAS for the Study Leg while Standing (by 
Treatment Arm) 
Full Analysis Set 
Figure 14.3.2 
Mean (SE) of VAS for the Study Leg at Rest (by Treatment 
Arm) 
Full Analysis Set 
Figure 14.3.3 
Mean (SE) of VAS While Standing by Study and Non-Study 
Leg for K-285 Group  
Full Analysis Set 
Figure 14.3.4 
Mean (SE) of VAS While Standing by Study and Non-Study 
Leg for Menthol Group 
Full Analysis Set 


Kowa Research Institute, Inc. 
 
Final Statistical Analysis Plan 
Protocol Number K-285-201 
 
13APR2021  
 
CONFIDENTIAL 
 
 Page 33 of 33 
 
 
Figure 14.3.5 
 
Full Analysis Set 
Figure 14.3.6 
 
 
Full Analysis Set 
Figure 14.4.1 
Kaplan-Meier Plot for Time to first dose of Rescue 
Medication (by Treatment Arm) 
Full Analysis Set 
Figure 14.5.1 
Kaplan-Meier Plot for Time to first onset of Perceptible Pain 
Relief for Study Leg while standing and at rest (by 
Treatment Arm) 
Full Analysis Set 
Figure 14.5.2 
 
Full Analysis Set 
Figure 14.5.3 
Kaplan-Meier Plot for Time to first onset of Meaningful Pain 
Relief for Study Leg while standing and at rest (by 
Treatment Arm) 
Full Analysis Set 
Figure 14.5.4 
 
Full Analysis Set 
 
 
 
 
 
 
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Prot_001.pdf: 
C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
 
 
 
A P h ase II, R a n d o mize d, D o u ble-bli n d, Acti ve C o m p ar at or, P ar allel 
Gr o u p St u d y t o E v al u ate t he Effic ac y a n d S afet y of K -2 8 5  C o m p are d 
w it h Me nt h ol Gel  f or t he Tre at me nt of Del a ye d O nset M uscle S ore ness 
( D O M S) i n t he L o wer E xtre mit y  
  
 
Cli nic al St u d y Pr ot oc ol  
 
 
Dr u g N a me:   
K -2 8 5  
St u d y N u m ber:  
K -2 8 5 -2 0 1  
U. S. I N D N u m ber:  
I N D 1 3 5 3 4 8 
Pr ot oc ol Ori gi n al Versi o n D ate : 1 0  A pril  2 0 2 0  
Ori gi n al Versi o n #:  
1. 0  
Pr ot oc ol A me n d me nt 1. 0  
2 8  Ma y 2 0 2 0  
Versi o n #:   
2. 0  
N a me of S p o ns or:  
K o w a Rese arc h I nstit ute, I nc.  
A d dress:  
 
 
 
M a n a gi n g C o ntr act Res e arc h 
Or g a niz ati o n ( C R O):  
 
A d dress:  
C o nt act N u m bers:  
 
 
 
 
Pr o pert y of K o w a Rese arc h I nstit ute, I nc.  
C o nfi de nti al  
M a y n ot  be use d, di v ul ge d, p u blis he d, or ot her wise discl ose d  
wit h o ut t he c o nse nt of K o w a Rese arc h I nstit ute, I nc.  
 
Cli nic al Tri als. g o v                            N C T 0 4 4 8 4 4 2 8
ClinicalTrials.gov                            NCT04484428


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
ii1 6 
 
I N V E S TI G A T O R’ S S T A T E M E N T 
I, t he in vesti gat or , u n d ersta n d t hat all i nf or mati o n c o ncer ni n g t he pr o d uct s u p plie d t o me 
b y K o wa Researc h I nstit ute, I nc. ( K RI) a n d  
,
 i n c o n necti o n 
wit h t his st u d y a n d n ot pre v i o usl y p u blis he d is c o nfi de ntial i nf or mati o n. T his i nf or mati o n 
i ncl u des t he I n vesti gat ors’ Br oc h ure, pr ot o c ol, cas e re p ort f or ms, assa y met h o ds, tec h nical 
met h o d ol o g y a n d basic s cie ntific data.  
I u n dersta n d t hat a n y c ha n ges t o t he pr ot oc ol m ust be a p pr o ve d i n writi n g b y K RI, 
 
 a n d t he I nstit uti o nal Re vie w B oar d /I n de pe n d e nt Et hics C o m mittee 
(I R B/I E C) bef ore i m ple me ntati o n, e xce pt 
w here necessar y t o eli mi nate a p pare nt 
i m me diate hazar ds t o t he s u bjects. 
I c o nfir m t hat I will re p ort all a d verse e ve nts ( A Es) f oll o wi n g t he re g ulati o ns i n dicate d i n 
t he pr ot oc ol. 
I c o nfir m t hat I will c o n d uct t his st u d y i n co nf or ma nce wit h t he pri nci ples of t h e 
Declarati o n of Helsi n ki, Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A), 
G o o d Cli nical Practice ( G C P), a n d t he la ws a n d re g ulati o ns of t he c o u ntr y w here t he st u d y 
is t o be c o n d ucte d. 
I c o nfir m t hat I a m i nf or me d of t he nee d f or rec or d ret e nti o n a n d t hat n o data ca n b e 
destr o ye d . 
B y m y si g nat ure bel o w, I here b y attest t hat I h a ve rea d, u n d erst o o d a n d a gree t o a bi de b y 
all c o n diti o ns, i nstr ucti o ns a n d restricti o ns c o ntai ne d i n t his versi o n of t he pr ot oc ol dat e d 
1 0  A pril 2 0 2 0 . 
 
I n vesti g at or’s S i g n at ure:  
Date :  
 
 
 
 
m m/ d d/yyyy  
Pri nte d N a me:  
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
iii1 6 
 
SI G N A T U R E P A G E  
 
 
 
 D ate   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
m m/ d d/yyyy  
 
        
 
 
 
 
 
 D ate   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
m m / d d/yyyy 
 
 D ate   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
m m / d d/yyyy 
s  
 D ate   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
   
m m/ d d/yyyy  
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
iv1 6 
 
P R O T O C O L S Y N O P SI S  
N a me of S p o ns or C o m p a n y:  
K o wa Researc h I nstit ute, I nc.  
Dr u g U n der St u d y:  
K -2 8 5  
Title of Pr ot oc ol:  
A P hase II, Ra n d o mize d, D o u ble-bli n d, Acti ve C o m parat or, Parallel Gr o u p St u d y t o E val uate 
t he Efficac y a n d Safet y of K-2 8 5 C o m pare d w it h Me nt h ol Gel f or t he Treat me nt of Dela ye d 
O nset M uscle S ore ness ( D O M S) i n t he L o wer E xtre mit y  
Pr ot oc ol N u m ber:  
K -2 8 5 -2 0 1  
P h ase:  
II 
I n dic ati o n: 
Ac ute pai n relief 
St u d y Desi g n:  
T his is a p hase II, ra n d o mize d, d o u ble -bli n d, acti ve c o m parat or, parallel gr o u p st u d y t o e val uate 
t he efficac y a n d safet y of K-2 8 5 c o m pare d wit h me nt h ol gel f or t he treat me nt of dela ye d o nset 
m uscle s ore ness ( D O M S ) i n t he l o wer e xtre mit y. T he st u d y will c o nsist of scree ni n g, a n e xercise 
visit ( D O M S i n d ucti o n ), i n-patie nt a n d o ut -patie nt peri o ds u p t o 3 wee ks, a n d a f oll o w-u p  
tele p h o ne call. 
 
D uri n g t he Scree ni n g Visit, s u bjects will pr o vi de i nf or me d c o nse nt a n d c o m plete scree ni n g 
assess me nts i ncl u di n g me dical hist or y, i de ntificati o n of t he d o mi na nt le g, p h ysical a n d s ki n 
e xa mi nati o ns, bl o o d a n d uri ne tests, vital si g ns meas ure me nts, electr ocar di o gra m ( E C G), a n d 
ot her scree ni n g pr oce d ures. S u bjects w h o are a ble t o partici p ate i n t he  st u d y ( Peri o d 1 a n d 2) 
a n d w h o meet t he pre -e xercise i ncl usi o n a n d e xcl usi o n criteria will be e nr olle d i nt o t he st u d y 
a n d ret ur n t o t he cli nic o n Da y -1 . 
 
Eli gi bilit y will be c o nfir me d a n d enr olle d s u bjects will perf or m a sta n dar dize d re petiti ve  
q ua drice ps m uscle e xercise t o create D O M S t o b ot h le gs  (Da y -1 ). T he e xercise re gi me n will 
c o nsist of a war m -u p, deter mi nati o n of ma xi m u m t olerate d wei g ht, a n d ti me d a n d u n -ti me d 
w or k o ut p hases . W it hi n 2 4  t o 3 0  h o urs after t he e xercise sessi o n  ( Da y 1), s u bjects will rate t he 
pai n of b ot h le gs  usi n g a cate g orical pai n scale a n d rec or d pai n i nte nsit y of b ot h le gs  at rest a n d 
w hile sta n di n g  usi n g a 0 -1 0 0 p oi nt electr o nic  vis ual a nal o g scale (eV A S ) (a ca pt ure pr o gra m  
will  li nearl y c o n vert t he pi xel t o uc he d t o a n i nte ger bet wee n 0 a n d 1 0 0) t o deter mi ne eli gi bilit y 
f or ra n d o mizati o n. T he s pecific p ost -e xercise  
 i ncl usi o n criteri o n will be mas ke d t o 
s u bjects. 
 
 
. If b ot h le gs meet p ost -e xercise i ncl usi o n criteria, t he st u d y le g will be t he 
d o mi na nt le g, base d o n ha n d  d o mi na nce. S u bjects n ot q ualif yi n g f or ra n d o mizati o n will be gi ve n 
a p pr o priate sta n dar d of care.  
 
A t otal of 2 4 0 s u bjects w h o meet p ost -e xercise i ncl usi o n criteria will be ra n d o ml y assi g ne d i n a 
1: 1 rati o t o Treat me nt Ar m A ( K -2 8 5 gel) or Treat me nt Ar m B ( Me nt h ol gel). 
 
 
 
 
  
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
v 1 6 
 
 
 
 
 
 
 
I n Peri o d 1 
 st u d y gels will be  a p plie d t o  ra n d o mize d s u bjects o n a 
 
 
 
 o n t he st u d y le g as f oll o ws: 
•  
Treat me nt Ar m A: Eac h s u bject will a p pl y K -2 8 5 t o t he st u d y le g.  
•  
Treat me nt Ar m B: Eac h s u bject will  a p pl y me nt h ol gel t o t he st u d y le g. 
 
T he first st u d y gel a p plicati o n t o t he st u d y le g will be a p plie d b y t he s u bject wit h i n vesti gat or 
( or desi g nee) o versi g ht t o e ns ure pr o per a p plicati o n at t he cli nic o n Da y 1  wit hi n 2 4  t o 3 0  h o urs 
after D O M S i n d ucti o n . S u bse q ue nt  st u d y gel a p plicati o ns at t he cli nic  will be a p plie d t o t he 
st u d y le g b y t he s u bject wit h i n vesti gat or ( or desi g nee) o versi g ht t o e ns ure pr o per a p plicati o n. 
O n Da y 2, p h ot o gra p hic a n d resi d ue e val uati o n of t he a p plicati o n site will be perf or me d pri or t o 
t he 
 st u d y gel a p plicati o n. S u bjects will re mai n i n t he cli nic u ntil t he y are 
disc har ge d f oll o wi n g c o m pleti o n of st u d y assess me nts  o n Da y  2 .  
 
P ai n i nte nsit y assess me nts will be perf or me d f or t he st u d y le g a n d n o n-st u d y le g at rest  a n d 
w hile sta n di n g usi n g a  0 -1 0 0 p oi nt e V A S  o n Da y 1 at Baseli ne ( 0 h o ur s) a n d at 
 
 
after t he first  st u d y gel a p plicati o n. P ai n assess me nts sc he d ule d bet wee n mi d ni g ht a n d 6  a m ma y 
be s ki p pe d if s u bject s are aslee p b ut s u bjects ma y n ot s ki p m ore t ha n t w o se q ue ntial assess me nts. 
A  ti me wi n d o w of  + 3 0  mi n utes will  be all o we d bet wee n q ualificati o n ( baseli ne assess me nt) a n d 
first gel a p plicati o n ( 0 h o ur). T he f oll o wi n g ti me wi n d o ws will be all o we d f or eac h pai n 
assess me nt  (e V A S, Perce pti ble Pai n 
Relief, a n d 
Mea ni n gf ul Pai n 
Relief)  ti me p oi nt: 
 
 
 
 
F oll o wi n g disc har ge fr o m t he cli nic o n Da y 2 , s u bse q ue nt st u d y gel a p plicati o ns a n d pai n 
i nte nsit y assess me nts will be perf or me d b y t he s u bject o n a n o ut -patie nt basis ( Da y 2  t hr o u g h 
Da y 8 ). S u bjects will be i nstr ucte d n ot t o s h o wer or bat he f or at least 3 0 mi n utes bef ore a n d at 
least 1 h o ur after gel a p plicati o n.  A ll pai n i nte nsit y assess me nts i ncl u di n g e V A S, Perce pti ble 
Pai n Relief , a n d Mea ni n gf ul Pai n Relief will be rec or de d i n e -diaries t hr o u g h Da y 8 ( Peri o d 1), 
a n d all st u d y gel a p plicati o ns a n d resc ue me dicati o ns will  be rec or de d i n  t he e-diar y  b y t he 
s u bject thr o u g h Da y  2 2  ( Peri o d 1 a n d 2). Perce pti ble Pai n Relief a n d Mea ni n gf ul Pai n Relief 
will be rec or de d i n t he e -diar y u ntil ac hie ve d  i n Peri o d 1. A tele p h o ne call will be c o n d ucte d b y 
st u d y staff o n Da y 5  (± 1  da y) t o assess safet y. S u bjects will ret ur n t o t he cli nic f or assess me nts 
o n Da y  8  ( ± 1 da y ). F or s u bjects w h o are assi g ne d t o recei ve st u d y gel f or 1 wee k, Da y 8  e n d of 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
vi 1 6 
 
st u d y ( E O S) (+ 1  da y ) will be a cli nic visit a n d a f oll o w -u p tele p h o ne call t o assess safet y will 
be c o n d ucte d b y st u d y staff o n Da y  1 5  ( ± 1 da y) . S u bjects w h o are assi g ne d t o recei ve st u d y gel 
f or 3 wee ks will c o nti n ue t o a p pl y st u d y gel o n a n o ut-patie nt basis fr o m Da y 8 t o Da y 2 2  
( Peri o d 2) acc or di n g t o t heir assi g ne d d osi n g re gi me n (
 (Ta ble 1  a b o ve). F or 
s u bjects w h o are d osi n g i n Peri o d 2, tele p h o ne calls t o assess safet y will be c o n d ucte d b y st u d y 
staff o n Da y 1 1  ( ± 1 da y ) a n d Da y  1 8 ( ± 1 da y) , st u d y gel a p plicati o ns a n d use of a n y resc ue 
me dicati o ns will be rec or de d i n e -diaries b y t he s u bjects t hr o u g h Da y 2 2 , a n d an e n d of st u d y 
( E O S) cli nic visit will occ ur o n Da y  2 2 ( + 1 da y).  A f oll o w-u p  tele p h o ne call t o assess safet y 
will be c o n d ucte d b y st u d y staff o n Da y  2 9  ( ± 1 da y). 
 
Use of a n y resc ue me dicati o n f or D O M S is str o n gl y disc o ura ge d u ntil 1 6 8 h o urs ( Da y 8) after 
t he first st u d y gel a p plicati o n, at w hic h ti me o ver -t he-c o u nter ( O T C ) aceta mi n o p he n ( o ne 
5 0 0  m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue me dicati o n f or 
D O M S is per mitte d if re q uire d. S u bjects e x perie nci n g se vere pai n or i na bilit y t o m o ve or wal k 
d ue t o pai n ma y be per mit te d t o use resc ue me dicati o n ( o ne 5 0 0 m g O T C aceta mi n o p he n ta blet 
t wice dail y, n ot m ore t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs after t he first st u d y gel a p plicati o n. 
If s u bjects ta ke resc ue me dicati o n bef ore t he first 1 6 8 h o urs, it will be ca pt ure d as a c onc o mita nt 
me dicati o n, a n d s u bjects will rec or d t heir pai n i nte nsit y i n t he e -diar y bef ore ta ki n g t he resc ue 
me dicati o n. T he n u m ber of ta blets ta ke n a n d t he date a n d ti me will be rec or de d i n t he e -diar y.   
W he n t he 
 
 
. T he i nteri m a nal ysis 
will assess f utilit y of t he trial (c o n diti o nal p o wer < 0. 0 5) . If f utilit y is deter mi ne d, t he st u d y will 
be ter mi nate d. If c o nti n uati o n of t he trial is deter mi ne d, s u bject e nr oll me nt will be res u me d . 
Pri m ar y O bjecti ve:  
•  
T o e val uate t he efficac y of K -2 8 5 c o m pare d wit h me nt h ol gel bet wee n 0 t o 2 4  h o urs after  
t he first gel a p plicati o n f or t he treat me nt of D O M S 
Sec o n d ar y O bjecti ves:  
•  
T o e val uate t he efficac y of K -2 8 5 c o m pare d wit h  me nt h ol gel after t he first gel a p plicati o n 
f or t he treat me nt of D O M S 
•  
T o e val uate t he safet y a n d t olera bilit y of K -2 8 5 c o m pare d wit h  me nt h ol gel after t he first 
gel a p plicati o n f or t he treat me nt of D O M S  
S u bject P o p ul ati o n:  
T he st u d y p o p ulati o n will be a d ult male a n d fe male s u bjects a ge d 1 8  t o 3 5  years, i ncl usi ve, wit h 
a b o d y mass i n de x ( B MI) bet wee n 1 8 a n d 3 2  k g/ m 2, i ncl usi ve. 
N u m ber of S u bjects:  
T otal 2 4 0  s u bjects wit h 1 2 0 s u bjects i n eac h of t he 2 treat me nt 
arm s (Ta ble  1  a b o ve).  
N u m ber of Ce nters:  
1 site i n t he U nite d States 
D ose Le vels:  
K -2 8 5 : 
 
Me nt h ol gel:  
  
R o ute of A d mi nistr ati o n:  
T o pical gel  
D ur ati o n of Tre at me nt:  
( Peri o d 1):  Eac h s u bject will a p pl y 
of st u d y gel 
 
 ( Peri o d 1  a n d 2):  Eac h s u bject will a p pl y 
of st u d y gel 
 
a n d t he n will a p pl y st u d y gel 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
vii 1 6 
 
Criteri a f or E v al u ati o n:  
Effic ac y:  
Pri mar y E n d p oi nt:  
•  
T he s u m of pai n i nte nsit y differe nce ( S PI D) bet wee n 
 
f or t he st u d y le g after t he first st u d y gel a p plicati o n w hile sta n di n g usi n g a 0 -1 0 0  p oi nt e V A S   
Sec o n dar y E n d p oi nt s: 
F or b ot h t he st u d y le g a n d t he n o n -st u d y le g 
•  
S PI D 0 -2 4 h o urs  after t he first st u d y gel a p plicati o n at rest usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D bet wee n 0 ( Baseli ne) t o 1 2 h o urs ( S PI D 0 -1 2) after t he first st u d y gel a p plicati o n w hile 
sta n di n g usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D 0 -1 2 h o urs  after t he first st u d y gel a p plicati o n at  rest usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D bet wee n 0 ( Baseli ne) t o 4 8 h o urs ( S PI D 0 -4 8) after t he first st u d y gel a p plicati o n  w hile 
sta n di n g usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D 0 -4 8 h o urs  after t he first st u d y gel a p plicati o n at rest usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D bet wee n 0 ( Baseli ne) t o 7 2 h o urs ( S PI D 0 -7 2) after t he first st u d y gel a p plicati o n w hile 
sta n di n g usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D 0 -7 2 h o urs  after t he first st u d y gel a p plicati o n at rest usi n g a 0 -1 0 0 p oi nt e V A S  
•  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
S afet y:  
Safet y assess me nts will i ncl u de a d verse e ve nts ( A Es), vital si g n meas ure me nts (s yst olic bl o o d 
press ure, diast olic bl o o d press ure, p ulse rate, res pirat or y rate, a n d oral b o d y te m perat ure), E C G , 
p h ysical e xa mi nati o n fi n di n gs i ncl u di n g wei g ht, st u d y gel  a p plicati o n site reacti o ns, cli nical 
la b orat or y test res ults, st u d y gel use , a n d c o nc o mita nt me dicati o n use . 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
viii 1 6 
 
Criteri a f or I ncl usi o n:  
Pre -e xercise Criteri a f or I ncl usi o n: 
1.  S u bject 
m ust pr o vi de i nf or me d c o nse nt bef ore a n y st u d y -s pecific e val uati o n is 
perf or me d.  
2.  S u bject is male a n d fe male a ge d 1 8 t o 3 5 years, i ncl usi ve.  
3.  S u bject has a b o d y mass i n de x of 1 8 t o 3 2  k g/ m 2, i ncl usi ve  
 
 
 
 
 
 
 
6.  S u bject he mat ol o g y, ser u m c he mistr y, uri nal ysis,  vital si g n meas ure me nts (s yst olic 
bl o o d press ure, diast olic bl o o d pre ss ure, p ulse rate, res pirat or y rate, a n d oral b o d y 
te m perat ure) a n d 1 2-lea d E C G res ults s h o w n o cli nicall y rele va nt a b n or malities, as 
j u d ge d b y t he i n vesti gat or at t he Scree ni n g V isit. 
7.  All fe male s u bjects m ust ha ve a ne gati ve ser u m pre g na nc y test res ult at scree ni n g a n d 
ne gati ve uri ne pre g na nc y test o n Da y  -1  pri or t o a d missi o n t o t he cli nic. Fe male s u bjects 
of c hil d beari n g p ote ntial m ust use o ne of t he f oll o wi n g acce pta ble birt h c o ntr ol met h o ds 
as s pecifie d bef ore e nr oll me nt a n d t hr o u g h o ut t he st u d y:  
a. S ur gical sterilizati o n ( bilateral t u bal li gati o n, 
h ysterect o m y, 
bilateral 
o o p h orect o m y) at least 6  m o nt hs bef ore t he first d ose of st u d y gel ; 
b.  I ntra uteri ne de vice i n place f or at least 3 m o nt hs bef ore t he first d ose of st u d y 
gel  a n d t hr o u g h o ut t he st u d y;  
c. Ba rrier met h o d (c o n d o m or  dia p hra g m) wit h s per mici de f or at least 1 4  da ys 
bef ore t he first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y;  
d.  S ur gical sterilizati o n of t he male part ner ( vasect o m y at least 6  m o nt hs bef ore 
t he first d ose of st u d y gel); 
e. H or m o nal c o ntr ace pti ves f or at least 3  m o nt hs wit h a barrier met h o d 1 4 da ys 
bef ore t he first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y ; 
f. A bsti ne nce.  
8.  S u bject is a ble a n d willi n g t o c o m pl y wit h t he pr ot oc ol a n d st u d y pr oce d ures.  
9.  S u bject has ne gati ve test res ults f or dr u gs a n d alc o h ol at scree ni n g a n d is a ble a n d 
willi n g t o a bstai n fr o m marij ua na a n d alc o h ol use f or 4  da ys bef ore Da y  1 a n d 
t hr o u g h o ut t he st u d y. N ote t hat a p ositi ve scree ni n g res ult f or marij ua na  is acce pta ble 
pr o vi de d t he s u bject will a bstai n f or t he s t u d y as descri be d a b o ve. 
1 0.  S u bject d oes n ot use nic oti ne or has q uit usi n g nic oti ne f or at least 6  m o nt hs bef ore t he 
first d ose of st u d y gel a n d will n ot use nic oti ne t hr o u g h o ut t he st u d y.  
 
 
 
 
 
 
  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
i x1 6 
 
Criteri a f or E xcl usi o n:  
Pre -e xercise Criteri a f or E xcl usi o n:  
 
 
 
 
 
 
 
 
 
3.  S u bject has recei ve d oral or t o pical a nal gesic me dicati o ns wit hi n 1 4  da ys bef ore t he 
S cree ni n g V isit. 
4.  S u bject has use d a s yste mic c ortic oster oi d wit hi n 3 0  da ys bef ore t he Scree ni n g V isit. 
5.  S u bject has a me dical hist or y t hat i ncl u des a c o ntrai n dicati o n f or t he use of me nt h ol or 
n o nster oi dal 
a nti -i nfla m mat or y 
dr u gs ( N S AI Ds) (e. g., 
gastr oi ntesti nal 
ulcer, 
gastr oi ntesti nal blee di n g).  
6.  S u bject is ta ki n g me dicati o ns or ot her s u bsta nces c o ntrai n dicate d beca use of t he nat ure 
of t he st u d y gel or t he p ote ntial f or dr u g  i nteracti o ns. T his i ncl u des s u bjects wit h 
aller gies t o prescri pti o n or O T C  pr o d ucts c o ntai ni n g me nt h ol or N S AI Ds.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 4.  S u bject is pre g na nt or n ursi n g.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
x 1 6 
 
1 5.  S u bject has partici pate d i n a n i n vesti gati o nal dr u g st u d y wit hi n 3 0  da ys bef ore 
Scree ni n g.  
1 6.  S u bject is a me m ber or a fa mil y me m ber of t he pr ofessi o nal or a ncillar y pers o n nel 
i n v ol ve d i n t he st u d y.  
1 7.  S u bject has partici pate d i n ot her cli nical trials f or K -2 8 5.  
1 8.  S u bject has a b n or mal fi n di n gs or assess me nts t hat are cli nicall y n ote w ort h y.  
1 9.  S u bject w h o, i n t he o pi ni o n of t he i n vesti gat or, s h o ul d n ot partici pate i n t he st u d y.  
St atistic al A n al ysis:  
I n ge neral, assess me nts wit h c o nti n u o us o utc o mes will be s u m marize d usi n g t he descri pti ve 
statistics n, mea n, sta n dar d de viati o n (S D ), me dia n, mi ni m u m a n d ma xi m u m. F or assess me nts 
wit h cate g orical o utc o mes, fre q ue nc y c o u nts a n d perce nta ge will be  calc ulate d. Detaile d 
statistical met h o d ol o g y will be prese nte d i n a se parate statistical a nal ysis pla n.  
St u d y P o p ul ati o ns:  
T hree  a nal ysis p o p ulati o ns will be e val uate d:  
•  
T he f ull a nal ysis set ( F A S) will i ncl u de all ra n d o mize d s u bjects w h o ha ve a baseli ne pai n 
sc ore, a n d at least 1  st u d y gel a p plie d  
•  
T he per -pr ot oc ol set ( P P S) will i ncl u de all ra n d o mize d s u bjects w h o ha ve a baseli ne pai n 
sc ore, at least 1 st u d y gel a p plie d, a n d n o maj or pr ot oc ol vi olati o ns.  
•  
T he safet y set will i ncl u de all s u bjects w h o ha ve at least 1 st u d y gel a p plie d.  
Pri m ar y Effic ac y A n al ysis:   
T he pri mar y a nal ysis p o p ulati o n is t he F A S. T he pri mar y a nal ysis will be re peate d usi n g t he 
P P S .
 
 
 
. If t here e xist missi n g V A S val ues t o be i m p ute d, a n y s uc h 
val ue s will be i m p ute d bef ore calc ulati n g t he S PI D. After calc ulati n g t he S PI D , an a nal ysis of 
c o varia nce ( A N C O V A)  m o del  will be a p plie d f or t he pri mar y e n d p oi nt wit h ge n der  a n d 
treat me nt as mai n effects  a n d baseli ne pai n as a c o variate.   
Sec o n d ar y Effic ac y A n al yses:  
A mi xe d effect m o del re peate d-meas ures ( M M R M) wit h t he sa me mai n effects a n d c o variate 
will be a p plie d t o t he PI D w hile sta n di n g  a n d PI D at rest t o i n vesti gate treat me nt differe nces.  
 
 T he ti me t o first d ose of resc ue me dicati o n, will be a nal yze d usi n g t he Ka pla n -Meier 
met h o d t o esti mate t he s ur vi val distri b uti o n f u ncti o n.  
S afet y : 
T he safet y e n d p oi nt data will be s u m marize d f or t he safet y set. A d verse e ve nts will be c o de d 
usi n g t he latest versi o n of t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). A d verse 
e ve nts a n d seri o us A Es ( S A Es) will be s u m marize d b y treat me nt gr o u p f or o verall n u m ber of 
A Es, se verit y, a n d relati o ns hi p t o st u d y gel. T he i nci de nce of A Es will be s u m marize d b y b o d y 
s yste m a n d treat me nt gr o u p. T he i nci de nce of treat me nt -e mer ge nt A Es ( T E A Es) will als o be 
s u m marize d b y s yste m or ga n class a n d preferre d ter m. Cli nical la b orat or y res ults will be 
s u m marize d b y treat me nt gr o u p al o n g wit h c ha n ge fr o m Baseli ne. Vital si g n meas ure me nts will 
be s u m marize d b y gr o u p a n d ti me p oi nt al o n g wit h c ha n ge fr o m Baseli ne. All A E, cli nical 
la b orat or y, vital si g n, p h ysical e xa mi nati o n, st u d y gel  a p plicati o n site reacti o n, st u d y gel use  
a n d c o nc o mita nt me dicati o n use will be prese nte d i n data listi n gs . 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xi 1 6 
 
 
 
 
 
 
 
 
 r
 
 
S a m ple  Size C alc ul ati o n : 
T he para meters are c o nser vati vel y esti mate d base d o n t he  D O M S st u d y wit h  
 gel.  T he 
bet wee n -gr o u p differe nce i n t he mea n 
 is 1 1. 0 7  wit h  a S D of 2 5. 6 2 . T o ha ve statistical 
p o wer of 9 0 %, 1 1 3 s u bjects per gr o u p are re q uire d. T a ki n g i nt o acc o u nt i nf or mati o n l oss ca use d 
b y missi n g data , it is esti mated t hat 1 2 0  s u bjects nee d  t o be treate d wit h eac h st u d y gel. 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xii 1 6 
 
T A B L E O F C O N T E N T S  
I N V E S TI G A T O R’ S S T A T E M E N T ............................................................................................. ii 
SI G N A T U R E P A G E  ..................................................................................................................... iii 
P R O T O C O L S Y N O P SI S  ............................................................................................................. i v 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  ............................................. x v  
1. 0  
I N T R O D U C TI O N A N D R A TI O N A L E F O R D O S E S E L E C TI O N ............................ 1  
1. 1  
B A C K G R O U N D I N F O R M A TI O N  ................................................................................... 1  
1. 2  
R A TI O N A L E F O R S T U D Y A N D D O S E S E L E C TI O N  ................................................... 2  
2. 0  
S T U D Y O B J E C TI V E S  ..................................................................................................... 4  
2. 1  
P RI M A R Y O BJ E C TI V E  .................................................................................................... 4  
2. 2  
S E C O N D A R Y O BJ E C TI V E S ............................................................................................ 4  
2. 3  
P RI M A R Y E F FI C A C Y E N D P OI N T  ................................................................................. 4  
2. 4  
S E C O N D A R Y E F FI C A C Y E N D P OI N T S  ......................................................................... 4  
2. 5  
S A F E T Y E N D P OI N T S  ...................................................................................................... 5  
3. 0  
S T U D Y D E S C RI P TI O N  .................................................................................................. 6  
3. 1  
S T U D Y D E SI G N  ............................................................................................................... 6  
4. 0  
S U B J E C T E LI GI BI LI T Y A N D WI T H D R A W A L C RI T E RI A  ................................. 1 4  
4. 1  
I N C L U SI O N C RI TE RI A  ................................................................................................. 1 4  
4. 1. 1  
Pre -e xercise I ncl usi o n Criteria  .......................................................................................... 1 4  
4. 1. 2  
P ost -e xercise Ra n d o mizati o n I ncl usi o n Criteria:  .............................................................. 1 5  
4. 2  
E X C L U SI O N C RI T E RI A  ................................................................................................ 1 5  
4. 3  
DI S C O N TI N U A TI O N A N D WI T H D R A W A L C RI T E RI A  ............................................ 1 6  
4. 3. 1  
Disc o nti n uati o n d ue t o a n A p plicati o n Site Reacti o n  ....................................................... 1 7  
5. 0  
P R O C E D U R E S F O R E F FI C A C Y A N D S A F E T Y E V A L U A TI O N S  ....................... 1 8  
5. 1  
E F FI C A C Y E V A L U A TI O N S  .......................................................................................... 1 8  
5. 1. 1  
Pai n I nte nsit y  .................................................................................................................... 1 8  
5. 1. 1. 1  Vis ual A nal o g Scale  .......................................................................................................... 1 8  
5. 1. 1. 2  Cate g orical Pai n Scale  ...................................................................................................... 1 8  
5. 1. 2  
Use of Resc ue Me dicati o n  ................................................................................................ 1 8  
5. 1. 3  
Ti me t o O nset of First Perce pti ble a n d Mea ni n gf ul Pai n Relief  ....................................... 1 9  
5. 1. 3. 1  O nset of Perce pti ble Pai n Relief  ....................................................................................... 1 9  
5. 1. 3. 2  O nset of Mea ni n gf ul Pai n Relief  ...................................................................................... 1 9  
5. 2  
S A F E T Y E V A L U A TI O N S  .............................................................................................. 1 9  
5. 2. 1  
A d verse E ve nts  ................................................................................................................. 1 9  
5. 2. 2  
Cli nical La b orat or y Tests  .................................................................................................. 2 0  
5. 2. 2. 1  Ele vate d Le vels of Ser u m Creati ne Ki nase ....................................................................... 2 0  
5. 2. 3  
Vital Si g ns ......................................................................................................................... 2 1  
5. 2. 4  
Electr ocar di o gra m  ............................................................................................................. 2 1  
5. 2. 5  
P h ysical E xa mi nati o n  ....................................................................................................... 2 1  
5. 2. 6  
S ki n E xa mi nati o n ( A p plicati o n Site Reacti o n)  ................................................................. 2 1  
5. 2. 7  
C o nc o mita nt Me dicati o ns  ................................................................................................. 2 2  
5. 3  
O T H E R E V A L U A TI O N S  ................................................................................................ 2 2  
5. 3. 1  
De m o gra p hics, Me dical Hist or y a n d Ot her Baseli ne C haracteristics  ............................... 2 2  
5. 3. 2  
Dr u g a n d Alc o h ol Scree ni n g  ............................................................................................. 2 3  
5. 3. 3  
Pre g na nc y .......................................................................................................................... 2 3  
5. 3. 4  
Sta n dar dize d E xercise Re gi me n  ....................................................................................... 2 3  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xiii 1 6 
 
5. 3. 5  
P h ot o gra p h a n d Resi d ue E val uati o n  ................................................................................. 2 4  
5. 3. 5. 1  P h ot o gra p hic A nal ysis  ...................................................................................................... 2 4  
5. 3. 5. 2  Resi d ue E val uati o n  ........................................................................................................... 2 4  
5. 4  
T O T A L B L O O D V O L U M E ............................................................................................. 2 4  
6. 0  
C O N D U C T O F S T U D Y  ................................................................................................. 2 4  
6. 1  
S T U D Y B LI N DI N G A N D R A N D O MI Z A TI O N  ............................................................ 2 4  
6. 2  
S U BJ E C T I N F O R M E D C O N S E N T  ................................................................................ 2 5  
6. 3  
S T U D Y VI SI T S  ................................................................................................................ 2 6  
6. 4  
C O M P LI A N C E WI T H T H E P R O T O C O L  ...................................................................... 3 3  
6. 5  
T E R MI N A TI O N O F T H E S T U D Y .................................................................................. 3 3  
7. 0  
S T U D Y M E DI C A TI O N  ................................................................................................. 3 3  
7. 1  
D E S C RI P TI O N O F S T U D Y M E DI C A TI O N  .................................................................. 3 3  
7. 2  
D R U G P A C K A GI N G  ....................................................................................................... 3 4  
7. 3  
D R U G L A B E LI N G  .......................................................................................................... 3 4  
7. 4  
D R U G S T O R A G E  ............................................................................................................ 3 5  
7. 5  
DI S P E N SI N G A N D A D MI NI S T R A TI O N O F T R E A T M E N T  ....................................... 3 5  
7. 5. 1  
Dis pe nsi n g of St u d y Gel  ................................................................................................... 3 5  
7. 5. 2  
A p plicati o n Trai ni n g  ......................................................................................................... 3 5  
7. 5. 3  
Dr u g A d mi nistrati o n  ......................................................................................................... 3 5  
7. 5. 4  
e-Diar y  .............................................................................................................................. 3 7  
7. 5. 5  
P h ysical E xercise  .............................................................................................................. 3 7  
7. 6  
C O M P LI A N C E WI T H P R E S C RI B E D S T U D Y G E L D O SI N G R E GI M E N  .................. 3 7  
7. 7  
D R U G A C C O U N T A BI LI T Y  ........................................................................................... 3 7  
7. 8  
P R O C E D U R E F O R U N B LI N DI N G  ................................................................................ 3 8  
8. 0  
C O N C O MI T A N T M E DI C A TI O N  ............................................................................... 3 9  
8. 1  
G E N E R A L C O N SI D E R A TI O N S  .................................................................................... 3 9  
8. 2  
P R O HI BI T E D M E DI C A TI O N A N D T H E R A PI E S  ........................................................ 3 9  
8. 3  
P E R MI T T E D M E DI C A TI O N  .......................................................................................... 3 9  
9. 0  
A D V E R S E E V E N T S  ...................................................................................................... 4 0  
9. 1  
A D V E R S E E V E N T D E FI NI TI O N  .................................................................................. 4 0  
9. 2  
R E P O R TI N G A D V E R S E E V E N T S  ................................................................................ 4 0  
9. 3  
F O L L O W -U P O F A D V E R S E E V E N T S  .......................................................................... 4 2  
1 0. 0  
S E RI O U S A D V E R S E E V E N T S  .................................................................................... 4 3  
1 0. 1  
LI F E -T H R E A T E NI N G A D V E R S E E V E N T  ................................................................... 4 3  
1 0. 2  
H O S PI T A LI Z A TI O N  ....................................................................................................... 4 3  
1 0. 3  
I M P O R T AN T M E DI C A L E V E N T  .................................................................................. 4 3  
1 0. 4  
P R E G N A N C Y  .................................................................................................................. 4 3  
1 0. 5  
S U BJ E C T DI S C O N TI N U A TI O N A N D WI T H D R A W A L  ............................................. 4 4  
1 0. 6  
S E RI O U S U N E X P E C T E D S U S P E C T E D A D V E R S E R E A C TI O N S ............................. 4 4  
1 0. 7  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  ................................................................. 4 5  
1 1. 0  
S T A TI S TI C A L M E T H O D S A N D D A T A A N A L Y SI S  ............................................... 4 6  
1 1. 1  
S A M P L E SI Z E J U S TI FI C A TI O N  ................................................................................... 4 6  
1 1. 2  
S T U D Y P O P U L A TI O N S  ................................................................................................. 4 6  
1 1. 3  
DI S P O SI TI O N  .................................................................................................................. 4 6  
1 1. 4  
D E M O G R A P HI C / B A S E LI N E I N F O R M A TI O N ............................................................ 4 6  
1 1. 5  
A N A L Y SI S O F E F FI C A C Y P A R A M E T E R S  ................................................................. 4 6  
1 1. 5. 1  Pri mar y Efficac y Para meters  ............................................................................................ 4 6  
1 1. 5. 2  Sec o n dar y Efficac y Para meters  ........................................................................................ 4 7  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xiv 1 6 
 
1 1. 6  
A N A L Y SI S O F S A F E T Y D A T A  .................................................................................... 4 7  
1 1. 7  
I N T E RI M A N A L Y SI S ..................................................................................................... 4 8  
1 2. 0  
S T U D Y M A N A G E M E N T A N D D A T A C O L L E C TI O N  ............................................ 4 9  
1 2. 1  
E T HI C A L C O N D U C T O F T H E T RI A L  ......................................................................... 4 9  
1 2. 2  
I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T E T HI C S C O M MI T T E E ........ 4 9  
1 2. 3  
S U BJ E C T I N F O R M E D C O N S E N T  ................................................................................ 4 9  
1 2. 4  
A M E N D M E N T S T O T H E P R O T O C O L  ......................................................................... 5 0  
1 2. 5  
S T U D Y I NI TI A TI O N  ...................................................................................................... 5 0  
1 2. 6  
S T U D Y M O NI T O RI N G  .................................................................................................. 5 0  
1 2. 7  
C A S E R E P O R T F O R M  .................................................................................................... 5 1  
1 2. 8  
V E RI FI C A TI O N P R O C E D U R E S .................................................................................... 5 1  
1 2. 9  
R E T E N TI O N O F R E C O R D S ........................................................................................... 5 1  
1 2. 1 0  I N S U R A N C E A N D I N D E M NI T Y .................................................................................. 5 2  
1 2. 1 1  A U DI T  .............................................................................................................................. 5 2  
1 3. 0  
U S E O F I N F O R M A TI O N  ............................................................................................. 5 3  
1 3. 1  
G E N E R A L A S P E C T S  ...................................................................................................... 5 3  
1 3. 2  
S U BJ E C T C O N FI D E N TI A LI T Y A N D D A T A P R O T E C TI O N  ..................................... 5 3  
1 3. 3  
FI N A L R E P O R T A N D P U B LI C A TI O N P O LI C Y  .......................................................... 5 3  
1 4. 0  
R E F E R E N C E S  ................................................................................................................ 5 5  
1 5. 0  
A p pe n dices  ....................................................................................................................... 5 6  
1 5. 1  
A P P E N DI X 1  .................................................................................................................... 5 6  
VI S U A L A N A L O G S C A L E  ( E X A M P L E O F P A P E R V A S) ...................................................... 5 6  
VI S U A L A N A L O G S C A L E  ( E X A M P L E O F E L E C T R O NI C V A S) .......................................... 5 7  
1 5. 2  
A P P E N DI X 2  .................................................................................................................... 5 8  
C A T E G O RI C A L P AI N S C A L E A S S E S S M E N T  ......................................................................... 5 8  
1 5. 3  
A P P E N DI X 3  .................................................................................................................... 5 9  
K -2 8 5 -2 0 1 A P P LI C A TI O N I N S T R U C TI O N S  ............................................................................. 5 9  
1 5. 4  
A P P E N DI X 4  .................................................................................................................... 6 2  
E X A M P L E I M A G E S O F A P P LI C A TI O N SI T E R E A C TI O N S  .................................................. 6 2  
 
 
List of T a bles  
T a ble 1: Tre at me nt Assi g n me nt  ................................................................................................... 7  
T a ble 2: Cli nic al E v al u ati o n Sc he d ule  ....................................................................................... 1 0  
T a ble 3. Cli nic al L a b or at or y Test P ar a meters  .......................................................................... 2 0  
 
 
List of Fi g ures  
Fi g ure 1. St u d y Sc he m a  ................................................................................................................. 9  
Fi g ure 2. St u d y Gel All oc ati o n  .................................................................................................... 3 4  
Fi g ure 3: Me as uri n g St u d y Gel  .................................................................................................. 3 6  
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xv 1 6 
 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
A PI  
acti ve p har m ace utical i n gre die nts  
A E  
ad verse e ve nt  
A L T  
ala ni ne a mi n otra nsferas e 
A N C O V A  
anal ysis of c o varia nce  
A S T  
as partate a mi n otra nsferas e 
A U C  
area u n d er t he c ur ve 
 
 
B MI  
b o d y mass i n de x  
C F R  
C o de of Fe d eral Re g ulati o ns  
C K  
creati ne ki n ase  
C K -M B  
creati ne ki n ase -m y ocar di al ba n d  
C K -M M  
creati ne ki n ase  i n s keletal m uscle 
C ma x  
m a xi m u m c o nce ntrati o n  
C O X (-2 ) 
c ycl o o x y ge nas e i n hi bit ors  
C R F  
case re p ort/rec or d for m  
C R O  
C o ntract Researc h Or g a nizati o n  
D O M S  
d ela ye d o nset m uscle s ore ness  
E C G  
electr ocar di o gra m 
e C R F 
electr o nic Cas e Re p ort/ Rec or d F or m 
e-diar y  
electr o nic d iar y d e vice  
e V A S  
electr o nic vis ual a nal o g s cale 
E T  
earl y ter mi nati o n  
F A S  
full a nal ysis set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
GI  
gastr oi ntesti nal  
I C F 
inf or me d c o nse nt f or m  
I C H 
I nter nati o nal C ou ncil f or Har m o nisati o n  
I E C 
I n d e pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
 
 
 
 
 
 
 
 
xvi 1 6 
 
K RI  
K o wa Researc h I nstit ute, I n c.  
L D H  
lactate de h y dr o ge nas e  
L O C F  
last o bser vati o n carrie d f or war d 
M A R  
m issi n g at ra n d o m 
M D M A  
3, 4 -met h yle ne di o x y -met ha m p heta mi ne ( E cstas y) 
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
MI  
m ulti ple im p utati o n  
M T W  
Ma xi m u m t olerate d wei g ht  
N S AI D  
n o n -ster oi dal a nti-i nfla m mat or y dr u g 
O T C  
o ver -t he-c o u nter  
P C P  
p he nc ycli di ne  
PI D  
p ai n i nte nsit y differe n ce  
P K  
p har mac o ki netics  
P P S  
p er-pr ot oc ol s et  
 
 
S A E  
Seri o us A d verse E v e nt  
S D  
sta n dar d de viati o n 
S O P  
Sta n dar d O perati n g Pr oce d ure/s  
S PI D  
su m of pai n i nte nsit y differe nce  
S PI D 0 -1 2  
su m of pai n i nte nsit y differe nce o v er 1 2  h o urs after t he first gel a p plicati o n  
S PI D 0 -2 4  
su m of pai n i nte nsit y differe nce o v er 2 4 h o urs after t he first gel a p plicati o n  
S PI D 0 -4 8  
su m of pai n i nte nsit y differe nce o ver 4 8 h o urs after fi rst gel a p plicati o n 
S PI D 0 -7 2  
su m of pai n i nte nsit y differe nce o ver 7 2 h o urs after first gel a p plicati o n  
 
 
S T E  
s h ort ti me e x p os ure 
S U S A R  
Seri o us U ne x pect e d S us pecte d A d v erse Reacti o n  
T E A E  
Treat me nt -e mer ge nt A E  
T R P  
tra nsie nt rece pt or p ote nti al  
V A S  
V is ual A nal o g S cale  
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1  of 6 2  
 
1. 0  
I N T R O D U C TI O N A N D R A TI O N A L E F O R D O S E S E L E C TI O N 
1. 1  
B A C K G R O U N D I N F O R M A TI O N  
N o n -ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds), i ncl u di n g n o n-selecti ve N S AI Ds a n d 
t he m ore selecti ve c ycl o o x y ge nase ( C O X-2) i n hi bit ors, are e xte nsi vel y use d i n t he U nite d 
Sta tes a n d rest of w orl d f or t he relief of pai n a n d t he re d u cti o n of i nfla m mati o n. T his class 
of me dicati o ns is t he m ost wi del y use d w he n prescri pti o n a n d o ver -t he-c o u nter (O T C ) 
pr o d ucts are c o nsi dere d. H o we v er, its oral us e is n ot wit h o ut ris k, w hi c h m ost n o ta bl y 
i ncl u des t o xicit y ass ociate d wit h gastr oi ntesti nal ( GI) i nfla m mati o n a n d blee di n g. 
Half of patie nts ta ki n g N S AI Ds re g ularl y ha ve e n d osc o picall y c o nfir me d gastric er osi o ns, 
a n d 1 0 %-3 0 % h a ve ulc ers. 1 T hese ris ks are a m plifi e d i n hi g h ris k gr o u ps, i ncl u di n g t he 
el derl y, t h ose 
wit h pre -e xisti n g gastr o pat h y, c hr o nic a d mi nistrati o n, c o nc o mita nt 
c ortic oster oi d use a n d H elic o bacter p yl ori i nfecti o n pri or t o N S AI D t hera p y. 2 T he use of 
selecti ve C O X-2 i n hi bit ors, pr u de nt use of pr ot o n p u m p i n hi bit ors, a n d alter nati ve 
me dicati o ns ha ve i m pr o ve d t he i nci de nce of g astr o pat h y, b ut ha ve n ot eli mi nate d it.  
C O X -2 i n hi bit ors still de m o nstrate a si g nifica nt ris k of GI c o m plicati o ns. 3   
T he wi des prea d use of O T C N S AI Ds, w hic h i ncl u des all n o n -selecti ve C O X i n hi bit ors, 
p oses a great ris k of GI c o m plicati o ns. Rece nt acti vit y has als o s h o w n t he p ote ntial f or 
car di o vas c ular ris k fr o m t he s yste mic use of C O X -2 i n hi bit ors, w hic h was hi g hli g hte d  b y 
t he 2 0 0 4 wit h dra wal of r ofec o xi b ( Vi o x x® ). Wit h t his bac k gr o u n d, t here is a nee d f or safer 
alter nati ves t o orall y a d mi nistere d N S AI Ds, es peciall y f or t h ose i n hi g her ris k gr o u ps, or 
t h ose i nt olera nt of orall y a d mi nistere d N S AI Ds.  
T o pical a nal g esics of fer a n alter nati ve t o t he us e of s yste mic N S AI Ds f or relief of f ocal 
pai n a n d i nfla m mati o n. T hese fall i nt o se veral cate g ories, i ncl u di n g a nest hetics, 
c o u nterirrita nts a n d a n al gesics. T he first t w o cat e g ories are ill ustrate d b y t he a p pr o ve d 
li d ocai ne 5 % p atc h ( Li d o der m® ), a n d ca psaici n, res pecti vel y. Flect or®  ( dicl ofe nac 
e p ola mi ne t o pical patc h 1. 3 %) is a n e x a m ple of a prescri pti o n N S AI D a nal gesic patc h. A 
meta -a nal ysis of 2 6 d o u ble -bli n d place b o -c o ntr olle d 
N S AI Ds trials t hat e nr olle d 
2, 8 5 3  patie nts de m o nst rate d t hat i n 1 9/ 2 6 tri als t he N S AI D was s u peri or t o place b o a n d 
was s h o w n t o be safe. 4  
l-Me nt h ol is a nat urall y occ urri n g c y clic m o n oter pe ne alc o h ol of pla nt ori gi n. Its use 
e xte n ds fr o m c uli nar y ite ms t o c os metic pr o d ucts t o  p har mace utical i n gre die nts. 
Wit h 
re gar ds t o its 
me dici n al p ur p oses, b ot h pres cri be d a n d 
O T C 
me nt h ol c o ntai ni n g 
me dicati o ns are c urre ntl y a vaila ble t hr o u g h o ut t he w orl d f or a h ost of c o n diti o ns, i ncl u di n g 
res pirat or y dise ases, GI dis or ders, c o m m o n c ol d, a nd m usc ul os keletal pai n. It is als o 
c o m m o nl y use d as part of a nal g esic, a ntise ptic, t o pical a nti pr uritic, a n d c o u nterirrita nt 
pr o d ucts. Its a bilit y t o m o d ulate Tra nsie nt Rece pt or P ote ntial ( T R P) cati o n c ha n nels a n d 
n u mer o us 
ot her i o n 
c ha n nels 
ma y 
u n derlie i ts 
re p ute d 
a nal gesic 
effects.5 
Me nt h ol -c o ntai ni n g O T C 
me dicati o ns are c urre ntl y 
mar kete d i n t he U S as t o pical 
a nal gesics at c o nce ntr ati o ns u p t o 1 6 % l -me nt h ol i n t he U S.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2  of 6 2  
 
1. 2  
R A TI O N A L E F O R S T U D Y A N D D O S E S E L E C TI O N  
K o wa C o m pa n y Lt d. h a s de vel o pe d K-2 8 5, a pr o d uct c o ntai ni n g 
 
f or relief of pai n d ue t o m uscle 
s ore ness, s prai ns a n d strai ns. 
T he acti ve p h ar mace utical i n gre die nts ( A PI) i n K -2 8 5 t o pical gel are 
 
 T he me nt h ol gel c o ntai ns 
.  
 
 
 
 
 
  
  
  
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3  of 6 2  
 
T he 
m ost c o m m o nl y re p orte d treat me nt -relate d, treat me nt-e mer g e nt a d verse e v e nt s 
(T E A Es ) (i.e., t h ose re p orte d b y m ore t h a n 2 s u bj ects o verall) were a p plicati o n site pai n, 
a p plicati o n site er yt he m a, a p plicati o n site disc ol orati o n, a p plicati o n site e xf oliati o n, 
a p plicati o n site pr urit us, a n d a p plicati o n site dr y ness.  All T E A Es re p ort e d were mil d i n 
se verit y. T here were n o m o derate or se v ere T E A Es, seri o us a d verse e ve nts ( S A Es) , or 
deat hs re p orte d d uri n g t h e st u d y. O ne s u bject ( 6. 7 %) disc o nti n ue d fr o m t he st u d y d ue t o a 
treat me nt-relate d T E A E of a p plicati o n site disc har ge. All T E A Es were res ol ve d b y t he e n d 
of t he st u d y.  Der mat ol o gical fi n di n gs relate d t o t he a p plicati o n site were re p ort e d as 
T E A Es, b ut t hese e ve nts a n d cli nical l a b orat or y assess me nts, vital si g n meas ure me nts, 
electr ocar di o gra m  (E C G ) assess me nts, a n d p h ysical e x a mi nati o ns were n ot c o nsi dere d 
cli nicall y si g nifica nt.  M ulti ple a p plicati o ns of K -2 8 5 were s afe a n d ge n erall y well t olerate d 
b y h ealt h y s u bjects i n t his st u d y.   
Base d o n t he P hase  1 st u d y res ults, t he d os a ge of K -2 8 5, 
), 
s h o we d hi g her 
, a n d t h us  was selecte d t o e val uate efficac y a n d safet y  at 
1  wee k  ( Peri o d 1) . F or P eri o d 2,  b ot h t he 
 
d osi n g re gi me ns were sel ecte d t o e val uate t he a d diti o nal safet y pr ofile  at 2 wee ks . 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4  of 6 2  
 
2. 0  
S T U D Y O B J E C TI V E S  
2. 1  
P RI M A R Y O B J E C TI V E  
T he pri mar y o bjecti ve is t o e val uate t he efficac y of K -2 8 5 c o m pare d wit h me nt h ol gel 
bet wee n 0 t o 2 4  h o urs after t he first g el a p plicati o n f or t he treat me nt of dela ye d o ns et 
m uscle s ore ness  (D O M S ). 
2. 2  
S E C O N D A R Y O B J E C TI V E S  
T he sec o n d ar y o bjecti ves are:  
•  
T o e val uat e t he effi cac y of K -2 8 5 c o m pare d wit h me nt h ol gel aft er  t he first gel 
a p plicati o n  f or t he treat m e nt of D O M S 
•  
T o e val uat e t he safet y a n d t olera bilit y of K -2 8 5 c o m pare d wit h me nt h ol g el after first 
gel a p plicati o n f or t he tr eat me nt of D O M S  
2. 3  
P RI M A R Y E F FI C A C Y  E N D P OI N T  
Pri mar y E n d p oi nt:  
•  
T he s u m of pai n i nte nsit y differe nce (
 
 f or t he st u d y le g after t he first st u d y gel a p plicati o n w hile sta n di n g usi n g a 
0 -1 0 0 p oi nt electr o nic vis ual a nal o g scal e (e V A S)  
2. 4  
S E C O N D A R Y E F FI C A C Y  E N D P OI N T S  
Sec o n dar y E n d p oi nts:  
F or b ot h t he stu d y le g a n d t he n o n -st u d y le g 
•  
S PI D 0 -2 4 h o urs  after t h e first st u d y gel a p plicati o n at rest usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D bet wee n 0 ( Baseli n e) t o 1 2 h o urs ( S PI D 0 -1 2) after t he first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D 0 -1 2 h o ur s after t h e first st u d y gel a p plicati o n at rest usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D bet wee n 0 ( Baseli n e) t o 4 8 h o urs ( S PI D 0 -4 8) after t he first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D 0 -4 8 h o urs  after t h e first st u d y gel a p plicati o n at rest usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D bet wee n 0 ( Baseli n e) t o 7 2 h o urs ( S PI D 0 -7 2) after t he first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0 -1 0 0 p oi nt e V A S  
•  
S PI D 0 -7 2 after t he first st u d y gel a p plicati o n at rest usi n g a 0 -1 0 0 p oi nt e V A S  
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5  of 6 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
2. 5  
S A F E T Y E N D P OI N T S  
Safet y assess me nts will i ncl u de ad verse e ve nts ( A Es), vital si g n meas ure me nts (s yst olic 
bl o o d press ure, diast oli c bl o o d press ur e, p ulse rate, res pirat or y rate, a n d oral b o d y 
te m perat ur e), E C G, p h ysical e xa mi nati o n fi n di n gs i ncl u di n g wei g ht, st u d y gel a p plicati o n 
site reacti o ns (i ncl u di n g via a n irritati o n rati n g scale), cli nical la b orat or y test res ults, st u d y 
gel  use , a n d c o n c o mita nt me dicati o n use . 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 6  of 6 2  
 
3. 0  
S T U D Y D E S C RI P TI O N  
3. 1  
S T U D Y D E SI G N  
T his is a p has e II, ra n d o mize d, d o u ble -bli n d, acti ve c o m parat or, p arallel gr o u p st u d y t o 
e val uate t he effi cac y a n d safet y of K -2 8 5 c o m p are d wit h me nt h ol gel f or t he treat me nt of 
D O M S i n t he l o wer e xtr e mit y.  
T he st u d y will c o nsist of scree ni n g, a n e xercise visit ( D O M S i n d ucti o n ), i n-patie nt a n d 
o ut -patie nt peri o ds u p t o 3  wee ks, a n d a f oll o w-u p  tele p h o ne call. D uri n g t he Scree ni n g 
Visit, s u bjects will pr o vi de i nf or me d c o nse nt a n d c o m plete scree ni n g assess me nts 
i ncl u di n g me dical hist or y, i de ntificati o n of t he d o mi na nt le g as deter mi ne d b y ha n d 
d o mi na nce , p h ysical a n d s ki n e xa mi nati o ns, bl o o d a n d uri ne tests, vital si g ns 
meas ure me nts, E C G, a n d ot her scree ni n g pr oce d ures. S u bjects w h o are a ble t o p artici pate 
i n t he st u d y ( Peri o d 1 a n d 2) a n d w h o meet t he pre-e xercis e i ncl usi o n a n d e xcl usi o n criteria 
will be e nr olle d i nt o t h e st u d y a n d ret ur n t o t h e cli nic o n Da y -1 . Eli gi bilit y will be 
c o nfir me d a n d e nr olle d s u bjects will perf or m a sta n dar dize d re pe titi ve q ua drice ps m uscl e 
e xercis e t o creat e D O M S t o b ot h le gs  ( Da y -1 ). T he e xercise re gi me n will c o nsist of a 
war m -u p, d eter mi nati o n of ma xi m u m t olerate d wei g ht, a n d ti me d a n d u n -ti me d w or k o ut 
p hases.  
Wit hi n 2 4  t o 3 0  h o urs aft er t he e x ercis e sessi o n ( Da y 1), s u bjects will rat e t he pai n of b ot h 
le gs usi n g a cate g oric al pai n scale a n d rec or d p ai n i nte nsit y of b ot h le gs  at rest a n d w hile 
sta n di n g usi n g a 0-1 0 0  p oi nt e V A S  (a ca pt ur e pr o gra m  will  li nearl y c o n vert t he pi xel 
t o uc he d t o a n i nte ger bet wee n 0 a n d 1 0 0) t o d eter mi ne eli gi bilit y f or ra n d o mizati o n. T he 
s pecific p ost-e x ercise  
 i ncl usi o n crit eri o n will be mas ke d t o s u bjects. 
 
 
 
 If b ot h le gs meet p ost-e xercise i ncl usi o n criteria, t he st u d y le g will be t he 
d o mi na nt le g, base d o n h a n d d o mi n a nce. S u bjects n ot q ualif yi n g f or ra n d o mizati o n will be 
gi ve n a p pr o priate sta n d ar d of care. A t otal of 2 4 0 s u bjects w h o meet p ost -e xercise 
i ncl usi o n criteria will be ra n d o ml y assi g ne d i n a 1: 1 rati o t o Treat me nt Ar m A ( K-2 8 5 gel) 
or Treat me nt Ar m B ( Me nt h o l gel). 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 7  of 6 2  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n Peri o d 1 (
 
 
 
 o n t he st u d y le g as f oll o ws:  
•  
Treat me nt Ar m A: E ac h s u bject will  a p pl y  K -2 8 5 t o t he st u d y le g.  
•  
Treat me nt Ar m B: Eac h s u bject will  a p pl y  me nt h ol gel t o t he st u d y le g. 
T he first st u d y gel a p plicati o n t o t he st u d y le g will be a p plie d b y t he s u bject wit h 
i n vesti gat or ( or desi g nee) o versi g ht t o e ns ure pr o per a p plicati o n at t he cli nic o n Da y 1  
wit hi n 2 4  t o 3 0  h o urs after D O M S i n d ucti o n . S u bse q u e nt st u d y gel a p plicati o ns at t he cli nic 
will be a p plie d t o t he st u d y le g b y t he s u bject wit h i n vesti gat or ( or d esi g nee) o versi g ht t o 
e ns ure pr o per a p plicati o n. O n Da y 2, p h ot o gra p hic a n d resi d ue e val uati o n of t he 
a p plicati o n site will be p erf or me d pri or t o  t he 
 st u d y gel a p plicatio n. S u bjects 
will re mai n i n t he cli nic u ntil t he y are disc h ar ge d f oll o wi n g c o m pleti o n of st u d y 
assess me nts o n D a y  2 . P ai n i nte nsit y assess me nts will be p erf or m e d f or t h e st u d y le g a n d 
n o n -st u d y le g at rest a n d w hile sta n di n g usi n g a 0-1 0 0  p oi nt e V A S  o n Da y  1 at Baseli ne ( 0 
h o urs) a n d at 
 
 after t he first st u d y gel a p plicati o n. Pai n assess me nts 
sc he d ule d bet w ee n mi d ni g ht a n d 6 a m ma y be s ki p pe d if s u bjects are asle e p b ut s u bjects 
ma y n ot s ki p m or e t ha n t w o se q ue ntial assess me nts. A  ti me wi n d o w of  + 3 0  mi n utes will 
be all o we d bet w ee n q u alif yi n g pai n assess me nts a n d first st u d y gel a p plicati o n ( 0 h o urs).   
T he f oll o wi n g ti me wi n d o ws will be all o we d f or  eac h p ai n assess m e nt  (e V A S, Perce pti ble 
Pai n Relief , a n d Mea ni n gf ul Pai n Relief)  ti me p oi nt: ± 1 5 mi n utes f or assess me nts fr o m 1 
t o 1 2 h o urs ( Da y  1), -2 0  mi n utes t o + 3 0  mi n utes f or assess me nts at 1 8 t hr o u g h 2 4 h o urs 
( Da y 2), a n d -2 0  mi n utes t o + 1  h o ur f or assess me nts at 3 6 t o 
 (
 
F oll o wi n g disc har ge fr o m t he cli nic o n Da y 2 , s u bse q ue nt st u d y gel a p plicati o ns a n d pai n 
i nte nsit y assess me nts will be perf or me d b y t h e s u bject o n a n o ut -p atie nt basis ( Da y 2  
t hr o u g h Da y 8 ). S u bjects will be i nstr uct e d n ot t o s h o wer or bat h e f or at least 3 0  mi n utes 
bef ore a n d at least 1  h o ur after gel a p plicati o n.   
All pai n i nte nsit y assess me nts i ncl u di n g e V A S, Perce pti ble Pai n Relief, a n d Mea ni n gf ul 
pai n relief will be rec or de d i n e -diari es t hr o u g h Da y  8 ( Peri o d 1), a n d all  st u d y gel 
a p plicati o ns a n d resc ue me dicati o ns will be rec or de d i n  t he e-diar y  b y t he s u bject t hr o u g h 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 8  of 6 2  
 
Da y  2 2  (Peri o d 1  a n d 2 ). Perce pti ble Pai n Relief a n d Mea ni n gf ul Pai n Relief will be 
rec or de d i n t he e-diar y u ntil ac hie ve d i n Peri o d 1. A tele p h o ne call will be c o n d ucte d b y 
st u d y staff o n Da y 5 (± 1 da y) t o assess safet y. S u bjects will ret ur n t o t he cli nic f or 
assess me nts o n Da y  8  (± 1 da y) . F or s u bjects w h o are assi g ne d t o recei ve st u d y gel f or 1 
wee k, Da y  8  (+ 1 da y)  will be a n e n d of st u d y ( E O S) cli nic visit a n d a f oll o w -u p tele p h o ne 
call t o assess s afet y will be c o n d uct e d b y st u d y st aff o n Da y  1 5  ( ± 1 da y) . S u bjects w h o are 
assi g ne d t o recei v e st u d y gel f or 3  wee ks will c o nti n ue t o a p pl y st u d y gel o n a n o ut -patie nt 
basis fr o m Da y  8 t o Da y 2 2  ( Peri o d 2) acc or di n g t o t heir assi g ne d d osi n g re gi me n ( 
 
) (Ta ble 1 : Treat me nt Assi g n me nt ). F or s u bjects w h o are dosi n g i n Peri o d 2, tele p h o n e 
calls t o assess safet y will be c o n d u cte d b y st u d y st aff o n Da y  1 1  (± 1 da y)  a n d Da y  1 8 ( ± 1 
da y), st u d y gel a p plicati o ns a n d use of a n y resc ue me dicati o ns will be rec or de d i n e -diaries 
b y t he  s u bjects t hr o u g h D a y 2 2 , a n d an e n d of st u d y ( E O S)  cli nic visit will occ ur o n Da y  2 2 
(+ 1 d a y).  A f oll o w -u p tele p h o ne call t o ass ess safet y will be c o n d ucte d b y st u d y staff o n 
Da y  2 9  (± 1 da y) . 
Use of a n y resc ue me dicati o n f or D O M S is str o n gl y disc o ura ge d  u ntil 
 
after t he first st u d y gel a p plicati o n, at w hic h ti me o ver -t he-c o u nter ( O T C) aceta mi n o p he n 
( o ne 5 0 0 m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue 
me dicati o n f or D O M S is per mitte d if re q uire d. S u bjects e x p erie nci n g se vere p ai n or 
i na bilit y t o m o ve or w al k d ue t o pai n m a y b e per mitte d t o use res c ue me dicati o n 
( o ne 5 0 0  m g O T C aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) pri or t o 
1 6 8 h o urs after t he first st u d y gel a p plicati o n. If s u bjects ta ke res c ue me dicati o n bef ore t he 
first 1 6 8 h o urs, it will be ca pt ure d as a c o n c o mita nt me dicati o n, a n d s u bjects will rec or d 
t heir pai n i nte nsit y i n t he e-diar y bef ore ta ki n g t he resc u e me dicati o n. T he n u m ber of 
ta blets ta ke n a n d t he d ate a n d ti me will be rec or de d i n t he e -diar y.  
 
 
 T he 
i nteri m a nal ysis will assess f utilit y of t he trial (c o n diti o nal p o wer < 0. 0 5). If f utilit y is 
deter mi ne d, t he st u d y will be ter m i nate d. If c o nti n uati o n of t he trial is deter mi ne d, s u bject 
e nr oll me nt will be res u m e d.  
A st u d y sc he matic is s h o w n i n Fi g ur e 1 . T he s c he d ule of assess me nt s is s h o w n i n Ta ble  2 .  
 
 


C O N FI D E N TI A L  
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 9  of 6 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 0  of 6 2 
 
 
T a ble 2 : Cli nic al E v al u ati o n Sc he d ule   
A S S E S S M E N T S 
P E R F O R M E D  
Scree ni n g 
Visit  
E xercis
e Visit  
Peri o d 1  
Peri o d 2  
E O S Visit/ E T k 
F oll o w - 
u p call  
I n  
patie nt  
O ut  
patie nt  
Safet y 
Visit  
O ut  
patie nt  
Safet y  
Visit  
O ut  
patie nt  
Da y  
-3 0 t o -2  
-1  
1  
2  
3 -8  
8  
( ± 1 da y) 
9 -1 4  
1 5  
( ± 1 da y) 
1 6 -2 2  
8 or 2 2  
(+ 1 da y)  
1 5 or 2 9  
( ± 1 da y)  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
De m o gra p h y  
X  
 
 
 
 
 
 
 
 
 
 
Me dical/ me dicati o n 
hist or y  
X  
X  
 
 
 
 
 
 
 
 
 
Pre -e x ercise i ncl usi o n 
criteria, e x cl usi o n 
criteria  
X  
X  
 
 
 
 
 
 
 
 
 
A d missi o n t o cli nic a 
 
  
X  
 
 
 
 
 
 
 
 
Disc h ar ge fr o m cli nic a 
 
 
 
X  
 
 
 
 
 
 
 
V isit t o cli nic ( o ne 
da y)  
X  
X  
 
 
 
X  
 
X  
 
X  
 
Tele p h o ne Call ( Da ys 
5, 1 1, 1 8 , a n d Da y 1 5 
or  2 9) b 
 
 
 
 
X  
 
X   
 
 
X   
 
 
X   
Pre -e x ercise p ai n 
assess me nt ( pa p er 
V A S)  
 
X  
 
 
 
 
 
 
 
 
 
D O M S i n d ucti o n 
e x ercise  
 
X  
 
 
 
 
 
 
 
 
 
e-diar y, st u d y trai ni n g  
 
X  
 
 
 
 
 
 
 
 
 
Iss ue e-diar y  
 
 
X  
 
 
 
 
 
 
 
 
eV A S q ualif yi n g p ai n 
assess me nts c (e-diar y)   
 
 
X  
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 1  of 6 2 
 
A S S E S S M E N T S 
P E R F O R M E D  
Scree ni n g 
Visit  
E xercis
e Visit  
Peri o d 1  
Peri o d 2  
E O S Visit/ E T k 
F oll o w - 
u p call  
I n  
patie nt  
O ut  
patie nt  
Safet y 
Visit  
O ut  
patie nt  
Safet y  
Visit  
O ut  
patie nt  
Da y  
-3 0 t o -2  
-1  
1  
2  
3 -8  
8  
( ± 1 da y) 
9 -1 4  
1 5  
( ± 1 da y) 
1 6 -2 2  
8 or 2 2  
(+ 1 da y)  
1 5 or 2 9  
( ± 1 da y)  
Cate g orical q ualif yi n g 
p ai n assess me nts c (e-
diar y)  
 
 
X  
 
 
 
 
 
 
 
 
P ost -e x ercise incl usi o n 
criteria  
 
 
X  
 
 
 
 
 
 
 
 
Ra n d o mizati o n  
 
 
X  
 
 
 
 
 
 
 
 
Hei g ht a n d wei g ht  
X  
 
 
 
 
 
 
 
 
 
 
Vital si g ns d  
X  
X  
X  
X  
 
X  
 
X  
 
X  
 
Electr ocar di o gra m  
X  
X  
 
 
 
 
 
 
 
X  
 
P h ysical e xa mi nati o n  
X  
X  
 
 
 
X  
 
X  
 
X  
 
S ki n e x a mi nati o n / 
assess me nt at st u d y gel  
site  
X  
X  
X  
X  
 
X  
 
X  
 
X  
 
Pre g na n c y test e 
X  
X  
 
 
 
 
 
 
 
X  
 
Uri ne dr u g scree n a n d 
alc o h ol test  
X  
X  
 
 
 
 
 
 
 
 
 
Cli nical la b orat or y 
tests ( he mat ol o g y, 
ser u m c h e mistr y, a n d 
uri nal ysis)  
X  
 
 
 
 
 
 
 
 
X  
 
eV A S pai n i nte nsit y 
assess me nt sc (e-diar y)  
 
 
X  
X  
X  
X  
 
 
 
( X)l 
 
Perce pti ble a n d 
Mea ni n gf ul pai n relief  
assess me nts c (e-diar y)  
 
 
X  
 
 
 
( X) l 
 
P h ot o gra p hic a n d 
resi d ue e v al uati o nf 
 
 
 
X  
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 2  of 6 2 
 
A S S E S S M E N T S 
P E R F O R M E D  
Scree ni n g 
Visit  
E xercis
e Visit  
Peri o d 1  
Peri o d 2  
E O S Visit/ E T k 
F oll o w - 
u p call  
I n  
patie nt  
O ut  
patie nt  
Safet y 
Visit  
O ut  
patie nt  
Safet y  
Visit  
O ut  
patie nt  
Da y  
-3 0 t o -2  
-1  
1  
2  
3 -8  
8  
( ± 1 da y) 
9 -1 4  
1 5  
( ± 1 da y) 
1 6 -2 2  
8 or 2 2  
(+ 1 da y)  
1 5 or 2 9  
( ± 1 da y)  
P h ot o gra p hic  
e v al uati o n of 
a p plicati o n site 
reacti o nsg 
 
 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
 
Dis pe nse st u d y gel  
 
 
 
X  
 
X  
 
X  
 
 
 
A p pl y st u d y gel h 
 
 
X  
X  
X  
X  
X  
X  
X  
(X )  
 
Rec or d a d verse e ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Rec or d c o nc o mita nt 
me dicati o ns i 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Rec or d resc ue 
me dicati o n use j (e-
diar y)  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
C ollect st u d y gel  
 
 
 
 
 
 
 
 
 
X  
 
C ollect s u bject e -diar y  
 
 
 
 
 
 
 
 
 
X  
 
 
; D O M S, del a y e d o nset m uscle s ore ness; e -diar y, electr o nic diar y de vice; E O S, e n d of st u d y; E T, earl y ter mi nati o n; 
 a 
; 
V A S, vis ual  a n al o g scale ; ( X), perf or me d as i n dicate d i n t he f o ot n ote.  
a S u bjects will e nter t he cli nic o n Da y 1 a n d will be disc har ge d o n  Da y  2 after st u d y assess m e nt s at 
 st u d y gel a p plicati o n  are c o m plete d. 
b  St u d y staff will c o ntact s u bjects b y tele p h o ne f or assess me nt of A E s, s ki n c o n diti o n a n d c o nc o mita nt me dicati o ns, a n d use of resc ue me dicati o n. All s u bjects 
will be c o ntacte d o n Da y 5 ( ± 1 da y). S u bjects partici pati n g i n Peri o d 1 will be c o ntacte d o n Da y 1 5  ( ± 1 da y). S u bjects partici pati n g i n Peri o d 2 will be 
c o ntacte d o n Da y 1 1 ( ± 1 da y), Da y 1 8 ( ± 1 da y), a n d Da y 2 9 ( ± 1 da y). 
c V A S a n d cate g orical q ualif yi n g pai n assess me nts will be perf or me d o n b ot h le gs wit hi n 2 4 -3 0 h o urs of e xercise t o i n d uce D O M S. Pai n i nte nsit y assess m e nts  
(e V A S, Perce pti ble Pai n Relief, a n d Mea ni n gf ul Pai n Relief)  will be perf or me d f or t he st u d y le g a n d n o n-st u d y le g at rest a n d w hile sta n di n g usi n g a 0 -1 0 0 
p oi nt e V A S o n Da y 1 at Baseli ne ( 0 h o urs) a n d at 
 
 after t he first st u d y gel a p plicati o n. Baseli ne ( 0 h o urs) is t he ti me p oi nt f or t he  first st u d y gel a p plicati o n; a ti me wi n d o w of + 3 0 mi n utes will be all o we d 
bet wee n q ualif yi n g pai n assess me nts  (q ualif yi n g p ost -e xercise i ncl usi o n criteria)  a n d first st u d y gel a p plicati o n  ( 0 h o ur). T he f oll o wi n g ti me wi n d o ws will 
be all o we d f or eac h pai n assess me nt (e V A S, Perce pti ble Pai n Relief, a n d Mea ni n gf ul Pai n Relief) ti me p oi nt: ± 1 5 mi n utes f or assess me nts fr o m 1 t o 1 2  h o urs 
( Da y 1), -2 0  mi n utes t o + 3 0 mi n utes f or assess me nts at 1 8 t hr o u g h 2 4  h o urs ( Da y  2), a n d -2 0  mi n utes t o + 1 h o ur f or assess me nts at 3 6 t o 1 6 8 h o urs ( Da y  2 
t o 8). Ti me t o perce pti ble a n d mea ni n gf ul pai n relief will be rec or de d b y s u bjects i n t heir e -diar y  u ntil ac hie ve d  i n Peri o d 1. W he n st u d y gel a p plicati o n a n d 
pai n assess me nt o cc ur at t he sa me ti me p oi nt, pai n assess me nts will be perf or me d bef ore st u d y gel a p plicati o n. 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 3  of 6 2 
 
d  Vital si g n meas ure me nts will i ncl u de s yst olic bl o o d press ure, diast olic bl o o d press ure, p ulse rate,  res pirat or y rate, a n d oral b o d y te m perat ure. Bl o o d press ure 
a n d p ulse rate will be meas ure d after t he s u bject has bee n resti n g i n t he s u pi ne p ositi o n f or at least 5  mi n utes.  
e Ser u m pre g na n c y test at Scree ni n g a n d uri ne pre g na nc y test at E xercise visit , E O S  V isit (D a y 8  or Da y 2 2 ) (fe males o nl y). 
f P h ot o gra p hic a n d resi d ue e v al uati o ns of t he a p plicati o n site will be perf or me d bef ore t he 
 st u d y gel a p plicati o ns o n Da y 2.  
g  Be gi n ni n g wit h t he 
 w he n a n a p plicati o n site reacti o n is o bser ve d at t he cli nical site, p h ot o gra p hs of t he a p plicati o n 
site will be ta ke n b y site staff t o vis ually d oc u me nt t he s ki n c o n diti o n at t he site of gel a p plicati o n.  If nee de d, t he p h ot o gra p hs will be peri o dicall y ta ke n t o 
f oll o w-u p t he a p plicati o n site reacti o n.  If a n a p plicati o n site reacti o n is o bser ve d at h o me, p h ot o gra p hs of t he a p plicati o n site will be ta ke n b y site staff w he n 
s u bject ret ur ns t o t he cli nical site. All p h ot o gra p hs s h o ul d be ta ke n pri or t o gel a 
  
h 
 
 
 
T he f oll o wi n g ti me wi n d o ws will be all o we d f or eac h st u d y g el a p plicati o n ti me p oi nt: + 3 0 mi n utes  f or first st u d y gel a p plicati o n  ( 0 h o ur) after q ualif yi n g 
pai n assess me nts , ± 1 5 mi n utes f or t he 
 a p plicati o ns, -2 0  mi n utes t o + 3 0 mi n utes  f or t he 
 a p plicati o ns , a n d -2 0  mi n utes 
t o +1 h o ur f or ot her a p plicati o n  ti me p oi nts.  
At t he site,  st u d y gel is a p plie d t o t he st u d y le g b y t he s u bject wit h i n vesti gat or ( or desi g nee) o versi g ht t o e ns ure pr o per a p plicati o n. F oll o wi n g disc har ge 
fr o m t he cli nic o n Da y 2 , s u bse q ue nt st u d y gel a p plicati o ns will be perf or me d b y t he s u bject.  F or s u bjects partici pati n g o nl y i n Peri o d 1, t he last a p plicati o n 
of st u d y gel is a p plie d at 6 a m o n Da y 8 . F or s u bjects partici pati n g i n Peri o d 2, t he last a p plicati o n of st u d y gel is a p plie d at 6 a m o n Da y 2 2.  
i All me dicati o ns a n d ot her treat me nts ta ke n b y s u bjects wit hi n 3 0 da ys bef ore d osi n g a n d  d uri n g t he st u d y will be rec or de d i n t he eC R F. A n y c h a n ges i n t he 
c o nc o mita nt me dicati o ns after disc h ar ge fr o m t he cli nic o n Da y 2 , eit her prescri be d or self-a d mi nistere d, will be d oc u me nte d a n d re vie we d d uri n g tele p h o ne 
calls, Safet y visits a n d at t he E O S  Visits.  
j S u bjects will rec or d all resc ue me dicati o n use i n t he e -diar y a n d it will be e ntere d i nt o t he e C R F as a c o nc o mita nt me dicati o n.  
k F or s u bjects partici pati n g o nl y i n Peri o d 1 E O S is o n Da y 8 (+ 1 da y),  f or s u bjects partici pati n g i n Peri o d 2 E O S is o n Da y 2 2 (+ 1 da y).  N ote t hat E O S visits 
ha v e a wi n d o w of + 1 da y w hereas Safet y visits ha ve a wi n d o w of ± 1 da y.  
l F or Da y 8, Peri o d 1.  


C O N FI D E N TI A L  
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1 , St u dy Pr ot oc ol 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 4  of 6 2  
 
4. 0  
S U B J E C T E LI GI BI LI T Y A N D WI T H D R A W A L C RI T E RI A  
S u bjects w h o d o n ot meet eli gi bilit y criteria will be classifie d as s cree n fail ures a n d t he 
reas o n(s) will be rec or de d i n t he case re p ort f or m ( C R F)/electr o ni c C R F (e C R F). 
4. 1  
I N C L U SI O N C RI T E RI A  
4. 1. 1  
Pre -e xercise I ncl usi o n Criteri a  
S u bjects are eli gi ble f or t he st u d y if all of t he f oll o wi n g criteria are met:  
1.  S u bject 
m ust pr o vi de i nf or me d c o nse nt bef ore a n y st u d y -s pecific e val uati o n is 
perf or me d.  
2.  S u bject is male a n d fe male a ge d 1 8 t o 3 5  years, i n cl usi ve.  
3.  S u bject has a b o d y mass i n de x  ( B MI) of 1 8 t o 3 2  k g/ m 2, i ncl usi ve  
 
 
 
 
 
 
 
 
 
6.  S u bject he mat ol o g y, ser u m c he mistr y, uri nal ysis, vital si g n meas ure me nts (s yst olic 
bl o o d press ure, diast olic bl o o d press ure, p ulse rate, res pirat or y rat e, a n d oral b o d y 
te m perat ur e) a n d 1 2 -lea d E C G res ults s h o w n o cli nicall y rele va nt a b n or malities, as 
j u d ge d b y t he i n vesti gat or at t he Scree ni n g  V isit. 
7.  All fe male s u bjects m ust ha ve a ne g ati ve ser u m pre g na nc y test res ult at Scree ni n g a n d 
ne gati ve uri n e pre g na nc y test o n  Da y  -1  pri or t o a d missi o n t o  t he cli ni c. Fe male 
s u bjects of c hil d beari n g p ote ntial m ust use o ne of t he f oll o wi n g acce pta ble birt h c o ntr ol 
met h o ds as s pecifie d b ef ore e nr oll me nt a n d t hr o u g h o ut t he st u d y:  
a. S ur gical  
sterilizati o n 
( bilateral 
t u bal 
li gati o n, 
h ysterect o m y, 
bilateral 
o o p h orect o m y) at least 6  m o nt hs bef ore t he first d ose of st u d y gel; 
b.  I ntr a uteri ne de vic e i n place f or at least 3 m o nt hs b ef ore t he first d ose of st u d y gel 
a n d t hr o u g h o ut t he st u d y;  
c. Barrier met h o d (c o n d o m  or  dia p hra g m) wit h s per mici de f or at least 1 4  da ys bef ore 
t he first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y;  
d.  S ur gical sterilizati o n of t he male part ner ( vasect o m y at least 6  m o nt hs bef ore t he 
first d ose of st u d y gel); 
e. H or m o nal c o ntr ace pti ves f or at least 3  m o nt hs wit h a barrier met h o d 1 4  da ys bef ore 
t he first d ose of st u d y gel an d t hr o u g h o ut t he st u d y ; 
f. A bsti ne nce.  
8.  S u bject is a ble a n d willi n g t o c o m pl y wit h t he pr ot oc ol a n d st u d y pr oce d ures.  
9.  S u bject has ne g ati ve test res ults f or dr u gs a n d alc o h ol at scree ni n g a n d is a ble a n d 
willi n g t o a bstai n fr o m marij ua na a n d al c o h ol use f or 4  da ys bef ore Da y  1 a n d 
t hr o u g h o ut t he st u d y. N ote t hat a p ositi ve scree ni n g res ult f or marij ua na  is acce pta bl e 
pr o vi de d t he s u bject will a bstai n f or t he st u d y as d escri be d a b o ve.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 5  of 6 2  
1 0.  S u bject d oes n ot use nic oti ne or has q uit usi n g nic oti ne f or at least 6  m o nt hs bef ore t he 
first d ose of st u d y gel a n d will n ot use nic oti ne t hr o u g h o ut t he st u d y.  
 
 
 
 
 
 
 
 
 
4. 2  
E X C L U SI O N C RI T E RI A   
S u bjects are e x cl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria are met:  
 
 
 
 
 
 
  
  
  
  
  
  
 
  
 
 
 
 
3.  
S u bject has recei ve d oral or t o pical a nal gesic m e dicati o ns wit hi n 1 4  da ys bef ore t h e 
S cree ni n g V isit. 
4.  
S u bject has use d a s yste mic c ortic oster oi d wit hi n 3 0  da ys bef ore t he Scree ni n g V isit. 
5.  
S u b ject has a me dical hist or y t hat i ncl u des a c o ntr ai n dicati o n t o t he use of me nt h ol or 
N S AI Ds (e. g., g astr oi ntesti nal ulcer, gastr oi ntesti nal blee di n g).  
6.  
S u bject is ta ki n g me dicati o ns or ot her s u bsta nces c o ntrai n dicate d beca us e of t he nat ure 
of t he st u d y g el or t he p ote ntial f or dr u g i nteracti o ns. T his i ncl u des s u bjects wit h 
aller gies t o pres cri pti o n or O T C  pr o d ucts c o ntai ni n g me nt h ol or N S AI Ds.  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 6  of 6 2  
 
 
 
 
 
 
 
 
 
 
 
1 4.  S u bject is pre g na nt or n ursi n g.  
1 5.  S u bject has partici pate d i n a n i n vesti gati o nal dr u g st u d y wit hi n 3 0  da ys bef ore 
Scree ni n g.  
1 6.  S u bject is a me m ber or a fa mil y me m ber of t he pr ofessi o nal or a ncillar y pers o n nel 
i n v ol ve d i n t he st u d y.  
1 7.  S u bject has part ici pate d i n ot her cli nical trials f or K-2 8 5.  
1 8.  S u bject has a b n or mal fi n di n gs or assess me nts t hat are cli nicall y n ote w ort h y.  
1 9.  S u bject w h o, i n t he o pi ni o n of t he i n vesti gat or, s h o ul d n ot partici pate i n t he st u d y.  
4. 3  
DI S C O N TI N U A TI O N A N D  WI T H D R A W A L C RI T E RI A  
S u bject s ma y v ol u ntaril y wit h dra w fr o m t he st u d y at a n y ti me a n d f or a n y reas o n wit h o ut 
prej u dice t o t heir f ut ure me dical care b y t he i n vesti gat or or at t he st u d y site. T he 
in vesti gat or ma y disc o nti n ue treat me nt of a s u bject or wit h dra w a s u bject fr o m t he st u d y 
u n der s pecific circ u msta nces, des cri be d b el o w. T he pri mar y reas o n(s) f or disc o nti n uati o n 
or wit h dra w al ( b y t he s u bject or t he in vesti gat or) will be  d oc u me nt e d  a n d rec or de d i n t he 
case re p ort f or m C R F/e C R F .  
T he s u bject will be disc o nti n ue d fr o m st u d y gel  if a n y of t he f oll o wi n g occ ur : 
1.  
T here is a deteri or ati o n i n t he s u bject’s si g ns/s y m pt o ms a n d/ or t he s u bject de vel o ps a 
disease or c o n diti o n t hat i n t he o pi ni o n of t he in vesti gat or , w o ul d c o m pr o mise t he 
s u bject’s safet y b y c o nti n ui n g i n t he st u d y. 
2.  
I n t he in v esti gat or’s  j u d g me nt, it is i n t he s u bject’s best i nterests. 
3.  
Vi olati o n of t he pr ot oc ol i ncl usi o n a n d e xcl usi o n criteria . 
4.  
T he s u bject be gi ns t o ta k e a n y me dicati o n(s) t hat is e xcl u de d b y t he pr ot o c ol . 
5.  
It is deter mi ne d t hat t here is disc ol orati o n, e xf oli ati o n or er osi o n , e d e ma, disc har ge, 
blisteri n g , e x u date, ≥2 p oi nt o n der mal res p o nses sc ore ( Secti o n 5. 2. 6 ), a n d/ or a n y 
ot her der m al c ha n g e t hat i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o m pr o mise t he 
s u bject’s safet y b y c o nti n ui n g i n t he st u d y at t h e a p plicati o n site.  T he pr ocess f or 
disc o nti n uat i o n d ue t o a n a p plicati o n site reacti o n is descri be d i n Secti o n  4. 3. 1  bel o w.  
6.  
Occ urre nce of seri o us a d verse e v e nt (s). 
7.  
Pre g na nc y . 
T he s u bject will be wit h dra w n fr o m t he  st u d y if a n y of t he f oll o wi n g occ ur : 
1.  
T he s u bject  wit h dra ws c o nse nt.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 7  of 6 2  
2.  
T he s u bject  is l ost t o f oll o w-u p.  
3.  
A n y of t he c o n diti o ns are met i n Secti o n 6. 5 , Ter mi nati o n of t he St u d y. 
4.  
T he s u bject is u na ble or u n willi n g t o c o o perate wit h st u d y staff . 
5.  
Deat h . 
 
S u bject s w h o di sc o nti n ue or wit h dra w fr o m t he trial d ue t o t he a b o ve criteria or a n y ot her 
reas o n, will be e nc o ura g e d t o c o m plete t he fi nal e val uati o ns as detaile d i n Ta ble  2 . If a 
s u bject decli nes t o c o m pl ete earl y ter mi nati o n pr oce d ures, t his decisi o n will be rec or de d i n 
t he case re p ort f or m C R F/e C R F.  
If a s u bject di sc o nti n ues or wit h dra ws fr o m t he st u d y d ue t o a n A E , t he s u bject will be 
as ke d t o ret ur n t o t he cli nic f or, at a mi ni m u m, t he e val uati o ns sc h e d ule d f or t he E O S / E T 
Visit ( Da y 8 / Da y 2 2). If t he A E  has still n ot res ol ve d, a d diti o nal f oll o w -u p will be 
perf or me d , as a p pr o pri ate , a n d d oc u me nte d i n t he s u bject’s me dical rec or ds.  As a mi ni m u m 
re q uire me nt, A Es m ust be f oll o we d f or 3 0 d a ys after t he s u bject’s last d ose of st u d y gel or 
u ntil res ol uti o n or u ntil u nres ol ve d A Es are j u d ge d b y t he i n vesti gat or ( or d esi g nee) t o h a ve 
stabilize d .  
If s u bjects are l ost t o f oll o w-u p, atte m pts t o c o ntact t he m m ust be ma de a n d d oc u me nte d 
i n t he me dical rec or ds. S u bjects w h o fail t o ret ur n f or a st u d y visit  will be c o ntacte d directl y 
b y t he st u d y staff. A mi ni m u m of 2 d oc u me nte d p h o ne calls will be ma de. If t he st u d y staff 
recei v es n o res p o nse, t he y will se n d a certifie d lett er re q u esti n g t hat t he s u bject c o ntact t he 
st u d y site re gar di n g his or her stat us i n t he st u d y.  
Disc o nti n ue d  or w it h dra w n s u bjects will n ot  be re place d.  
4. 3. 1  D isc o nti n u ati o n d ue t o a n A p plic ati o n S ite R e acti o n  
1.  D uri n g a cli nical site visit, t he a p plicati o n site reacti o n will be assesse d b y st u d y 
staff. If t here are a n y si g nifica nt fi n di n gs , t hey w ill be n ote d i n eac h s u bject’s 
s o urce d oc u m e nts.  
•  
If t he a p plicati o n site reacti o n is j u d ge d t o meet t he disc o nti n uati o n criteria 
(Secti o n 4. 3 ), t he s u bject will be disc o nti n ue d fr o m t he st u d y. 
 
2.  D uri n g t he o ut -patie nt peri o d at h o me, a p plicati o n site reacti o ns will be assesse d 
b y t he s u bject. If a n y  a p plicati o n site reacti o n is n otice d, t he s u bject will c o ntact 
t he site bef ore d osi n g.  
•  
T he s u bject will n ot a p pl y st u d y gel u ntil recei vi n g c o nfir mati o n fr o m t he site 
t o pr ocee d. 
•  
If t he s u bject c o ntacts t he site a n d t he n t he a p plicati o n site reacti o n is j u d ge d 
t o meet t he 
disc o nti n uati o n criteria (Secti o n 4. 3 ), t he s u bject will be 
disc o nti n ue d  fr o m t he st u d y. At t h at ti me, t he s u bject will be as ked t o gat her 
safet y refere nce i nf or mati o n as f oll o ws:  
o  
R ec or d t he s c ore of d er mal res p o nse (S ecti o n 5. 2. 6 ) in t he e -diar y. 
R efere n ce  i ma ges of 
a p plicati o n site reacti o ns are  s h o w n i n 
A p pe n di x  1 5. 4 .  
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 8  of 6 2  
5. 0  
P R O C E D U R E S  F O R E F FI C A C Y  A N D S A F E T Y 
E V A L U A TI O N S  
5. 1  
E F FI C A C Y  E V A L U A TI O N S  
5. 1. 1  P ai n I nte nsit y   
Pri or t o e xercise  t o i n d uce D O M S, pai n will be assesse d f or b ot h le gs at rest a n d w hile 
sta n di n g usi n g a 0 -1 0 0 p oi nt pa per V A S  t o e xcl u d e s u bjects wit h ot her pai n. 
F oll o wi n g e xercise t o i n d uce D O M S, p ai n at rest a n d w hile sta n di n g will be assesse d f or 
b ot h le gs usi n g a  0 -1 0 0 p oi nt  e V A S a n d a cate g orical pai n scale t o det er mi ne q ualificati o n 
f or ra n d o mizati o n a n d t o i de ntif y t he st u d y le g ( baseli ne assess me nt). All p ai n assess me nts 
will be rec or de d i n t he e-diar y.  
After ra n d o mizati o n, pai n at r est a n d w hile sta n di n g will be assesse d f or t he st u d y le g a n d 
t he n o n-st u d y le g usi n g a  0 -1 0 0  p oi nt eV A S  at all p ost -st u d y gel a p plicati o n ti me p oi nt s i n 
Peri o d 1  (T a ble 2 ). W he n st u d y gel a p plicati o n a n d pai n assess me nt occ ur at t he sa me ti me 
p oi nt, pai n assess me nts will be perf or me d b ef ore st u d y gel a p plicati o n.  
T he s u bject will rest q uietl y f or at least 5 mi n u tes bef ore assessi n g pai n at rest f or t he st u d y 
le g a n d n o n-st u d y le g (t he st u d y le g will be ass esse d first). T he s u bject will sit f or at least 
5  mi n utes,  t he n sta n d u p a n d rate t he w orst p ai n ca use d b y sta n di n g (t he act of m o vi n g 
fr o m a sitti n g t o sta n di ng p ositi o n) f or t he st u d y le g a n d n o n-st u d y le g (t he st u d y le g will 
be assesse d  first). 
5. 1. 1. 1  
Vis u al A n al o g Sc ale  
T he pai n V A S , a u ni di me nsi o nal meas ure of pai n i nte nsit y, is a c o nti n u o us scale fr o m 0 t o 
1 0 0 c o m prise d of a h oriz o ntal li ne a nc h ore d b y 2  descri pt ors, o ne f or eac h s y m pt o m 
e xtre me: “ n o pai n” (sc ore of 0) a n d “ w orst p ossi ble pai n” (sc ore of 1 0 0).  A pa per versi o n  
of t he pai n V A S  will be use d f or pre -e x ercise p ai n assess me nts ( A p pe n di x 1 ). 
T he pai n eV A S is el ectr o nicall y dis pla ye d  a n d  is c o m plete d b y t he s u bject f or baseli ne a n d 
eac h p ost -ra n d o mizati o n pai n i nte nsit y assess me nt b y  t o uc hi n g t he p oi nt  o n t he e V A S  t hat 
re pres e nts t heir pai n i nte nsit y. (A ca pt ure pr o gra m will li nearl y c o n vert t he pi xel t o uc he d 
t o a n i nte ger b et wee n 0 a n d 1 0 0). T he i nte g ers of t he e V A S will be referre d t o as p oi nts.  
T he assess me nt d ate a n d ti me f or t he st u d y le g a n d f or t he n o n -st u d y le g is rec or de d i n t he 
e-diar y  (A p pe n di x 1 ).  
5. 1. 1. 2  
C ate g ori c al P ai n Sc ale  
A 4 -p oi nt cate g orical pai n scale ( n o ne, mil d, m o derate, se vere) at rest will be use d t o assess 
pai n i nte nsit y f oll o wi n g t he e xercise sessi o n. A cate g orical pai n scale is pr o vi de d i n 
A p pe n di x 2 . 
5. 1. 2  Use of R es c ue M e dic ati o n  
Use of a n y resc u e me dicati o n f or D O M S is str o n gl y disc o ura ge d u ntil 1 6 8  h o urs after  t he 
first st u d y gel a p plicati o n, at w hic h ti me O T C  aceta mi n o p he n ( o ne 5 0 0 m g aceta mi n o p he n 
ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue me dicati o n is per mitted if 
re q uire d.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 1 9  of 6 2  
S u bjects e x perie nci n g  s e vere p ai n, or i na bilit y t o m o ve or wal k d ue t o pai n , ma y be 
per mitte d t o use resc ue me dicati o n ( o ne 5 0 0 m g O T C aceta mi n o p he n ta blet t wice dail y, 
n ot m ore t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs after t he first st u d y g el a p plicati o n. If 
s u bjects ta ke res c ue me dicati o n wit hi n  t he first 1 6 8  h o urs  after t he first st u d y gel 
a p plicati o n , it will be rec or de d i n t he e-diar y as resc ue me dicati o n , a n d e ntere d i nt o t he 
e C R F as a c o n c o mita nt me dicati o n , a n d will be pr o gra m maticall y cate g orize d  as a 
c o nc o mita nt me dicati o n . S u bjects  will rec or d t heir pai n i nte nsit y i n t he e -diar y bef ore 
ta ki n g t he resc ue me dicati o n. T he n u m ber of ta blets ta ke n a n d t he date a n d ti me will be 
rec or de d i n t he e-di ar y.  
5. 1. 3  Ti m e t o O nset of First Perce pti ble a n d Me a ni n gf ul P ai n Relief  
Pai n assess me nts of t i me t o first perce pti ble pai n relief a n d ti me t o mea ni n gf ul pai n relief 
f or b ot h le gs at rest a n d w hile sta n di n g will be rec or de d b y s u bjects usi n g t heir e -diar y  u ntil 
ac hie ve d  i n Peri o d 1. At t he ti me of first perce pti ble pai n relief a n d at t he ti me of 
mea ni n gf ul pai n relief, s u bjects will use t heir e -diar y t o rec or d t he ti me  t he e ve nts are 
e x perie n ce d . Si nce t h es e assess me nts will be  ca pt ure d i n t he e -diar y, t he electr o ni c 
data base will be t he di rect p oi nt of data ca pt ur e a n d will ser ve as s o ur ce f or t his varia ble.  
5. 1. 3. 1  
O nset of Perce pti ble P ai n Relief  
O nset of perce pti ble pai n relief will be ass esse d f or t he st u d y le g a n d n o n-st u d y le g at rest 
a n d w hile sta n di n g b y res p o n di n g “ n o ” or “yes” t o a q uesti o n  s uc h as t he f oll o wi n g 
e xa m ple: 
Please c o nfir m t hat y o u w o ul d li ke t o re p ort t hat y o u ha ve e x p erie nce d perce pti ble pai n 
relief at R E S T / w hile S T A N DI N G  i n y o ur S T U D Y / N O N-S T U D Y  le g. Please n ote t hat 
“p erce pti ble p ai n relief” mea ns a n y pai n r elief at a ll. If y o u feel t he pai n is getti n g e ve n a 
little bit better, t he n please a ns wer “ Y E S.”  
5. 1. 3. 2  
O nset of Me a ni n gf ul P ai n Relief  
O nset of mea ni n gf ul pai n relief is ass esse d f or t h e st u d y le g a n d n o n -st u d y le g at rest a n d 
w hile sta n di n g  o nl y after o nset of perce pti ble pai n relief has bee n ac hie ve d. T he s u bject 
res p o n ds “n o ” or “yes” t o a q uesti o n  s uc h as t he f oll o wi n g e xa m ple: 
Please c o nfir m t hat y o u w o ul d li ke t o re p ort t hat y o u ha ve e x p erie nce d mea ni n gf ul pai n 
relief at R E S T/ w hile S T A N DI N G i n y o ur S T U D Y/ N O N -S T U D Y le g. P lease n ote t hat 
“ mea ni n gf ul pai n r elief” is “ W he n t he relief fr o m pai n is mea ni n gf ul or si g nifica nt t o 
y o u. ” T his d oes n ot necessaril y mea n t hat y o u feel c o m pletel y better, alt h o u g h y o u mi g ht. 
Re me m ber t o tell t he Diar y w he n y o u first  e x p erie nce mea ni n gf ul p ai n relief.  
5. 2  
S A F E T Y E V A L U A TI O N S  
5. 2. 1  A d verse E ve nts  
A d verse e ve nts will be rec or de d  acc or di n g t o t he sc he d ule i n Ta bl e 2 . All A Es, w het her 
ascri be d t o st u d y pr oce d ures or n ot, will be d oc u me nte d  o n t he e C R F a n d will i ncl u de t he 
date a n d ti me of o nset, a descri pti o n of t he A E, se verit y, d urati o n, acti o ns ta ke n, o utc o me, 
a n d t he relati o ns hi p bet wee n t he st u d y gel a n d t he e ve nt. 
A n y s u bject 
w h o 
disc o nti n ues/ wit h dra ws fr o m t he st u d y d ue t o a n A E will be f oll o we d u p  u ntil t he o utc o me 
is deter mi ne d a n d writte n re p orts are pr o vi de d b y t he i n v esti gat or. A d verse e ve nt 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 0  of 6 2  
defi niti o ns, a n d re p orti n g a n d f oll o w -u p re q uire me nts are descri be d i n Secti o n  9. 1 , 9. 2 , a n d 
9. 3 , res pecti vel y. 
5. 2. 2  Cli nic al L a b or at or y Tests  
Cli nical la b orat or y tests will be perf or me d b y a ce ntral la b orat or y. Bl o o d sa m ples will be 
c ollecte d acc or di n g t o t he sc he d ule i n Ta ble 2  a n d pr ocesse d as detaile d i n t he 
La b orat or y  M a n ual.   
Uri nal ysis will be perf or me d b y a ce ntral la b orat or y acc or di n g t o t he s c he d ule i n Ta bl e 2 . 
Uri ne sa m ples will be c ollecte d a n d pr ocesse d as detaile d i n t he La b orat or y  Ma n ual. If 
micr osc o p y is re q uire d, a uri ne sa m ple will be se nt t o t he l ocal la b orat or y.  
T he para meters b ei n g  me as ure d  are s h o w n i n  T a ble 3 . 
T a ble 3 . Cli nic al L a b or at or y Test P ar a meters  
He m at ol o g y  
Cli nic al C he mistr y  
Uri n al ysis  
Bas o p hils  
E osi n o p hils  
He m at ocrit 
( Pac k e d cell 
v ol u me)  
He m o gl o bi n  
L y m p h oc ytes  
Mea n cell 
he m o gl o bi n  
Mea n cell 
he m o gl o bi n 
c o nce ntrati o n  
Mea n cell v ol u me  
M o n oc ytes  
Ne utr o p hils  
Platelet c o u nt  
Re d bl o o d cell 
 c o u nt 
W hite bl o o d cell 
c o u nt 
 
Ala ni ne a mi n otra nsferase  
Al b u mi n  
Al kali ne p h os p hatase  
As partate a mi n otra nsferase  
Bicar b o nate  
Bilir u bi n (t otal)  
Bilir u bi n ( direct; o nl y if t otal is ele v ate d)  
Calci u m  
C hl ori de  
Creati ne ki nase 1 
Creati ni ne  
F ollicle -sti m ulati n g h or m o ne ( p ost-me n o pa usal fe male 
patie nts o nl y)  
Ga m ma gl uta m yl tra nsferase  
Tri gl yceri des  
Gl uc ose (fasti n g)  
H u ma n c h ori o nic g o na d otr o pi n (all fe male patie nts)  
Lactate de h y dr o ge nase  
Ma g nesi u m  
P otassi u m  
P h os p hate (i n or ga nic)  
Pr o tei n (t otal) 
S o di u m  
Bl o o d urea nitr o ge n ( B U N)  
Uric aci d  
Bilir u bi n  
Bl o o d  
Gl uc ose  
Ket o nes  
Le u k oc ytes  
Nitrites  
p H  
Pr otei n  
S pecific gra vit y  
Ur o bili n o ge n  
At t he discreti o n of 
t he i n vesti g at or b ase d 
o n uri n al ysis res ults  
Micr o bi ol o g y  
Uri ne Micr osc o p y  
1 Ele vate d le vels of creati ne ki n ase are e x pecte d as a res ult of t h e e xercise perf or me d o n Da y -1  a n d will be ha n dle d as 
descri b e d i n Secti o n  5. 2. 2. 1 . 
 
5. 2. 2. 1  
Ele v ate d Le vels of Ser u m Cre ati ne Ki n ase  
Ele vati o ns of ser u m creati ne ki nase  ( C K) are e x p ecte d t o o cc ur as a c o ns e q ue nce of t h e 
e xercis e perf or me d o n D a y -1  a n d will n ot be re p orte d as A Es.  A d diti o nal s afet y ste ps will 
be ta ke n t o m o nit or t he s u bjec ts f or si g ns of r ha b d o m y ol ysis. If a s u bject has a ser u m C K  
a b o ve 1 0, 0 0 0 U/ L (a n d ass ociate d el e vati o ns of lactate de h y dr o ge nas e  [L D H ], as partate 
a mi n otra nsferase  [ A S T], or al a ni ne a mi n otr a nsferase [ A L T]), b ut n o si g nifica nt si g ns or 
s y m pt o ms of r ha b d o m y ol ysis ot her t ha n m uscle pai n a n d s welli n g at t he e x ercise d m uscles, 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 1  of 6 2  
t he f oll o wi n g acti o ns will be ta ke n wit h t he s u bject u ntil t he E O S  Visit ( Da y 8 f or s u bjects 
d osi n g d uri n g Peri o d 1 a n d Da y 2 2 f or s u bjects d osi n g d uri n g Peri o d 2) : 
•  
S u bjects will be i nstr ucte d t o m o nit or t he uri ne f or c ha n ges i n c ol or caref ull y.  
•  
S u bjects will be i nstr ucte d t o re p ort a n y uri ne disc ol orati o n , s uc h as dar k yell o w , 
b ro w n,  c ola or t ea c ol or e d  uri ne,  t o st u d y pers o n nel. 
•  
S u bjects wil l be i nstr ucte d t o mai ntai n a de q uate h y drati o n at h o me  (a p pr o xi matel y 1 5. 5 
c u ps [3. 7 liters ] of fl ui ds f or m ales a n d 1 1. 5 c u ps [2. 7 liters ] of fl ui ds a d a y f or fe males) 
  
I n a d diti o n, t he f oll o wi n g acti o ns ma y be ta ke n wit h t he s u bject at t he discreti o n of t he 
i n vesti gat or: 
•  
S u bjects will be as ke d t o sta y o ver ni g ht at t he st u d y site w here vi g or o us h y drati o n will 
be a d mi nistere d a n d m o nit ori n g f or a n y cli nical si g ns or s y m pt o ms of r ha b d o m y ol ysis 
will be u n derta ke n. T he s u bject will be release d w he n, per t he i n vesti gat or’s discr eti o n, 
it is a p pr o priate t o d o s o. Pri or t o releas e, t he s p o ns or’s M e dical M o nit or will be 
n otifie d . 
•  
S u bjects will ha ve a ser u m C K  cli nical la b orat or y re peat e d as cli nicall y i n dicate d.  
•  
S u bjects will ha ve a uri n al ysis re peate d as cli nicall y i n dicate d.  
 
If there is a n ele vati o n i n C K a n d r ha b d om y ol ysis is s us pecte d , t he w or k-u p  s h o ul d als o 
i ncl u de e val uati o n of C K  Pa nels (t otal C K , C K -m y ocar dial ba n d [C K -M B ], C K i n s keletal 
m uscle [C K -M M ] a n d C K i n brai n [ C K-B B]) , tr o p o ni n, creati ni ne, m y o gl o bi n (ser u m a n d 
ur i ne), tra nsa mi nases, t otal bilir u bi n le vels, a n d uri nal ysis i ncl u di n g uri ne se di me nt. A  
p h ysical e xa mi nati o n s h o ul d be perf or me d  t o d oc u me nt fi n di n gs s uc h as m uscle te n der ness, 
wea k ness, or ras h. A n E C G s h o ul d als o be perf or me d . A b n or malities s h o ul d be f oll o we d 
u ntil t he y ha ve ret ur n e d t o baseli ne, or u ntil t he i n v esti gat or c o nsi ders t he m cli nicall y sta ble. 
5. 2. 3  Vit al Si g ns  
Vital si g n meas ure me nts will i ncl u de s yst olic bl o o d press ure, diast olic bl o o d press ure, 
p ulse rate,  res pirat or y rat e, a n d oral b o d y te m perat ure. Bl o o d press ure a n d p ulse rate will 
be meas ure d after t he s u bject has bee n resti n g i n t he s u pi ne p ositi o n f or at least 5  mi n utes.  
Meas ure me nts will be p erf or me d acc or di n g t o t he sc he d ule i n Ta ble 2 . 
5. 2. 4  Electr oc a r di o gr a m  
T he E C Gs will be perf or me d acc or di n g t o t he sc h e d ule i n Ta ble 2 .  
5. 2. 5  P h ysic al E x a mi n ati o n  
G e neral p h ysical e xa mi n ati o n s will be perf or me d  acc or di n g t o t he sc he d ul e i n Ta ble 2 . T he 
exa mi nati o n will i ncl u de  t he f oll o wi n g: ge neral c o n diti o n, der mat ol o gic, e yes, ears, n os e, 
t hr oat, nec k, t h yr oi d, heart, res pirat or y s yste m, a b d o me n, ki d ne ys, s k eletal s yste m, 
e xtre mities,  l y m p hatic s yste m, ner v o us s yste m .  
5. 2. 6   S ki n E x a mi n ati o n ( A p plic ati o n S ite R e acti o n) 
S ki n e xa mi nati o n  will be perf or me d  acc or di n g t o t he sc he d ul e i n T a ble 2 . T he i n vesti gat or  
or desi g nee  will assess t he tar g et a p plicati o n site  t o e ns ure t hat t he s ki n is n ot br o ke n or 
irritate d bef ore eac h st u d y gel a p plicati o n a n d d oc u me nt  t he s ki n c o n diti o n i n t he e C R F 
usi n g f oll o wi n g rati n g scales.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 2  of 6 2  
Der m al Res p o nses  
0 = n o e vi de nce of irritati o n  
1 = mi ni mal er yt he ma, b arel y perce pti ble  
2 = defi nite er yt he ma, rea dil y visi ble; mi ni mal e de ma or mi ni mal pa p ular res p o nse  
3 = er yt he ma a n d pa p ules  
4 = defi nite e d e ma  
5 = er yt he ma, e de ma a n d pa p ules  
6 = vesic ular er u pti o n  
7 = str o n g reacti o n s prea di n g be y o n d a p plicati o n site  
N otes: Pa p ules are defi ne d as s oli d, circ u mscri be d s ki n ele v ati o ns u p t o t he size of a s plit pea ( 5 m m). 
Vesicles are defi ne d as s ma ll blisters. 
 
Ot her Effects ( Wit h C o rres p o n di n g N u m eric Sc ore)  
N o ne ( 0)  =  n o c ha n g e i n a p peara nce  
A ( 0 ) = sli g htl y glaze d a p peara n ce 
B ( 1 ) = mar k e d glaze d a p peara n ce 
C ( 2 ) = glazi n g wit h peeli n g a n d crac ki n g 
F ( 3 ) = glazi n g wit h fiss ures 
G ( 4 ) = fil m of drie d ser o us e x u dates c o v eri n g all or part of t he a p plicati o n site 
H ( 5 ) = s mall pete c hial er osi o ns a n d/ or sca bs 
 
S u bjects will be i nstr ucte d t o n otif y st u d y staff if t he y e x perie nce a n y dr y ness, itc hi n g, 
b ur ni n g, pai n, s ore ness, or ot her s y m pt o m at t he a p plicati o n site e ve n d uri n g t he o ut -patie nt 
peri o d. If t here are u nsc he d ule d visit s d ue t o A E s, t he i n vesti gat or will assess t he tar get 
a p plicati o n site a n d all a p plicati o n site reacti o ns will be rec or de d i n t he e C R F.  
T hese si g ns of s ki n irritati o n will b e i ncl u de d i n t he A E s ecti o n of t he e C R Fs. If a s u bject 
is disc o nti n ue d fr o m t h e st u d y d ue t o a n a p plicati o n site reacti o n , t he A E will be f oll o we d 
t o res ol uti o n or u p t o 3 0 da ys after t h e last d ose, w hic he ver c o mes first. 
S u bjects w h o disc o nti n ue d d ue t o a p plicati o n site reacti o n ma y u n der g o a patc h test, at t he 
discreti o n of t he i n vesti g at or.  
S u bjects w h o c h o ose t o disc o nti n ue fr o m partici p ati n g i n t he st u d y will rate t heir der mal 
res p o nse i n t he e-diar y. Der mal Res p o nses sc ore d b y s u bjects will n ot be re c or de d i n t he 
e C R F.   
5. 2. 7  C o nc o mit a nt Me dic ati o ns  
C o nc o mita nt me dicati o ns will be rec or de d  acc or di n g t o t he sc he d ule i n Ta ble 2 .  
5. 3  
O T H E R E V A L U A TI O N S  
5. 3. 1  De m o gr a p hics , Me dic al Hist or y  a n d Ot her B aseli ne C h ar acteristics  
De m o gra p hics a n d ot her baseli ne c haracteristics  (a ge, se x, race,  et h nicit y , hei g ht, a n d 
wei g ht ) as well as m e dical hist or y i nf or mati o n  i ncl u di n g i de ntificati o n of d o mi na nt le g, 
s ki n c o n diti o n ( hist or y of ras h, aller g y, ecze ma, etc.) a n d a n y aller g y hist or y (i ncl u di n g 
fra gra nce, j e welr y, d ust, cl ot hi n g, h o use d ust, a ni mal, metal, r u b ber, n yl o n, f o o d, p olle n 
allerg y, etc. ) will be c ollecte d o n all s u bjects  at t he Scree ni n g  V isit. 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 3  of 6 2  
5. 3. 2  Dr u g a n d Alc o h ol Scree ni n g  
A  uri ne dr u g scree n a n d alc o h ol breat h test, or alc o h ol sali va test , will be c o n d ucte d 
acc or di n g t o t he sc he d ule i n Ta ble 2 . Uri ne dr u g scree n will i ncl u de uri ne scree n f or 
c ocai ne, marij ua na, o piates, a m p heta mi nes, m et ha m p heta mi nes, p he nc y cli di ne ( P C P), 
be nz o diaze pi nes,  
b ar bit urates,  
met ha d o n e,  
o x yc o d o ne, 
3, 4 -met h yle ne di o x y -
met ha m p heta mi ne  (M D M A  or ecstas y), b u pre n or p hi ne ( B U P 9), m or p hi ne, pr o p o x y p he ne, 
a n d tric yclic a nti de pressa nts. 
5. 3. 3  Pre g n a nc y  
All fe male s u bjects will ha ve a ser u m pre g n a nc y test at t he Scree ni n g V isit. S u bjects wit h 
a p ositi ve pre g na n c y test res ult  will  n ot be ra n d o mize d. A uri ne pre g na nc y test will be 
perf or me d at t he E xercis e visit a n d at t he E O S / E T V isits ( Da y 8 or  Da y  2 2) . 
5. 3. 4  St a n d ar dize d E xercise Re gi m e n  
A ll e nr olle d s u bjects will perf or m a sta n d ar dize d re petiti ve q u a drice ps m uscle e x ercise 
c o nsisti n g of war m -u p, deter mi nati o n of ma xi m u m t olerate d wei g ht (M T W ), a n d ti me d 
a n d u nti me d w or k -o ut p hases , des cri be d b el o w . S u bjects will be i nstr uct e d t o sta y well 
h y drate d b y i ncreasi n g t h eir water i nta ke, mi ni mizi n g caffei nate d be v era g es, a n d a v oi di n g 
alc o h ol d uri n g t he e xercise re gi me n.  
1. War m -u p a n d deter mi nati o n of M T W  
S u bjects will c o m plete a war m -u p of 4 sets of 1 0 re g ular b o d y wei g ht s q uat e xercises fr o m 
sta n di n g p ositi o n ( 2 sets wit h o ut wei g hts a n d 2 sets wit h a p pr o xi matel y 1 0-2 0 p o u n ds  of 
wei g ht). T he M T W o n t he le g c url mac hi ne is t he n deter mi ne d f or eac h le g  b y ha vi n g  t he 
s u bject d o a f ull e xte nsi o n a n d fle xi o n wit h resista nce starti n g wit h a l o w b ut reas o na bl e 
wei g ht selecte d b y t he st u d y staff a n d i ncreasi n g it wit h e ver y re petiti o n u ntil s u bjects reac h 
t heir M T W. T h e M T W is defi ne d as t he hi g h est wei g ht u n der w hic h a s u bject c o ul d 
perf or m a f ull e xte nsi o n a n d fl e xi o n.  
2. W or k o ut: ti me d p hase  
Starti n g wit h t he d o mi na nt le g, s u bjects will perf or m 6 sets of 1 0 le g e xte nsi o n a n d fle xi o n 
e xercis es wit h eac h l e g  o n  t he c url mac hi ne u n d er 8 0 % of t he M T W f or t hat le g. Eac h 
re petiti o n is perf or me d t hr o u g h t he f ull pai n-free ra n ge of m oti o n i n a sl o w, c o ntr olle d 
ma n ner. S u bjects perf or m t he c o nce ntric p orti o n of t he re p etiti o n f or 2 sec o n ds, pa use at 
f ull c o ntracti o n f or 1 sec o n d, a n d t he n c o m plete t he ecce ntric p orti o n o ver a 4 sec o n d 
peri o d (f or a t otal of 7 sec o n ds per r e petiti o n). S u bjects perf or m eac h set as t olerate d a n d 
are gi v e n a 1 -2  mi n ute rest peri o d i n bet w ee n s ets. Re petiti o ns are p erf or me d u ntil s u bjects 
are u na bl e t o m o ve t he wei g ht l oa d t hr o u g h t he f ull ra n ge of m oti o n. If s u bjects are u n a ble 
t o c o m plete t he f ull 6 s ets u n der 8 0 % M T W, t he wei g ht is decreas e d i n 5 p o u n d i ncre me nts 
u ntil s u bjects ca n n o l o n ger c o m plete 6 0 % M T W, or 6  sets are c o m plete d. 
3. W or k o ut: u nti me d p hase  
S u bjects c o m plete u nti me d fle xi o n -a n d-e xte nsi o n e xercises ( 1 5 -2 0 re petiti o ns) be gi n ni n g 
wit h t he last wei g ht use d i n t he ti me d p hase. T he wei g hts are gra d u all y decrease d i n 
i ncre me nts of 5 p o u n ds u ntil n o wei g ht is use d.  
T he sa me pr ot oc ol is perf or me d o n t he s u bject’s o p p osite le g.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 4  of 6 2  
5. 3. 5  P h ot o gr a p h a n d R esi d ue E v al u ati o n  
5. 3. 5. 1  
P h ot o gr a p hic A n al ysis  
T o vis ualize t he s ki n c o n diti o n at t he site of  st u d y gel a p plicati o n, p h ot o gra p hs of t he 
a p plicati o n site will be ta ke n bef ore  t he 
st u d y gel a p plicati o ns o n 
  
Als o , w he n  a n a p plicati o n site reacti o n is o bser ve d at t he cli nical site, p h ot o gra p hs of t he 
a p plicati o n site will be ta ke n b y site staff  t o vis uall y d oc u me nt t he s ki n c o n diti o n at t he site 
of gel a p plicati o n . P h ot o gra p hs ma y  be t a ke n  peri o dicall y  as nee d e d  t o f oll o w-u p o n t he 
c o n diti o n of t he a p plicati o n site reacti o n. If a n a p plicati o n site reacti o n is o bser ve d at h o me, 
p h ot o gra p hs of t he a p plicati o n  site will be ta ke n b y site staff w he n s u bject ret ur ns t o t he 
cli nical site. 
P h ot o gra p h s s h o ul d be ta ke n at a n a n gle of less t h a n 4 5 de grees relati ve t o t he s ki n pla ne 
wit h t he area of g el a p plicati o n cl osest t o t he di gital ca mera. Eac h p h ot o gra p h will i ncl u de 
a pa p er la b el i n t he p h ot o gra p h i de ntif yi n g t he s u bj ect n u m ber, date, assess m e nt ti m e p oi nt, 
a n d i nitials of t he p h ot o gra p her.  T he la bel will b e place d o n t he s ki n a djace nt t o t he gel 
a p plicati o n.  
5. 3. 5. 2  
Resi d ue E v al u ati o n   
T o e val uate t he s u bject’s i m pressi o n of t he drie d w hite gel resi d ue, t he f oll o wi n g rati n g 
scale will be assesse d b ef ore t he fift h a n d si xt h st u d y gel a p plicati o ns o n Da y  2 a n d will be 
rec or de d o n t he a p pr o priate f or m. S u bjects m ust n ot s h o wer, bat he, or was h t he treate d area  
u ntil after disc har ge o n D a y 2 . 
T he f oll o wi n g rati n g scal e will be use d:  
0 = N o drie d w hite resi d ue was  o bser ve d  
1 = Drie d w hite resi d ue was o bser v e d b ut n o disc o mf ort.  
2 = Drie d w hite resi d ue was o bser v e d a n d sli g ht disc o mf ort ( bet wee n 1 a n d 3)  
3 = Drie d w hite resi d ue was o bser v e d a n d u nc o mf orta ble  
 
5. 4  
T O T A L B L O O D V O L U M E  
T he t otal bl o o d v ol u me pla n ne d f or c ol lecti o n d uri n g t he st u d y will be d escri be d i n t h e 
i nf or me d c o nse nt f or m (I C F). 
 
6. 0  
C O N D U C T O F S T U D Y  
6. 1  
S T U D Y B LI N DI N G A N D R A N D O MI Z A TI O N   
T he st u d y will be d o u ble -bli n d.  T he i n vesti gat or, s u bjects, a n d s p o ns or pers o n nel i n v ol ve d 
i n t he m o nit ori n g or c o n d uct of t he st u d y will be bli n de d t o t he i de ntit y of t he treat me nt 
fr o m t he ti me of ra n d o mizati o n u ntil t he ti me of u n bli n di n g. U n bli n di n g will o nl y occ ur i n 
t he case of s u bject e mer g e ncies  (Secti o n 7. 8 ) a n d at t he c o ncl usi o n of t he st u d y. St u d y staff 
will i nstr uct s u bjects n ot t o tal k a b o ut t h eir st u d y me dicati o n, t heir pai n i nte nsit y, st u d y 
desi g n etc. , a m o n g s u bje cts.  
 will pre pare t he ra n d o mizati o n s c he d ule bef ore 
t he st u d y. E nr olle d , eli gi ble s u bjects will recei ve  a kit c o ntai ni n g st u d y gels acc or di n g t o 
a n all ocati o n ta ble t hat ra n d o ml y assi g ns s u bjects b y or der of e nr oll me nt t o recei v e st u d y 
gel f or 
 i n 1 of 2  treat me nt ar ms ( A or B ) 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 5  of 6 2  
(Secti o n  7. 2 ). Se parate  all ocati o n ta ble s will be pre pare d f or  1 2 0 mal e a n d 1 2 0 fe mal e  
s u bjects. Male or fe mal e e nr oll me nt ma y e xcee d t he tar get sa m ple size ( n = 1 2 0  eac h 
ge n der ) b y ± 1 0 %. If t he t ar get s a m ple size is e x cee de d i n o ne ge n der, t he ne xt a vaila ble kit 
n u m ber i n t he ot her ge n d er will be assi g ne d.  
T he i de ntit y of t he st u d y gels i n t he treat me nt ar ms will be mas ke d  b y h a vi n g i de ntical 
a p peara nce, pac k a gi n g, la beli n g a n d sc he d ul e of a d mi nistrati o n.  Ra n d o mizati o n data are 
ke pt strictl y c o nfi de ntial, accessi ble o nl y t o a ut h orize d pers o ns, u ntil t he ti me of u n bli n di n g.   
6. 2  
S U B J E C T I N F O R M E D C O N S E N T  
Writte n c o nse nt will  be o btai ne d fr o m t he s u bject pri or t o a n y st u d y s p ecifi c pr oce d ure or 
i n vesti gati o n. 
I nf or mati o n a b o ut t h e st u d y will be gi ve n t o t h e s u bject b ot h ver ball y a n d i n writi n g. T he 
writte n s u bject i nf or mati o n will e x plai n t he o bjecti ves of t he st u d y, its p ote n tial ris ks a n d 
be nefits. T he s u bject m ust ha ve a de q uate ti me t o rea d t he i nf or mati o n a n d t o as k t he 
i n vesti gat or a n y q u esti o ns.  T he i n vesti gat or m ust be satisfie d t hat t h e s u bject h as 
u n derst o o d t he i nf or mati o n pr o vi de d b ef ore writt e n c o nse nt is o btai ne d. If t here is a n y 
d o u bt as t o w het her t he s u bject has u n derst o o d t he writte n a n d v er bal i nf or mati o n, t he 
s u bject s h o ul d n ot e nter t he st u d y. 
Partici pati n g s u bjects w ill be as ke d t o si g n a n d date a n I C F, t he ori gi nal c o p y of w hic h will 
be ke pt b y t he in vesti g at or. A c o p y of t he si g ne d I C F will be gi ve n t o t he s u bject. A rec or d 
will be ma de i n t he n otes t hat t he s u bject v ol u ntaril y a gree d t o partici p ate i n t he st u d y . T he 
ori gi nal si g ne d I C F m ust be ma de a v aila ble t o t he st u d y m o nit or f or i ns pecti o n.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 6  of 6 2  
6. 3  
S T U D Y VI SI T S  
N ote: Ti mi n g of pr oce d ures a n d assess me nts are pr o vi de d as e xa m ples . Act ual ti mi n g ma y 
var y f or eac h s u bject.  Ti me p oi nts a n d ti me wi n d o ws  f or st u d y gel a p plicati o n a n d pai n 
assess me nts  are d escri b e d i n Ta ble 2 . 
•  Da y -3 0 t o Da y -2 :  
o  Scree ni n g Visit: T he S cree ni n g V isit at t he cli nic t o deter mi ne s u bject 
eli gi bilit y  ca n ta ke place a n yti m e wit hi n t his ti me peri o d . Assess me nts 
i ncl u de t he f oll o wi n g: 
▪ I nf orme d c o ns e nt  
▪ De m o gra p hics  
▪ Me dical/ me dicati o n hist or y  
▪ Pre -e xercise i ncl usi o n  criteria, excl usi o n criteria  
▪ Hei g ht a n d wei g ht  
▪ Vital si g ns  
▪ E C G  
▪ P h ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess me nt at st u d y gel site  of b ot h le gs  
▪ Pre g na nc y test  (ser u m) (fe males o nl y) 
▪ Uri ne dr u g scree n a n d al c o h ol test  
▪ Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis)  
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
•  Da y -1 :  
o  E xercise Visit : O n Da y -1  p r oce d ures a n d assess me nts  are as f oll o ws:  
▪ U p date Me dical/ me dicati o n hist or y  
▪ Pre -e xercise i ncl usi o n a n d e xcl usi o n criteria  
▪ Pai n assess me nt ( pre -e x ercise t o e xcl u de s u bjects wit h ot her pai n 
usi n g a pa per V A S)  
▪ D O M S i n d ucti o n e xercis e   
▪ Vital si g ns  
▪ E C G  
▪ P h ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess me nt  at st u d y gel site  of b ot h le gs  
▪ e-diar y, st u d y trai ni n g  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 7  of 6 2  
▪ Uri ne dr u g scree n a n d al c o h ol test  
▪ Pre g na nc y test  ( uri ne) (fe males o nl y) 
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ S u bjects ret ur n h o me after c o m pleti n g pr oce d ures a n d assess me nts  
•  Da y 1 t o Da y 2  
o  A d missi o n Visit : O n Da y 1, s u bjects will be a d mitte d t o  t he cli nic. Da y 1 
pr oce d ures a n d a ss ess me nts are as f oll o ws:  
▪ Iss u e e-di ar y (s u bjects will rec or d e V A S a n d Cate g orical Q ualif yi n g 
Pai n Assess me nts i n e -diar y pri or t o r a n d o mizati o n)  
▪ V A S Q ualif yi n g Pai n assess me nt . N ote : Ti me 0 h o urs is t he baseli ne 
ti me p oi nt f or t he first st u d y gel a p plicati o n a n d occ urs wit hi n 
3 0  mi n utes  of q ualif yi n g pai n assess me nt s ( p ost-e xercis e i ncl usi o n 
criteria). 
▪ Cate g orical Q ualif yi n g P ai n assess me nt . N ote: Ti me 0 h o urs is t he 
baseli ne ti me p oi nt f or t he first st u d y gel a p plicati o n a n d occ urs 
wit hi n 3 0 mi n utes  of q ualif yi n g pai n assess me nt s ( p ost-e xercise 
i ncl usi o n criteria). 
▪ P ost -e xercise incl usi o n criteria  
▪ Ra n d o mizati o n  (f or s u bjects w h o meet p ost -e xercise eli gi bilit y  
criteria)  
▪ Vital si g ns  
▪ S ki n e xa mi nati o n / assess me nt at st u d y gel site  
▪ A p pl y st u d y gel  acc or di n g t o treat me nt sc he d ule   
▪ V A S pai n i nte nsit y assess me nt  ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess me nt occ ur at t he sa me ti me 
p oi nt ). 
▪ Perce pti ble a n d m ea ni n gf ul pai n rel ief assess me nts ( bef ore st u d y gel 
a p plicati o n  w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt). Pai n assess me nts of ti me t o first perce pti ble 
a n d mea ni n gf ul pai n reli ef f or b ot h le gs at rest a n d w hile sta n di n g 
will be rec or de d b y s u bjects u ntil ac hie ve d i n Peri o d 1.  
▪ P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns , as nee d e d  
( bef ore st u d y gel a p plicati o n, be gi n ni n g wit h t he sec o n d st u d y gel 
a p plicati o n ) 
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 8  of 6 2  
o  Da y 2 pr oce d ures a n d ass ess me nts are as f oll o ws: 
▪ Vital si g ns  
▪ S ki n e xa mi nati o n / assess me nt at st u d y gel site  
▪ V A S pai n i nte nsit y assess me nt  ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess me nt occ ur at t he sa me ti me 
p oi nt ) 
▪ Perce pti ble a n d m ea ni n gf ul pai n rel ief assess me nts ( bef ore st u d y gel 
a p plicati o n  w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt). Pai n assess me nts of ti me t o first perce pti ble 
a n d mea ni n gf ul pai n reli ef f or b ot h le gs at rest a n d w hile sta n di n g 
will be rec or de d b y s u bjects u nti l ac hie ve d i n Peri o d 1. 
▪ P h ot o gra p hic a n d resi d ue e val uati o n  ( bef ore t he fift h a n d si xt h st u d y 
gel a p plicati o n s) 
▪ P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee d e d 
( bef ore st u d y gel a p plicati o n) 
▪ A p pl y st u d y gel  acc or di n g t o treat me nt sc he d ule 
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n  
▪ Dis pe nse st u d y gel  (f or o ut-patie nt p orti o n)  
▪ Disc har ge fr o m t he cli nic (aft er st u d y assess me nts at 2 4 h o urs a n d 
t he si xt h st u d y gel a p plicati o n are c o m plet e d)  
•  Da y 3  t o Da y 8  
o  O ut -pa tie nt p orti o n Peri o d 1: S u bjects a p pl y st u d y gel acc or di n g t o t heir 
assi g ne d treat me nt a n d rec or d assess me nts as f oll o ws:  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 2 9  of 6 2  
▪ V A S pai n i nte nsit y assess me nt  ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess me nt occ ur at t he sa me ti me 
p oi nt )  
▪ Perce pti ble a n d m ea ni n gf ul pai n rel ief assess me nts ( bef ore st u d y gel 
a p plicati o n  w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt). Pai n assess me nts of ti me t o first perce pti ble 
a n d mea ni n gf ul pai n reli ef f or b ot h le gs at rest a n d w hile sta n di n g 
will be rec or de d b y s u bjects u ntil ac hie ve d i n Peri o d 1.   
▪ P h ot o gra p hic e val u ati o n  of a p plicati o n site reacti o ns , as nee d e d 
( bef ore st u d y gel a p plicati o n) 
▪ A p pl y st u d y gel  acc or di n g t o treat me nt sc he d ule   
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  
•  Da y 5  (± 1  da y) : 
o  Tele p h o ne Call Peri o d 1 t o as sess safet y a n d s ki n c o n diti o n. 
▪ Rec or d A Es  
▪ Rec or d s ki n c o n diti o n if a p plica ble.  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  
•  Da y 8:  
o  E O S Visit  Peri o d 1  (+ 1  da y) . Pr oce d ures a n d assess me nts  are as f oll o ws:  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 0  of 6 2  
▪ Vital si g ns  
▪ E C G  
▪ Pre g na nc y test ( uri ne) (fe males o nl y) 
▪ Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis)  
▪ P h ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess me nt at st u d y gel site  
 
  
 
 
 
▪ A p pl y st u d y gel  at 6 a m o n Da y 8  
▪ P h ot o gra p hic e val u ati o n  of a p plicati o n site reacti o ns , as nee d e d 
( bef ore st u d y gel a p plicati o n) 
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  
▪ C ollect st u d y gel  
▪ C ollect e -diar y  
o  Safet y Visit  Peri o d 2  (± 1  da y) . Pr oce d ures a n d ass ess me nts are as f oll o ws: 
▪ Vital si g ns  
▪ P h ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess me nt at st u d y gel site  
 
  
 
 
 
 
 
▪ P h ot o gra p hic e val u ati o n  of a p plicati o n site reacti o ns , as nee d e d 
( bef ore st u d y gel a p plicati o n) 
▪ Rec or d A Es  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 1  of 6 2  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  
▪ A p pl y st u d y gel  (
 acc or di n g t o treat me nt assi g n me nt. 
N ote: s o me st u d y gel a p plicati o ns ma y occ ur o utsi de t he cli nic visit. 
▪ Dis pe nse st u d y gel (f or o ut -patie nt p orti o n)  
•  Da y 9  t o Da y 2 2 : 
o  O ut -patie nt p orti o n Peri o d 2 : S u bjects a p pl y st u d y gel acc or di n g t o t heir 
assi g ne d treat me nt a n d rec or d assess me nts as f oll o ws:  
▪ A p pl y st u d y gel  (
 acc or di n g t o treat me nt assi g n me nt.  
▪ P h ot o gra p hic e val u ati o n  of a p plicati o n site reacti o ns , as nee d e d 
( bef ore st u d y gel a p plicati o n) 
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  
•  Da y 1 1  (± 1  da y) : 
o  Tele p h o ne Call Peri o d 2  t o assess safet y a n d s ki n c o n diti o n . 
▪ Rec or d A Es  
▪ Rec or d s ki n c o n diti o n if a p plica ble  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  
•  Da y 1 5  (± 1  da y) : 
o  F oll o w -u p Tele p h o ne Call Peri o d 1 t o assess safet y a n d s ki n c o n diti o n.  
▪ Rec or d A Es  
▪ Rec or d s ki n c o n diti o n if a p plica ble  
▪ Rec or d c o n c o mita nt me dicati o ns  
o  Safet y Visit  Peri o d 2  
▪ Vital si g ns  
▪ P h ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess me nt at st u d y gel site  
▪ P h ot o gra p hic e val u ati o n  of a p plicati o n site reacti o ns , as nee d e d 
( bef ore st u d y gel a p plicati o n) 
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 2  of 6 2  
▪ A p pl y st u d y gel  (
 acc or di n g t o treat me nt assi g n me nt . 
N ote: s o me st u d y gel a p plicati o ns ma y occ ur o utsi de t he cli nic visit.  
▪ Dis pe nse st u d y gel (f or o ut -patie nt p orti o n)  
•  Da y 1 8  (± 1  da y) : 
o  Tele p h o ne Call Peri o d 2  t o assess safet y a n d s ki n c o n diti o n . 
▪ Rec or d A Es  
▪ Rec or d s ki n c o n diti o n if a p plica ble. 
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  
•  Da y 2 2  (+ 1  d a y) : 
o  E O S Visit  Peri o d 2 : T he v isit pr oce d ures i ncl u de safet y assess me nts, a n d 
c ollect i o n of st u d y gel  a n d e-diaries.  
▪ Vital si g ns  
▪ E C G  
▪ Pre g na nc y test ( uri ne) (fe males o nl y)  
▪ Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis)  
▪ P h ysical e xa mi nati o n  
▪ S ki n e xa mi nati o n / assess me nt at st u d y gel site  
▪ A p pl y st u d y gel  at 6 a m o n Da y 2 2  
▪ P h ot o gra p hic e val u ati o n  of a p plicati o n site reacti o ns , as nee d e d 
( bef ore st u d y gel a p plicati o n) 
▪ Rec or d A Es  
▪ Rec or d c o n c o mita nt me dicati o ns  
▪ Rec or d res c ue me di cati o n use  
▪ C ollect st u d y gel  
▪ C ollect e-diar y  
•  Da y 2 9  (± 1  da y) : 
o  F oll o w -u p Tele p h o ne Call Peri o d 2  t o assess safet y a n d s ki n c o n diti o n . 
▪ Rec or d A Es  
▪ Rec or d s ki n c o n diti o n if a p plica ble.  
▪ Rec or d c o n c o mita nt me dicati o ns  
T he pr oce d ures a n d assess me nts t o be perf or me d at eac h visit are i n dicate d i n Ta ble  2 .  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 3  of 6 2  
6. 4  
C O M P LI A N C E WI T H T H E P R O T O C O L  
T he in vesti gat or m ust a gree t o i m ple me nt t he st u d y pr ot oc ol as writte n a n d a d here t o t he 
g ui deli nes gi ve n i n t he “ I n v esti gat or’s State me nt”, w hic h will be si g ne d pri or t o t he start 
of t he st u d y. T he st u d y will be perf or me d i n acc or da nce wit h Healt h I ns ura nce P orta bilit y 
a n d Acc o u nta bilit y 
A ct, 
Declarati o n 
of 
Helsi n ki, I nter nati o nal 
C o nfere nce 
o n 
Har m o nisati o n (I C H) G o o d Cli nical Practice ( G C P ) g ui deli nes , l ocal la ws, F o o d a n d Dr u g 
A d mi nistrati o n ( F D A) G C P re g ulati o ns ( 2 1 C o de of Fe deral Re g ulati o ns [ C F R] Parts 1 1, 
5 0, 5 4, 5 6, a n d 3 1 2), a n d ot her a p plica ble g ui d a nce d oc u me nts .  
If t he i n v esti gat or c o nsi d ers e nr olli n g a s u bject t hat d oes n ot meet all i ncl usi o n or e x cl usi o n 
criteria, a n e xe m pti o n m ust be re q ueste d fr o m t h e  K o wa Res earc h I nstit ute, I nc.  (K RI ) 
Me dic al M o nit or pri or t o s u bject e nr oll me nt . T he j ustificati o n f or t he e xe m pti o n m ust be 
d oc u me nt e d b y t he in vesti gat or. T he a p pr o val or rejecti o n of t he e xe m pti o n m ust be 
d oc u me nte d b y t he K RI Me dical M o nit or pri or t o t he s u bject’s e nr oll me nt  or scree n fail ure .  
Pr ot oc ol n o nc o m plia nce m ust be re p orte d t o t he C o ntract Researc h Or ga nizati o n [ C R O ] 
Me dical M o nit or a n d  K RI. Eac h de viati o n a n d t he reas o n f or its o cc urre nce m ust b e 
d oc u me nte d a n d e ntere d o n t he C R F /e C R F. K RI retai ns t he ri g ht t o re q uire t he wit h dra wal 
of a n y s u bject w h o vi olat es t he pr ot oc ol.  
6. 5  
T E R MI N A TI O N O F T H E S T U D Y  
If, i n t he o pi ni o n of t he in vesti gat or, t he cli nical o bser vati o ns i n t he st u d y s u g gest t hat it 
ma y be u n wise t o c o nti n ue,  or if t here is a n u n e x p ecte d, u nacce pta ble or si g nifica nt safet y 
ris k p ose d t o w ar d st u d y s u bjects, t he st u d y ma y b e ter mi nated after c o ns ultati o n wit h  t he 
a n d K RI. A writte n state m e nt f ull y d oc u me nti n g t he reas o n (s) f or 
t he ter mi nati o n will be pr o vi de d t o K RI . I n a d diti o n, K RI  ma y ter mi nate t he st u d y at a n y 
ti me.  
If it bec o mes a p p are nt t hat s u bject e nr oll me nt is u nsatisfact or y wit h res p ect t o q ualit y or 
q ua ntit y, or data rec or di n g is i nacc urate or i nc o m plete o n a c hr o nic b asis,  or pr ot oc ol 
re q uire me nts are n ot bei n g met, K RI  h as t he ri g ht t o ter mi nate t he st u d y a n d re m o ve all 
st u d y materials fr o m t he i n vesti gati o nal site. A writte n state me nt will be pr o vi de d t o t he 
in vesti gat or, t he I nstit uti o nal Re vie w B oar d/I n d e pe n de nt Et hics C o m mittee (I R B/I E C), 
a n d re g ul at or y aut h orities, i f re q uir e d. I n t h e e v e nt of a n y seri o us or n o n-seri o us A Es  
ha vi n g occ urre d at a site, all d oc u me ntati o n relati n g t o t he e ve nt(s) m ust b e o btai ne d.  
7. 0  
S T U D Y M E DI C A TI O N  
7. 1  
D E S C RI P TI O N O F S T U D Y M E DI C A TI O N  
T he st u d y gels  i ncl u de K-2 8 5  a n d me nt h ol gel.  
•  
K -2 8 5 is a t o p ical g el w hic h c o ntai ns 
 
 
•  
Me nt h ol gel c o ntai ns 
 
 
Eac h of t he st u d y gels  c o ntai ns t he f oll o wi n g e xci pie nts: 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 4  of 6 2  
7. 2  
D R U G P A C K A GI N G   
T he st u d y gel s are  fille d i n al u mi n u m-la mi nate d t u bes at a wei g ht of 
 of st u d y gel 
per t u be.  
F or eac h treat me nt ar m, 2 t y pes of kits  c o ntai ni n g st u d y gel , d osi n g s p o o ns, a n d a p plicati o n 
te m plate materials will b e pre p are d  (f or 1 wee k of d osi n g a n d 3 wee ks of d osi n g)  (Fi g ur e  
2 ). 
 
 
 
 
 
 
 
 
T he b l ue c ol or b o x i n Fi g ure  2  re pres e nts kits f or s u bjects assi g ne d t o 
 
(Peri o d 1 ) (act ual cart o n will be w hite). Eac h s u bject will a p pl y
 of assi g ne d  st u d y 
gel 
. T h e a m o u nt of st u d y gel nee de d per s u bject is 
 
). Eac h s u bject will be assi g ne d  a kit  c o ntai ni n g t w o
 
). 
T he p i n k c ol or b o x i n Fi g ure  2  re prese nts kits f or s u bjects assi g ne d t o 
 
(Peri o d 1  a n d Peri o d  2 ) (act ual cart o n will be w hit e). Eac h s u bject will a p pl y 
 
. T he 
ma xi m u m a m o u nt of  st u d y gel nee de d per s u bject is 
 
 
. Eac h s u bject will be assi g ne d  a kit c o ntai ni n g  
 
l).  
Dis pe nsi n g of st u d y gel is descri be d i n Secti o n  7. 5. 1 . 
Re place me nt kit s will be pr o vi de d o nl y if p ac k a gi n g is da ma ge d pri or t o recei pt of deli ver y.  
7. 3  
D R U G L A B E LI N G  
St u d y gel  will be la bele d wit h t he f oll o wi n g i nf or mati o n:  
1)  St u d y n u m ber  
2)  C o nte nts a n d a m o u nt  
3)  L ot n u m ber  
4)  Kit N u m ber  
5)  T he st ora ge c o n diti o ns  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 5  of 6 2  
6)  Na me a n d a d dress of S p o ns or (e. g., KRI )  
7)  Ca uti o n - Ne w Dr u g Li mite d b y Fe deral La w t o In vesti gati o nal U se 
8)  Ca uti o n - Kee p o ut of reac h of c hil dre n  
9)  Ca uti o n –  A v oi d o pe n fire or s m o ki n g u ntil t he gel has dri e d  
1 0)  I nstr u cti o n –  A p pl y t he gel usi n g t he pr o vi de d d osi n g s p o o ns acc or di n g t o t he 
detaile d i nstr ucti o ns o n t he kit pac ka g e la bel  
7. 4  
D R U G S T O R A G E  
St u d y gels  m ust be st or e d at c o ntr olle d r o o m t e m perat ur e of 
) wit h 
e xc ursi o ns per mitte d bet wee n 
 as i n dicate d o n t h e dr u g la bel. 
7. 5  
DI S P E N SI N G A N D A D MI NI S T R A TI O N O F T R E A T M E N T  
7. 5. 1  Dis pe nsi n g of St u d y Gel  
St u d y gel will be dis pe nse d o n Da y 2 , Da y 8 a n d Da y 1 5 . A  s ufficie nt n u m ber of t u bes t o 
s u p pl y e n o u g h st u d y gel f or 1 wee k at a ti me  will be pr o vi de d . 
7. 5. 2  A p plic ati o n Tr ai ni n g  
O n Da y -1, s u bjects will recei ve tr ai ni n g o n t he a p plicati o n of st u d y gel i ncl u di n g vi de o 
trai ni n g. F urt her  ap plica ti o n instr ucti o ns are pr o vi de d i n A p pe n di x  1 5. 3 . 
7. 5. 3  Dr u g A d mi nistr ati o n   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 6  of 6 2  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 7  of 6 2  
 
 
7. 5. 4  e-Di ar y  
A n  e-d iar y will be iss ue d t o eac h s u bject b y st u d y staff  o n Da y 1  pri or t o ra n d o mizati o n . 
S u bjects will  rec or d pai n i nte nsit y assess me nts (e V A S, Cate g orical Q ualif yi n g Pai n Scale, 
Perce pti ble Pai n Relief , a n d 
Mea ni n gf ul Pai n Relief), i ncl u di n g der mal res p o nse  (if 
a p plica ble), resc u e me dicati o ns  (if a p plica ble) a n d st u d y gel a p plicati o ns  as detaile d i n t he 
e-diar y trai ni n g . D o c u me ntati o n f or t h e st u d y le g a n d n o n-st u d y l e g (if re q uire d) will b e 
perf or me d at t he ti me  p oi nts s pecifie d i n Ta ble 2 .  
T he act ual ti me a n d date t hat eac h set of pai n assess me nts is starte d at eac h ti me p oi nt m ust 
be rec or de d i n t he e-diar y.  
T he e-diar y will be c ollecte d fr o m t he s u bj ect o n Da y 8 (s u bjects d osi n g d uri n g Peri o d 1) 
or Da y 2 2 (s u bjects d osi n g d uri n g Peri o d 2) after t he E O S / E T assess me nt. 
7. 5. 5  P h ysic al E xercise  
T he sta n dar dize d re petiti ve q ua drice ps m uscle e xercise is descri be d i n Secti o n  5. 3. 4 . 
S u bjects will n ot e n ga ge i n a n y stre n u o us p h ysical acti vit y d uri n g st u d y peri o d. 
7. 6  
C O M P LI A N C E WI T H P R E S C RI B E D S T U D Y G E L  D O SI N G R E GI M E N  
T he st u d y  gel will be a p plie d at t he cli nic o n Da y s 1  a n d 2. T he st u d y gel f or a p plicati o n 
o n Da y 1 will be dis pe ns e d b y t he site p har mac y, a n d f or Da ys 2 -8 will be dis pe nse d t o t he 
s u bjects pri or t o disc har ge o n Da y 2. F or s u bjects assi g ne d t o Peri o d 2, st u d y gel f or 
a p plicati o n b y s u bjects will be dis pe nse d at t he Da y  8 a n d Da y 1 5  Safet y visits . S t u d y gel 
t u bes will be wei g he d, i n gra ms, a n d t he t otal wei g ht f or all t u bes rec or de d pri or t o 
dis pe nsi n g t o s u bjects. St u d y gel will be c ollecte d o n Da y 8 (f or Peri o d  1 s u bjects) a n d Da y 
2 2 (f or Peri o d 2 s u bjects), wei g he d a n d t he fi nal wei g ht rec or de d. C o m plia nce will be 
deter mi ne d fr o m t he fi nal wei g ht of t he t u be s c o m pare d t o t he e x pecte d decrease fr o m t he 
starti n g wei g ht, base d o n t he assi g ne d d osi n g sc h e d ule (
 ×  t he n u m b er 
of d oses).  
7. 7  
D R U G A C C O U N T A BI LI T Y  
T he i n vesti gat or or  desi g nee will si g n a recei pt f or t he st u d y gel w he n recei ve d . T he st u d y 
gel  m ust be st ore d as d es cri be d  (Secti o n 7. 4 ), ke pt i n a sec ure d l ocati o n t o w hic h o nl y t he 
i n vesti gat or a n d desi g nate d staff ha ve access , a n d dis pe nse d o nl y t o t h ose s u bjects f or mall y 
e nr olle d i n t he st u d y.  
T he i n vesti gat or or desi g nee m ust mai ntai n a n acc urat e rec or d of t he s hi p me nt a n d 
dis pe nsi n g of st u d y g el i n a dr u g acc o u nt a bilit y le d ger. Dr u g acc o u nt a bilit y will be 
m o nit ore d b y t he st u d y m o nit or d uri n g m o nit ori n g visits a n d at t he c o m pleti o n of t he st u d y.  
All dr u g will be i n ve nt ori e d b y 
 at t he c o ncl usi o n of t he st u d y. Sec ure dis p osal at t he 
e n d of t he st u d y will be arra n ge d after t he cli nical st u d y re p ort has bee n fi n alize d.   


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 8  of 6 2  
7. 8  
P R O C E D U R E F O R U N B LI N DI N G  
As nee de d, t he ra n d o mizati o n c o de ma y be br o ke n b y t he in vesti gat or t o ma na ge  a n ur ge nt 
me dical e ve nt.  W h e n  p ossi ble, u n bli n di n g will be reser ve d  f or sit uati o ns w he re treat me nt 
all ocati o n  is re q uire d t o be k n o w n f or safet y reas ons.  If p ossi ble, K RI  a n d t he  
 
is c o nta cte d t o disc uss t he cas e b ef ore t h e c o de is br o k e n.  
If it bec o mes n ecess ar y t o u n bli n d treat me nt i nf or mati o n d uri n g t he st u d y, t he reas o n f or 
u n bli n di n g is d oc u me nte d i n t he C R F /e C R F. T h e in vesti gat or  m ust c o ntact K RI a n d t h e 
 pr o m ptl y a n d e x plai n t he reas o n f or t he pre mat ure u n bli n di n g . 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 3 9  of 6 2  
8. 0  
C O N C O MI T A N T M E DI C A TI O N  
T he in vesti gat or m ust rec or d t he us e of all c o n c o mita nt me dicati o ns i ncl u di n g resc ue 
me dicati o ns , b ot h pres cri be d a n d o v er -t h e-c o u nt er, i n t he C R F /e C R F. T his i ncl u des dr u gs 
use d o n a c hr o nic a n d as -nee de d basis. S u bjects m ust be disc o ura ge d fr o m starti n g a n y ne w 
me dicati o n, b ot h prescri be d a n d o ver -t he-c o u nter, wit h o ut c o ns ulti n g t he in vesti gat or , 
u nless t he ne w me dic ati o n is re q uire d f or e mer g e n c y use.  
8. 1  
G E N E R A L C O N SI D E R A TI O N S  
All me dicati o ns a n d ot her treat me nts ta ke n b y s u bjects wit hi n 3 0  da ys bef ore d osi n g a n d 
d uri n g t he st u d y will be rec or de d i n t he C R F. A n y c ha n ges i n t he c o nc o mita nt me dicati o ns 
after disc h ar ge fr o m t he cli nic o n Da y 2 , eit her prescri be d or self -a d mi nistere d, will be 
d oc u me nte d a n d re vie we d  acc or di n g t o t he s c he d ule i n Ta ble  2 .  
8. 2  
P R O HI BI T E D M E DI C A TI O N  A N D T H E R A PI E S  
T he f oll o wi n g me dicati o ns  a n d t hera pies  are pr o hi bite d d uri n g t he st u d y:  
•  
Oral or t o pical a nal gesic me dicati o ns wit hi n 1 4  da ys bef ore t he S cree ni n g V isit. 
•  
S yste mic c ortic oster oi d wit hi n 3 0  da ys bef ore t he Scree ni n g V isit. 
•  
Prescri pti o n or o ver -t he-c o u nter pr o d u cts c o ntai ni n g me nt h ol or N S AI Ds.  
•  
Slee p 
me dicati o n, 
m uscle rela xa nt, a ntic o n v uls a nt, or a nti de press a nt i n t he last 
6  m o nt hs t o treat a c hr o nic pai n c o n diti o n.  
•  
A ntic o n v ulsa nt or a nti de pressa nt f or a n o n -p ai nf ul c o n diti o n at a d ose t hat h as n ot bee n 
sta ble f or at least 3 m o nt hs bef ore t he S cree ni n g V isit. 
•  
T he a p plicati o n or use of ice, heat, mass a ge, a n d wra p pi n g  o n t he le gs  
•  
Me dicati o ns or treat me nts t hat w o ul d si g nifica ntl y i nfl ue nce or e xa g gerat e res p o nses 
t o t he gel, or t hat w o ul d alter i nfla m mat or y or i m m u ne res p o nses t o t he g el, wit hi n 3 0 
da ys bef ore t he first d ose of st u d y g el (e. g., c ycl os p ori ne, tacr oli m us, c yt ot o xic dr u gs, 
i m m u ne glo b uli n, Bacill us Cal mette -G ueri n vacci ne, m o n ocl o nal a nti b o dies, ra diati o n 
t hera p y). 
•  
S u bjects will n ot e n ga ge i n a n y stre n u o us p h ysical acti vit y d uri n g st u d y peri o d.  
8. 3  
P E R MI T T E D M E DI C A TI O N  
Use of a n y resc u e me dicati o n f or D O M S is str o n gl y disc o ura ge d u ntil 1 6 8 h o urs after t he 
first st u d y gel a p plicati o n, at w hic h ti me o ver-t he-c o u nter ( O T C) acet a mi n o p he n ( o ne 
5 0 0  m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) as resc u e 
me dicati o n is per mitte d , if re q uire d. S u bjects e x p erie nci n g se vere pai n or i na bilit y t o m o ve 
or wal k d ue t o pai n m a y be per mitte d t o use resc ue me dicati o n ( o ne 5 0 0 m g O T C 
aceta mi n o p he n ta blet t wi ce dail y, n ot m or e t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs aft er t he 
first st u d y gel a p plicati o n. If s u bjects ta ke resc u e me dicati o n bef ore t he first 1 6 8 h o urs, it 
will be ca pt ure d as a c o n c o mita nt me dicati o n.  
N o ot her me dicati o ns (i ncl u di n g s u p ple me nts) are per mitte d d uri n g t he st u d y, e xce pt as 
necessar y t o treat a n A E, at t he i n vesti gat or’s discreti o n.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 0  of 6 2  
9. 0  
A D V E R S E E V E N T S  
9. 1  
A D V E R S E E V E N T D E FI NI TI O N  
A n A E  is a n y u nt o war d me dical occ urre nce i n a s u bject a d mi nistere d a p har mace utical 
pr o d uct  a n d w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t he p har mace utical 
pr o d uct. A n A E  ca n, t heref ore, be a n y u nfa v ora ble a n d u ni nte n de d si g n, s y m pt o m, or 
disease te m p orall y ass o ciate d wit h t he use of a m e dici nal pr o d uct, w het her or n ot relate d 
t o t he me dici nal pr o d uct. A n y w orse ni n g of t he s u bject’s disease u n der st u d y or ot her 
me dical c o n diti o ns will als o be c o nsi dere d t o be a n A E , u nless it is wit hi n t he n or mal ra n g e 
of disease fl u ct uati o n f or t hat s u bject.  
Cli nicall y mea ni n gf ul (f or a gi ve n s u bject) c h a n g es i n p h ysical e xa mi nati o n fi n di n gs a n d 
a b n or mal o bjecti ve test fi n di n gs (e. g. cli nical la b orat or y tests [e xce pt f or ele vate d test 
res ults f or ser u m C K, Secti o n 5. 2. 2. 1 ], E C Gs ) are als o rec or de d as A Es. T he criteria f or 
deter mi ni n g w het her a n a b n or mal o bjecti ve test fi n di n g s h o ul d be re p orte d as a n A E are as 
f oll o ws: 
1.  test res ult is ass ociate d wit h acc o m pa n yi n g s y m pt o ms, a n d/ or; 
2.  test res ult re q uires a d diti o nal dia g n ostic testi n g or me dical/s ur gical i nter ve nti o n, 
a n d/ or; 
3.  test res ult lea ds t o a c ha n ge i n st u d y d osi n g or disc o nti n uati o n fr o m t he st u d y, 
si g nifica nt a d diti o nal c o nc o mita nt dr u g treat me nt or ot her t hera p y, a n d/ or; 
4.  test res ult lea ds t o a n y of t he o utc o mes i ncl u de d i n t he defi niti o n of a seri o us A E  
( S A E).  
Merel y re p eati n g a test, i n t he a bse nce of a n y of t he a b o ve c o n diti o ns, d oes n ot meet 
co n diti o n n u m ber 2 a b o v e f or re p orti n g as a n A E.  
A n y a b n or m al test res ult t hat is deter mi ne d t o b e a n err or d o es n ot re q uire re p orti n g as a n 
A E.  
A T E A E is defi ne d as a n A E t hat be gi ns after t h e start of st u d y gel or a n e ve nt t hat be gi ns 
bef ore t h e start of t he st u d y gel a n d w orse ns i n i nt e nsit y after starti n g treat me nt.  
9. 2  
R E P O R TI N G A D V E R S E E V E N T S  
At eac h e val uati o n, t he in vesti gat or will deter mi ne w het her a n y A Es  ha v e occ urre d.  T h e 
s u bject will be q uesti o ne d i n a ge n eral wa y a n d n o s pecific s y m pt o ms will b e s u g geste d.  If 
a n y A Es  ha ve o cc urre d, t he y will be rec or de d o n t he A E  pa ges of t he C R F  or e C R F  a n d i n 
t he s u bject’s me dical rec or d. If k n o w n, t h e dia g n osis will  be rec or de d, i n prefere nce t o t he 
listi n g of i n di vi d ual si g ns a n d s y m pt o ms. 
A d verse e ve nt re p orti n g be gi ns w he n i nf or m e d c o nse nt is o btai ne d a n d e n ds at t he 
c o ncl usi o n of t he st u d y, u nless a n u nres ol ve d A E  is still bei n g f oll o we d. 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 1  of 6 2  
T he se verit y of t h e A E  will be gra de d as f oll o ws:  
 
Mil d  
T he A E  is easil y t olerat e d a n d d oes n ot i nterfere wit h n or mal dail y 
acti vities. 
 
M o derate  
T he A E  ca uses s o me i nterfere nce wit h dail y acti vities . 
 
Se vere  
T he A E  ca uses all n or mal dail y acti vities t o be c o m pletel y halte d . 
 
T he in vesti gat or will ma ke a j u d g me nt re gar di n g w het her or n ot t he A E  was relat e d t o t he 
st u d y gel. ( Please refer t o t he defi niti o ns bel o w. ) T he in vesti gat or will e val uat e a n y c ha n g es 
i n la b orator y val ues,  ma ke a deter mi nati o n as t o w het her or n ot t he c ha n ge is cli nicall y 
i m p orta nt, a n d w het her or n ot t he c h a n ges were relate d t o t he st u d y gel. H o we ver, e ve n if 
t he in vesti gat or feels t here is n o relati o ns hi p t o t he st u d y g el, t he A E  or l a b orat or y 
a b n or malit y M U S T  be rec or de d i n t he C R F /e C R F. T he f oll o wi n g g ui da nce will be use d 
b y i n vesti gat ors w he n assessi n g relati o ns hi p:  
Rel ate d  
•  
Occ urs wit hi n a reas o n a ble te m p oral se q ue n ce t o a d mi nistrati o n of st u d y gel or,  
•  
Ca n n ot be e x plai ne d b y c o nc urre nt diseas e or ot her dr u gs or c h e micals  or,  
•  
I m pr o v es or disa p p ears o n st o p pi n g or re d uci n g st u d y gel ( de-c halle n ge)  
•  
Rea p pears o n re p eate d e x p os ure t o st u d y gel (re-c halle n ge)  
•  
Is a n u n us ual e v e nt t hat is k n o w n t o be ass ociate d wit h t he dr u g or t his class of 
c o m p o u n d , a n d ca n n ot be e x plai ne d b y ot her t hera p y or t he p artici pa nt’s p h ysical 
c o n diti o n  
•  
U nli kel y t o be attri b ute d t o c o nc urre nt disease or ot her dr u gs or a cli nicall y reas o na bl e 
res p o nse o n wit h dra wal ( de-c halle n g e)  
U nrel ate d  
•  
Occ urs wit h a te m p oral relati o ns hi p  t o a d mi nistrati o n of st u d y gel w hic h ma kes a ca us al 
relati o ns hi p i m pr o ba ble or,  
•  
Ot her dr u gs, c he micals or u n derl yi n g dise ase pr o vi de pla usi ble e x pla nati o ns of 
ca usalit y  or,  
•  
Is k n o w n t o be ass ociat e d wit h t he partici pa nt’s cli nical c o n diti o n, or wit h ot her 
me dicati o n ta ke n b y t he partici pa nt  
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 2  of 6 2  
T he in vesti gat or will rec or d t he acti o n ta ke n a n d o utc o me f or eac h A E  acc or di n g t o t he 
f oll o wi n g: 
Acti o n t a ke n  
•  
N o ne  
•  
Treat me nt r e q uire d  
•  
H os pitalizati o n  
•  
S u bject wit h dra w n  
•  
Ot her (s pecif y)  
Acti o n T a ke n Wit h St u d y Tre at me nt  
•  
D ose n ot c ha n g e d  
•  
Dr u g i nterr u pte d  
•  
Dr u g wit h dra w n  
•  
N ot a p plica ble  
O utc o me  
•  
Res ol ve d: T he e ve nt has rec o vere d  
− 
N ote: A n S A E/ A E st o p date s h o ul d be pr o vi de d.  
•  
Rec o vere d/ Res ol ve d wit h se q uelae: T he st u d y s u bject has rec o vere d as m uc h as ma y 
be e x pecte d b ut is left wit h se q uelae of t he e ve nt t hat are n ot e x p ecte d t o rec o ver f urt her  
− 
N ote: If t he se q uela e are se vere e n o u g h t o re prese nt a si g nifica nt disa bilit y or 
i nca pacit y t he n t he e ve nt s h o ul d be re p orte d as a n S A E. 
•  
Rec o veri n g/ Res ol vi n g: Ca n be use d i n cas es w here st u d y s u bject is k n o w n t o be clearl y 
rec o veri n g fr o m t he e ve nt at t he e n d of a st u d y, alt h o u g h t he e ve nt is n ot yet res ol ve d, 
a n d t he i n vesti gat or a n d M e dical M o nit or a gree t hat f urt her f oll o w -u p is n ot necessar y.  
•  
Fatal: T he st u d y s u bject die d as a res ult of t he A E  
− 
N ote: Deat h is c o nsi dere d a n o utc o me of a n A E rat her t ha n a n A E i n its o w n 
ri g ht, a n d t he ca us e of deat h s h o ul d be rec or de d as t he A E. T here ma y be rare 
circ u msta nces w here t he ca use of d eat h is u n k n o w n a n d t he deat h ma y h a ve t o 
be rec or d e d as t he e ve nt (e. g., “s u d de n car diac deat h”). A d verse e ve nts 
res ulti n g i n deat h are S A Es. 
•  
N ot rec o v ere d/ N ot res ol ve d: T he s u bject has a n A E t hat has n ot i m pr o ve d or 
rec u perate d at t he ti me of t he re p ort 
9. 3  
F O L L O W -U P O F A D V E R S E E V E N T S  
If a n y A Es  are pres e nt  w he n a s u bj ect c o m plet es t he st u d y , or w he n  a s u bject  disc o nti n ues 
or  is wit h dra w n fr o m t h e st u d y, t he s u bject will be re-e v al uate d . At t h e in vesti gat or’s 
discreti o n, mi n or A Es ca n be re -e val uate d via tel e p h o ne a n d d oc u me nte d. If t he A E is still 
n ot res ol ve d, a d diti o nal f oll o w -u p will be perf or me d as a p pr o priate. E v er y eff ort will be 
ma de b y t he in v esti gat or or del e gate t o c o ntact t he s u bject u ntil t he A E  is res ol ve d or 
sta bilize d, or t he M e dical M o nit or a n d in vesti gat or a gree t hat f urt her f oll o w-u p is n ot 
necessar y.  T h e f oll o w -u p of A Es will be d oc u me nte d i n t he s u bject’s me dical rec or ds.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 3  of 6 2  
1 0. 0  S E RI O U S A D V E R S E E V E N T S  
A n S A E is a n y u nt o war d me dical occ urre n ce t hat at a n y d ose: 
•  
Res ults i n deat h  
•  
Is life-t hreate ni n g 
•  
Re q uires s u bject  h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n  
•  
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  
Is a c o n ge nital a n o mal y/ birt h defect 
•  
I m p ort a nt m e dical ev e nt  
Me dical a n d scie ntific j u d g me nt will be e x ercis e d i n deci di n g w het h er e x pe d ite d re p orti n g 
is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot b e 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
s u bject or ma y re q uire i nter ve nti o n t o pre v e nt o ne of t he ot h er o u tc o mes liste d i n t he 
defi niti o n a b o ve.  E v e nts t hat re q uir e e x p e dite d re p orti n g will als o be c o nsi dere d t o be 
S A Es . 
1 0. 1  
LI F E -T H R E A T E NI N G A D V E R S E E V E N T  
T he ter m “life -t hr eate ni n g” i n t he defi niti o n of “s eri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of deat h at t he ti me of t he e v e nt . It d o es n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h , if it were m ore se vere. 
1 0. 2  
H O S PI T A LI Z A TI O N  
H os pitalizati o n is defi ne d as t he s u bject bei n g h os pitalize d o ver ni g ht, or t he s u bject’s 
h os pital sta y b ei n g pr ol o n ge d f or at least a n a d diti o nal o ver ni g ht sta y. Pre -pla n ne d h os pital 
sta ys or h os pital sta ys f or n o n-me dical s oci al reas o ns are n ot a p plica ble. T we nt y -t hree h o ur 
h os pitalizati o ns f or o bser vati o n will be disc usse d wit h t he M e dical M o nit or t o deter mi ne 
w het her t he y are a p pr o priate f or S A E re p orti n g.  
1 0. 3  
I M P O R T A N T M E DI C A L E V E N T 
Me dical a n d sci e ntific j u d g me nt will be e xercis e d i n deci di n g w het her e x p e dite d 
re p orti n g is a p pr o priat e i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot 
be i m me diatel y life -t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize 
t he s u bject or ma y re q uir e i nter ve nti o n t o pre v e nt o ne of t he ot her o ut c o mes liste d i n t he 
defi niti o n a b o ve . 
1 0. 4  
P R E G N A N C Y  
A n y s u bject 
w h o 
bec o mes 
pre g na nt 
d uri n g t he st u d y 
m ust i m me diatel y 
be  
disc o nti n ue d/ wit h dra w n. T he i n vesti gat or  is re q uire d t o n otif y t he K RI M e dical M o nit or 
a n d 
 if a n y s u bject bec o mes pre g n a nt d uri n g t he st u d y. 
Pre g na nt s u bjects will re q uire peri o dic f oll o w -u p wit h d oc u me ntati o n of t he o utc o me of 
t he pre g na n c y i n t he st u d y rec or ds. 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 4  of 6 2  
1 0. 5  
S U B J E C T DI S C O N TI N U A TI O N A N D WI T H D R A W A L  
If a s u bject e x perie n ces a n A E t hat lea ds t o disc o nti n uati o n of st u d y gel treat me nt a n d 
wit h dra wal fr o m t he st u d y, t he C R F /e C R F will i de ntif y t he A E as t he  reas o n f or 
wit h dra wal.  S u bjects t hat disc o nti n ue st u d y gel treat me nt will be as ke d t o c o nti n ue 
sc he d ule d st u d y visits t hr o u g h t he F oll o w-u p p h o n e call.  
1 0. 6  
S E RI O U S U N E X P E C T E D S U S P E C T E D A D V E R S E R E A C TI O N S  
Acc or di n g t o F D A C F R 3 1 2. 3 2(a) a n d F D A G ui da nce “ Safet y Re p orti n g Re q uire me nts f or 
I N Ds a n d B A/ B E St u dies ” fi nalize d Dece m ber 2 0 1 2, s us pecte d a d verse r e acti o n mea ns 
a n y A E f or w hic h t h ere is a reas o na bl e p ossi bilit y t hat t he m e dici nal pr o d uct ca us e d t he 
A E . T he p hrase “reas o n a ble p ossi bilit y” mea ns t here is e vi d e nce t o s u g gest a ca usal 
relati o ns hi p bet wee n t h e A E a n d t he me dici nal pr o d uct. 
 
T he f oll o wi n g are e x a m ples of t y pes of e vi de nce t hat w o ul d s u g gest a ca us al relati o ns hi p 
bet wee n t he dr u g a n d t he A E (i.e., re as o n a ble p ossi bility): 
•  
A si n gle occ urre n ce of a n e ve nt t hat is u n c o m m o n a n d k n o w n t o b e str o n gl y ass ociate d 
wit h dr u g e x p os ure (e. g., a n gi oe de ma, he patic i nj ur y, Ste ve ns -J o h ns o n S y n dr o me)  
•  
O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d wit h dr u g 
e x p os ure, b u t is ot her wise u nc o m m o n i n t he p o p ulati o n e x p ose d t o t he dr u g 
(e. g., te n d o n r u pt ur e)  
 
S us pecte d a dverse re a cti o ns are t he s u bset of all A Es f or w hic h t here is a reas o na ble 
p ossi bilit y t hat t he dr u g ca use d t he e v e nt.  
 
A s us pecte d a d v erse reacti o n is c o nsi dere d “ u ne x pecte d” if it is n ot liste d i n t he 
In v esti gat or ’s B r oc h ure or ot her a p plica ble pr o d uct i nf or mati o n or is n ot liste d at t he 
s pecificit y or se v erit y t hat has bee n o bser ve d. 
 
A n A E or s us pecte d a d v erse reacti o n is c o nsi dere d “seri o us” if, i n t he vie w of eit her t he 
in vesti gat or or s p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
Deat h, a 
life-t hreat e ni n g A E, i n-p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, a 
persiste nt or si g nifica nt i n ca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or m al 
life f u ncti o ns, or a c o n ge nital a n o mal y/ birt h defect. I m p ort a nt me dical e ve nts t hat ma y n ot 
res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d seri o us 
w he n,  base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o par dize t he patie nt or s u bject 
a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o n e of t h e o ut c o mes liste d i n 
t his defi niti o n. 
 
A n y A E meeti n g t he defi niti o ns of s us pecte d a d verse reacti o n, u ne x pecte d, a n d seri o us is 
c o nsi dere d a seri o us u ne x pecte d s us p ecte d a d verse reacti o n ( S U S A R). I n acc or da n ce wit h 
t he F D A G ui da n ce “ Safet y Re p orti n g Re q uir e me nts f or I N Ds a n d B A/ B E St u dies”, 
fi nalize d D ece m ber 2 0 1 2, K RI will u n bli n d t he st u d y data f or s u bjects e x peri e nci n g 
S U S A Rs a n d o nl y re p ort t h ose f or s u bjects w h o are o n st u d y gel. All s uc h re p orts will be 
s u b mitte d t o t he in vesti gat or(s), F D A, a n d I R B /I E C i n a n e x pe dite d ma n ner. 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 5  of 6 2  
1 0. 7  
S E RI O U S A D V E R S E E V E N T  R E P O R TI N G  
 
S E RI O U S A D V E R S E E V E N T S , W H E T H E R O R N O T R E LA T E D T O T H E S T U D Y 
G E L , M U S T B E R E P O R T E D I M M E DI A T E L Y T O T H E S T U D Y M E DI C A L 
M O NI T O R : 
 
 
 
 
 
Sites nee di n g t o c o ntact t he Me dical M o nit or s h o ul d use t he a b o ve 2 4/ 7 S A E h otli ne 
n u m ber a n d 
e mail bef ore c o ntacti n g  a n 
i n di vi d ual Me dical M o nit or. T he h otli ne n u m ber will e m pl o y a call tree t o c o ntact 
i n di vi d uals i n or der of a call list. 
 
 
L ot us Cli nic al Rese arc h, L L C  
 
 
 
 
 
 
K o wa Researc h I nstit ute, I n c. will c o n d uct a me di cal re vie w of S A E re p orts.  
 
K o w a Rese arc h I nstit ute, I nc.  
 
 
 
 
 
 
K o wa Researc h I nstit ute, I nc. will o btai n  d etails fr o m t he in vesti gat or  or C R O  of all 
seri o us, u ne x pecte d a n d relate d A Es  ( or ot her e ve nts de pe n di n g o n t he s pecific 
re q uire me nts) t hat s h o ul d be re p orte d t o I R Bs/I E Cs, as a p pr o priate.  Writte n c o nfir mati o n 
t hat t hese s eri o us, u n e x p ecte d a n d relate d A Es  ha ve bee n s u b mitte d t o t h e I R B /I E C m ust 
be f or w ar de d t o K RI a n d ke pt i n t he in vesti gat or files.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 6  of 6 2  
1 1. 0  S T A TI S TI C A L M E T H O D S A N D D A T A A N A L Y SI S  
I n ge n eral, ass ess me nts 
wit h c o nti n u o us o utc o mes 
will be s u m marize d usi n g t he 
descri pti ve statistics n, mea n, sta n dar d de vi ati o n (S D ), me dia n, mi ni m u m a n d ma xi m u m. 
F or assess me nts wit h cate g orical o utc o mes, fre q ue nc y c o u nts a n d perce nta ge will be 
calc ulate d. Det aile d statistical met h o d ol o g y will be prese nte d i n a se parate statistical 
a nal ysis pla n .  
1 1. 1  
S A M P L E SI Z E J U S TI FI C A TI O N  
T he para meters are c o ns er vati vel y esti mate d base d o n t he D O M S st u d y wit h  
 gel.  
T he bet wee n -gr o u p differe nce i n t he mea n 
 is 1 1. 0 7 wit h a S D  of 2 5. 6 2. T o ha ve 
statistical p o wer of 9 0 %, 
 
 Ta ki n g i nt o acc o u nt 
i nf or mati o n l oss ca us e d b y missi n g data, it is esti mate d t hat  
 nee d t o be treat e d 
wit h eac h st u d y gel. 
1 1. 2  
S T U D Y P O P U L A TI O N S  
T hree a nal ysis p o p ulati o ns will be e val uate d:  
•  
T he f ull a nal ysis set ( F A S) will i ncl u de all ra n d o mize d s u bjects w h o ha v e a b aseli ne 
pai n sc or e a n d at least 1  st u d y gel a p plie d. 
•  
T he per -pr ot o c ol set ( P P S) will i ncl u de all ra n d o mize d s u bjects w h o ha ve a baseli ne 
pai n sc ore, at least 1  st u d y gel a p plie d, a n d n o maj or pr ot oc ol vi olati o ns. 
•  
T he safet y s et will i ncl u de all s u bjects w h o ha v e at least 1 st u d y gel a p plie d. 
1 1. 3  
DI S P O SI TI O N  
T he n u m ber of s u bjects scree n e d, ra n d o mize d , a n d treate d will be s u m marize d. T he 
n u m ber of s u bjects disc o nti n ui n g treat me nt / wit h dra wi n g fr o m t he st u d y will be 
s u m marize d al o n g wit h t he reas o ns f or disc o nti n uati o n/ wit hdra wal . S u bjects w h o are 
scree n fail ures al o n g wit h t he  mai n  reas o ns f or fail ure will als o be s u m mari ze d. 
1 1. 4  
D E M O G R A P HI C/ B A S E LI N E I N F O R M A TI O N  
De m o gra p h ics a n d ot her baseli ne c haract eristics will be s u m marize d wit h descri pti ve 
statistics. F or  q u a ntitati ve data , mea ns, me dia ns, sta n dar d de viati o ns, mi ni m u m a n d 
ma xi m u m val ues w ill be deter mi ne d. F or q ualitati ve data, perce nt a ges  will be calc ul ate d.  
1 1. 5  
A N A L Y SI S O F E F FI C A C Y P A R A M E T E R S  
1 1. 5. 1  Pri m ar y  Effic ac y P ar a meters  
 
T he pri mar y a n al ysis p o p ulati o n is t he F A S. T he pri ma r y a nal ysis will be re peate d usi n g 
t he P PS . 
 
 
 
  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 7  of 6 2  
If t here e xist missi n g V A S val ues t o be i m p ute d, a n y s uc h val u es will be i m p ute d bef ore 
calc ulati n g t he  
. I nt er me diate missi n g V A S val ues d ue t o a n o mis si o n of rec or di n g 
pai n i nte nsit y or s u bject’s slee p will n ot be i m p ute d, t heref ore, t he o bs er ve d val ues bef ore 
a n d after t he missi n g meas ure m e nt will be directl y c o n necte d i n or der t o calc ulate t he 
 If s u bj ects nee d t o ta ke t he resc ue me di cati o n, t he y will rec or d t h eir pai n i nte nsit y 
i n t he e diar y bef ore ta ki n g t he resc ue me dicati o n. If t he resc ue me dicati o n is ta ke n wit hi n 
6 h o urs of a n o mi nal pai n i nte nsit y assess me nt ti me p oi nt, t he pai n i nte nsit y sc ore t h at was 
rec or de d bef ore t a ki n g t he res c ue medicati o n will be carrie d f or war d t o t he ne xt pai n 
i nte nsit y assess me nt ti me p oi nt. Missi n g val ues ca use d b y wit h dra wal fr o m t he st u d y d ue 
t o e ve nts w hic h are n ot prefera ble t o s u bjects s uc h as a n a d verse e v e nt a n d/ or lac k of 
effic ac y will be i m p ute d b y last o bs er vati o n carri e d for war d ( L O C F) w hile t h ose v al ues 
d ue t o l ost t o f oll o w -u p will be i m p ute d u n der t h e m issi n g at ra n d o m ( M A R) ass u m pti o n 
wit h t he m ulti ple im p utati o n  ( MI) t ec h ni q ue. B y usi n g t he MI t ec h ni q ue, 1 0 0 datasets will 
be ge n erat e d. After ca lc ul ati n g t he  
 a n a nal ysis of c o varia n ce ( A N C O V A) m o del will 
be a p plie d f or t h e pri mar y e n d p oi nt wit h ge n d er a n d treat me nt as mai n effects a n d b aseli ne 
pai n as a c o v ariate i n eac h dataset. M ulti ple res ults will be c o m bi ne d usi n g R u bi n’s r ule. 
As f or a  se nsiti vit y a nal ysis, t he L O C F val ues will be re place d b y t he w orst val ue o bser ve d 
i n t his st u d y, a n d t he n t he sa me pr o ce d ure will be a p plie d. 
1 1. 5. 2  Sec o n d ar y Effic ac y P ar a meters   
A mi xe d effect m o del re peate d -meas ures ( M M R M) will be a p plie d t o t he PI D w hile 
sta n di n g  a n d PI D at rest t o i n vesti gate treat me nt differe nces.  
 
. T he ti me t o first 
d ose of resc ue me di cati o n, will be a nal yze d usi n g t he Ka pla n -Meier met h o d t o esti mate 
t he s ur vi val distri b uti o n f u ncti o n.  
1 1. 6  
A N A L Y SI S O F S A F E T Y D A T A  
T he safet y e n d p oi nt data will be s u m marize d f or t he safet y set. 
T he A Es  will be c o de d usi n g t he latest versi o n of Me dical Dicti o nar y f or Re g ulat or y 
Acti vities  ( Me d D R A). A ge neral s u m mar y of t he A Es  a n d S A Es  will be s u m marize d b y 
o verall n u m ber of A Es , se verit y a n d relati o ns hi p t o st u d y gel, per treat me nt gr o u p. T he 
n u m ber of A Es  lea di n g t o disc o nti n uati o n/ wit h dra wal a n d S A Es  lea di n g t o deat h will als o 
be s u m marize d. T he i nci de nce of A Es  will be s u m marize d b y b o d y s yste m a n d treat me nt 
gr o u p.  T he i nci de nce of T E A Es will als o be s u m marize d b y s yste m or ga n class a n d 
preferre d t er m.  
T he cli nical  l a b orat or y d ata will be s u m marize d b y treat me nt gr o u p, al o n g wit h c ha n g es 
fr o m t he b aseli ne. T he v al ues t hat are b el o w t he l o wer li mit or a b o ve t he u p per li mit of t he 
refere nce ra n g e will be fl a g ge d. T h ose val u es or c ha n ges i n val ues, w hic h are i de ntifie d as 
bei n g cli nicall y si g nifica nt, will be fla g ge d.  
V ital si g ns will als o be s u m marize d b y treat me nt gr o u p a n d ti me p oi nt , al o n g wit h t he 
c ha n ges fr o m baseli ne.  
All A E, cli nical la b orat or y, vital si g n, p h ysical e xa mi nati o n, st u d y gel a p plicati o n site 
reacti o n, st u d y gel use a n d c o nc o mita nt me dicati o n use will be prese nte d i n data listi n gs. 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 8  of 6 2  
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 4 9  of 6 2  
1 2. 0  S T U D Y M A N A G E M E N T A N D D A T A C O L L E C TI O N  
1 2. 1  
E T HI C A L C O N D U C T O F T H E T RI A L  
T his st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol, F D A  G C P , as descri be d i n 2 1 C F R  
Parts 1 1, 5 0, 5 4, 5 6, a n d 3 1 2 ; t he W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki; t he 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A); a n d I C H G C P  ( E 6/ R 1). 
Eac h in vesti gat or will c o n d uct t he trial als o acc or di n g t o a p plica ble l ocal or re gi o nal 
re g ulat or y re q uire me nts. 
1 2. 2  
I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T E T HI C S 
C O M MI T T E E  
T he IR B/I E C m us t be c o nstit ute d acc or di n g t o t he a p plica ble state, fe d eral a n d l ocal  
re q uire me nts of eac h partici pati n g l ocati o n, a n d t h ose of t he I C H G C P g ui da nce a n d F D A 
G C P re g ulati o ns . 
It is t he res p o nsi bilit y of eac h i n vesti gati o nal site t o s u b mit t he pr ot oc ol, I n v esti gat or’s 
Br oc h ure, s u bject i nf or m e d c o nse nt, s u bject recr uit me nt materials (if a p plica ble), a n d ot her 
re q uire d d oc u m e ntati o n t o t he I R B /I E C f or re vi e w a n d a p pr o val. C o pies of t he writte n 
a p pr o val s m ust be pr o vi d e d t o 
 T h e  d oc u me ntati o n s h o ul d clearl y 
me nti o n t he a p pr o val/fa v ora ble o pi ni o n of t he pr ot oc ol, t he s u bject I C F, a n d s u bject 
recr uit me nt m aterials (if a p plica ble). T he res p ecti ve versi o n dates are t o b e i ncl u de d . T he 
writte n a p pr o val s a n d a list of t he v oti n g me m ber s, t heir titles or occ u pati o ns, a n d t heir 
i nstit uti o nal affiliati o ns m ust be o btai ne d fr o m t he I R B/I E C a n d pr o vi de d t o 
 
 pri or  t o t he release of cli nical st u d y s u p plies t o t he i n vesti gati o nal site a n d 
c o m me nce me nt of t he st u d y. If a n y  me m ber of t h e I R B /I E C has direct partici pati o n i n t h e 
st u d y, writte n n otificati o n re g ar di n g his or her a bsti ne nce fr o m v oti n g m ust als o be 
o btai ne d.  
Sites m ust a d here t o all re q uire me nts sti p ulate d b y t he I R B /I E C. T his i n cl u des n otificati o n 
t o t he I R B/I E C re g ar di n g pr ot oc ol a m e n d me nts; u p dates t o t he s u bject i nf or me d c o ns e nt  
a n d recr uit me nt materials i nte n de d f or vie wi n g b y s u bjects; I n vesti gati o nal Ne w Dr u g 
safet y re p orts; seri o us a n d u ne x pecte d A Es; u p dat es re gar di n g t he o n g oi n g re vie w of t he 
st u d y at i nter vals s pecifie d b y t he I R B/I E C; a n d fi nal st u d y re p orts or s u m maries. 
It is t he res p o nsi bilit y of eac h i n vesti gati o nal site t o s u b mit i nf or mati o n t o t he a p pr o priate 
I R B/I E C f or a n n ual re vi e w a n d a n n ual re-a p pr o val.  
1 2. 3  
S U B J E C T I N F O R M E D C O N S E N T  
Pri or t he i m ple me ntati o n of st u d y pr oce d ures, s u bj ects a n d pers o ns c o n d ucti n g t he c o nse nt 
disc ussi o n will be re q uir e d t o si g n a n d date t he I R B /I E C-a p pr o ve d I C F a n d eac h s u bject 
will be gi ve n a c o p y. I n a d diti o n, t his i nf or mati o n will be rec or de d i n t he s u bject’s me dical 
rec or d (i.e., s o urce d oc u me nt). 
T he writte n c o nse nt d oc u me nt will e m b o d y t he ele me nts of i nf or me d c o nse nt as descri be d 
i n t he HI P A A , W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki, 
F D A 2 1 C F R  Part  
5 0. 2 5, I C H G C P, a n d i n acc or da n ce wit h a n y l ocal  re g ulati o ns. T he in vesti gat or is 
res p o nsi ble f or t he pre p arati o n, c o nte nt, a n d I R B/I E C a p pr o val of t h e I C F. T he I C F m ust 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 0  of 6 2  
be a p pr o ve d b y t he site -d esi g nate d I R B /I E C a n d b e acce pt a ble t o  K RI  a n d  
 
. 
T he I C F m ust be writte n i n a la n g ua ge  f ull y c o m pre he nsi ble t o t he pr os pecti ve s u bject. T he 
in vesti gat or or desi g nee will gi ve t he s u bject a de q uate o p p ort u nit y t o rea d it bef ore it is 
si g ne d a n d dat e d. Inf or mati o n pr o vi de d will b e gi ve n i n b ot h oral a n d writte n f or m 
w he ne ver p ossi ble a n d i n t he ma n ner d ee me d a p pr o priate b y t he I R B/I E C. S u bjects m ust 
be gi ve n a m ple o p p ort u nit y t o i n q uire a b o ut st u d y details . 
1 2. 4  
A M E N D M E N T S T O T H E P R O T O C O L  
A n a me n d me nt m ust be a gree d t o i n writi n g b y K RI  a n d 
, s u b mitte d 
as a n I n vesti gati o nal Ne w Dr u g (I N D) a p plicati o n a me n d me nt , a n d s u b mitte d t o a n d 
a p pr o ve d b y t he res pecti ve I R B /I E C f or eac h i n v esti gati o nal site bef ore it is i m ple me nte d. 
Writte n a p pr o val of a pr ot oc ol a me n d me nt is n ot re q uire d pri or t o i m ple me ntati o n f or 
c ha n ges t o t he pr ot oc ol, w hic h eli mi nate i m me diate hazar d t o t he s u bject; h o we ver, 
a p pr o val m ust be o btai ne d as s o o n as p ossi ble t hereafter . A p pr o v e d a me n d me nts m ust als o 
be si g ne d b y t he in vesti gat or.  
1 2. 5  
S T U D Y I NI TI A TI O N  
T he in vesti gat or m ust n ot e nr oll a n y s u bjects pri or t o t he c o m pleti o n of a f or mal meeti n g 
c o n d ucte d b y a re prese ntati ve of 
 ( or K RI). T his meeti n g will 
i ncl u de a detaile d re vie w of t he st u d y pr ot oc ol a n d C R F/e C R Fs . St u d y gel  will n ot be 
su p plie d t o a n i n vesti gat or u ntil all t he necessar y pre -st u d y re q uire m e nts ha ve bee n 
c o m plete d a n d esse ntial si g ne d d oc u me nts are recei ve d b y 
, as 
a p plica ble, a n d K RI . 
1 2. 6  
S T U D Y M O NI T O RI N G  
It is t he res p o nsi bilit y of t he in vesti gat or t o e ns ure t hat t he st u d y is c o n d ucte d i n acc or da nce 
wit h t he pr ot oc ol, I C H / F D A G C P s, a p plica ble re g ulat or y re q uire me nts, HI P A A, a n d t he 
c urre nt Declarati o n of Helsi n ki . Vali d data are t o be e ntere d i nt o t he C R Fs /e C R Fs. 
M o nit ori n g acti vities will be c o n d ucte d as d escri be d i n a n a p pr o ve d M o nit ori n g Pla n.  
O versi g ht visits ma y  be c o n d ucte d b y K RI Cli nical O perati o ns t o assess m o nit or i n g 
perf or m an ce . 
T o ac hi e ve t his o bj ecti ve, t he m o nit or’s d uties are t o ai d t h e in ves ti gat or a n d, at t he sa me 
ti me, K RI  i n t he mai nte na nce of acc urat e, c o m plete, le gi ble, well -or ga nize d a n d easil y 
retrie va bl e data. T he m o nit or will re vie w t he pr ot oc ol wit h t he in vesti gat or.  I n a d diti o n, 
t he m o nit or will e x plai n t he in vesti gat or’s re p orti n g  res p o nsi bilities a n d all a p plica ble 
re g ulati o ns c o ncer ni n g t he cli nical e val u ati o n of t he st u d y gel. 
T he in vesti gat or will per mit t he re prese nt ati ves of K RI a n d  
 t o 
m o nit or an d o versee  t he st u d y as fre q ue ntl y as 
 ( or K RI) dee ms is 
necessar y t o deter mi ne t hat data rec or di n g a n d pr ot oc ol a d here nce are acce pta ble. T he 
C R Fs /e C RF s a n d relate d s o urce d oc u me nts will be re vi e we d i n detail b y t he m o nit or at 
eac h visit, i n acc or da n ce wit h rele va nt Sta n dar d O perati n g Pr oce d ures ( S O Ps) , I C H G C P 
g ui da nce, a n d F D A G C P  re g ulati o ns. T his i ncl u des res ults of tests perf or me d as a 
re q uire me nt f or partici p ati o n i n t his st u d y a n d a n y ot her me dical rec or ds re q uire d t o 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 1  of 6 2  
c o nfir m i nf or mati o n c o ntai ne d i n t he C R Fs , s uc h as past me dical hist or y a n d sec o n d ar y 
dia g n oses. T he in vesti gat or a n d staff will be e x pecte d t o c o o perate wit h t he m o nit or / K RI 
a n d pr o vi de a n y missi n g i nf or mati o n, w he ne v er p ossi ble.  
All m o nit ori n g a n d K RI o versi g ht acti vities will be re p orte d a n d arc hi ve d.  A n y iss ues 
i de ntifie d will be re p orte d a n d f oll o we d-u p u ntil res ol ve d.  I n a d diti o n, eac h m o nit ori n g 
visit will be i de ntifie d at t he i n vesti gati o nal site b y t he m o nit or’s / K RI’s si g nat ure a n d dat e 
o n t he st u d y -s pecific m o nit ori n g l o g. 
1 2. 7  
C A S E R E P O R T F O R M  
All s u bject data ge nerate d d uri n g t he st u d y will be rec or de d o n t he C R F / e C R F.  
T he in vesti gat or will e ns ure t hat all data are e ntere d pr o m ptl y, le gi bl y, c o m pletel y, 
acc uratel y a n d c o nf or m t o s o urce d oc u me nts, i n acc or da n ce wit h s pecifi c i nstr ucti o ns 
acc o m pa n yi n g  t he C R Fs /e C R Fs, desi g ne d s pecificall y f or t his st u d y a n d s u p plie d b y 
 
 f or eac h s u bject.  
 will o nl y c o nsi der t he C R Fs /e C R Fs t o be c o m plete after t he y are 
re vie we d a n d si g ne d b y t he in vesti gat or, i n dicati n g his/ her ass ura nce of t he acc urac y of all 
rec or de d dat a. It is e x p ecte d t hat t he in vesti gat or a n d staff will c o o p erate wit h t he 
m o nit ori n g tea m a n d pr o vi de missi n g data i n a ti mel y ma n ner.  
1 2. 8  
V E RI FI C A TI O N P R O C E D U R E S  
I n f ulfill me nt of t heir o bli gati o ns t o K RI a n d t o v erif y c o m plia nce wit h t his pr ot oc ol , I C H 
G C P  g ui da nce , a n d F D A G C P re g ul ati o ns, t he i n vesti gat or will per mit 
 
, t h e I R Bs/I E Cs, t he m o nit or, a n d re g ulat or y a ut h orities t o ha ve direct access t o 
t he s u bject’s me dical rec or ds. 
It is t he i n vesti gat or’s o bli gati o n t o e ns ure d oc u me ntati o n of all rele va nt data i n t he 
s u bject’s me dical rec or d, C R Fs/e C R Fs, a n d o n st u d y f or ms, w he n a p plica bl e, acc or di n g t o 
pr oce d ures pr o vi de d i n t he pr ot oc ol . 
T he in vesti gat or will m ai ntai n a S u bject I de ntifi cati o n C o de List t o e na ble u na m bi g u o us 
i de ntificati o n of t he s u bjects (s u bject na mes a n d c orres p o n di n g s u bject n u m bers). T he 
S u bject I d e ntificati o n C o de List is a n esse ntial d oc u me nt a n d as s uc h m ust be mai ntai ne d 
acc or di n g t o t he  I C H G C P g ui deli nes. 
1 2. 9  
R E T E N TI O N O F R E C O R D S  
All d oc u me ntati o n pertai ni n g t o t he st u d y will be retai n e d b y  K RI a n d 
 
 in  acc or da nce wit h U. S. F D A re g ulati o ns  a n d t he I C H G C P g ui d a nce d oc u me nt . 
 will pr o vi de eac h in vesti gat or wit h a st u d y  bi n der , w hic h will be 
use d t o file t he I n v esti gat or’s 
Br oc h ure ; pr ot oc ol ; dr u g acc o u nta bilit y rec or ds ; 
c orres p o n d e nce 
wit h t he I R B /I E C, K RI , a n d 
; a n d ot her 
st u d y-relate d d oc u m e nts. 
T he in v esti gat or a grees t o kee p rec or ds a n d t h ose d oc u me nts t h at i ncl u de ( b ut are n ot 
li mite d t o) t he i de ntificati o n of all partici pati n g s u bjects, me dical rec or ds, st u d y-s pecific 
s o urce d oc u me nts, s o ur ce w or ks heets, all ori gi nal si g ne d a n d date d I C Fs, c o pies of all 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 2  of 6 2  
C R Fs /e C R Fs, q uer y res p o nses, a n d detaile d rec or ds of dr u g dis p ositi o n, t o e na ble 
e val uati o ns or a u dits fr o m re g ulat or y a ut h orities a n d K RI or its desi g nees.  
T he i n vesti gat or a n d 
 will retai n rec or ds re q uir e d t o be mai ntai ne d 
u n de r fe d eral re g ul ati o ns f or a peri o d of 2 years f oll o wi n g t he date a mar keti n g a p plicati o n 
is a p pr o ve d f or t he dr u g f or t h e i n dicati o n f or w hic h it is bei n g i n v esti gate d; or, if n o 
a p plicati o n is t o be file d or if t he a p plicati o n is n ot a p pr o ve d f or s uc h i n d icati o n, u ntil 
2  years after t he i n vesti gati o n is disc o nti n ue d a n d F D A is n otifie d. H o we ver, t hese 
d oc u me nts will be retai n e d f or a l o n ger peri o d if re q uire d b y t he a p plica ble re g ulat or y 
re q uire me nt(s) or if nee d e d b y K RI . I n a d diti o n, t he in vesti gat or m ust ma ke pr o visi o n f or 
t he s u bject’s me dical rec or ds t o be ke pt f or t he s a me peri o d of ti me. 
S u bjects’ me dical rec or ds a n d ot her ori gi nal data will be arc hi ve d i n acc or da n ce wit h 
a p plica ble re g ulati o ns a n d re q uire me nts est a blis he d b y t he i n vesti gati o nal sites. 
1 2. 1 0  
I N S U R A N C E A N D I N D E M NI T Y 
K RI ’s o bli gati o ns re g ar di n g i ns ura nce a n d i n de m nificati o n are d escri be d i n ot her 
d oc u me nts or a gree me nts.  
1 2. 1 1  
A U DI T  
It is t he res p o nsi bilit y of 
 a n d K RI t o perf or m a u dits (if a p plica ble), 
as part of i m ple me nti n g q ualit y ass ura nce. T h e p ur p ose of a n a u dit, w hic h is i n de pe n d e nt 
of a n d se p arate fr o m r o uti ne m o nit ori n g o r q ualit y c o ntr ol f u ncti o ns, is t o e val uate trial 
c o n d uct a n d c o m plia nce wit h t he pr ot oc ol, S O Ps, I C H / F D A G C Ps, HI P A A, a n d ot her 
a p plica ble re g ul at or y re q uire me nt s. T he a u dit or a n d re g ulat or y a ut h oriti es will re q uire 
direct access t o t he s u bject’s me dical rec or ds a n d all st u d y rec or ds . 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 3  of 6 2  
1 3. 0  U S E O F I N F O R M A TI O N  
1 3. 1  
G E N E R A L A S P E C T S  
All i nf or mati o n c o ncer ni n g  
 a n d K RI, s uc h as pate nt a p plicati o ns, 
f or m ula, 
ma n ufact uri n g pr ocesses, basic scie ntific data or f or m ulati o n i nf or mati o n 
s u p plie d b y K RI an d n ot pre vi o usl y p u blis he d, are c o nsi dere d c o nfi de ntial a n d will re mai n 
t he s ole pr o pert y of K RI. T h e i nvesti gat or a grees t o us e t his i nf or m ati o n o nl y i n 
acc o m plis hi n g t his st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut t he writte n c o nse nt 
of K RI, e xce pt f or official re prese nt ati ves, s uc h as re g ulat or y a ut h orities.  
It is u n derst o o d b y t he in vesti gat or t hat t he i nf or m ati o n de vel o pe d i n t his cli nical st u d y, i n 
c o n necti o n wit h t he d e v el o p me nt of K -2 8 5  will be use d b y K RI a n d, t h eref ore, ma y b e 
discl ose d b y K RI as re q uire d t o ot her cli nical in vesti gat ors, ot her p har mace utical 
c o m pa nies a n d t o ot her g o ver n me nt a ge n cies . I n or der t o all o w f or t he use of t he 
i nf or mati o n deri ve d fr o m cli nical st u dies, it is u n derst o o d t hat t here is a n o bli gati o n t o 
pr o vi de t o K RI c o m plete test res ults a n d all data c o m pile d i n t his st u d y.  
1 3. 2  
S U B J E C T C O N FI D E N TI A LI T Y A N D D A T A P R O T E C TI O N  
K o wa Researc h I nstit ute, I n c . a n d its desi g nees affir m a n d u p h ol d t he pri nci ple of t he 
s u bject’s ri g ht t o pr otecti o n a gai nst i n vasi o n of pri vac y. T hr o u g h o ut t his st u d y, all data will 
be li n ke d t o t he C R F /e C R F via a u ni q ue i de ntificati o n n u m b er a n d t he s u bject's i nitials.  
T he d at a will be bli n de d c orres p o n di n gly i n all d at a a n alyses . 
H o we ver, i n c o m plia nce wit h t he g ui deli nes a n d re g ulati o ns of t he U S F D A c o ncer ni n g 
t he acce pta n ce of cli nical st u dies i n s u p p ort of I N D ap plicati o n s a n d t he I C H G C P ( w het her 
perf or me d i n t he U nite d States or else w h ere) , a n d i n f ulfill me nt of its o bli gati o ns t o K RI  
t o verif y c o m plia nce wit h t his pr ot oc ol, K RI’s desi g nee re q uir es t hat t he i nvesti gat or t o 
per mit its m o nit or, re prese ntati ves fr o m t he F D A, K RI’s  d esi g n ate d a u dit ors, I R Bs /I E Cs, 
a n d ot her g o ver n me ntal re g ulat or y a ut h orities t o re vie w t he s u bject’s pri mar y me dical 
rec or ds (s o urce data or d oc u me nts) i ncl u di n g, b ut n ot li mite d t o la b orat or y test res ult 
re p orts, E C G  re p orts, a d missi o n a n d disc har ge s u m maries f or h os pital a d missi o ns 
occ urri n g d uri n g a s u bj ect’s st u d y partici pati o n, a n d a ut o ps y re p orts rel ate d t o deat hs 
occ urri n g d uri n g t he st u d y.  
S h o ul d access t o s uc h me dical rec or ds re q uir e a wai ver or a ut h ori zati o n se parat e fr o m t he 
state me nt of i nf or me d c o nse nt, t he in vesti gat or will o btai n s uc h per missi o n i n writi n g fr o m 
t he s u bject bef ore t he s u bject is e ntere d i nt o t he st u d y. 
1 3. 3  
FI N A L R E P O R T A N D P U B LI C A TI O N P O LI C Y  
All i nf or mati o n re g ar di n g t his st u d y will be ke pt strictl y c o nfi de ntial. All data deri ve d fr o m 
the st u d y will be t he pr o pert y of K RI. T he in vesti gat or m ust u n derta ke n ot t o s u b mit a n y 
part of t he data fr o m t his st u d y f or p u blicati o n wit h o ut pri or c o nse nt of K RI. K RI ma y 
discl ose data deri ve d fr o m t he st u d y t o ot her in vesti gat ors a n d dr u g re g ulat or y a ut h orities.  
A fter c o m pleti o n of t he st u d y, a n d as a gree d b y t h e in vesti gat or a n d K RI, t he i n vesti gat or 
ma y se n d a draft ma n us cri pt t o K RI t o be re vie we d i n or der t o reac h a n a gree me nt re gar di n g 
p u blicati o n. T he i n vesti gat or m ust recei ve writte n a p pr o val fr o m K RI bef ore t he fi n al 
versi o n of t he ma n uscri pt is s u b mitte d f or p u blicati o n.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 4  of 6 2  
At t he c o ncl usi o n of t he st u d y, after t he d ata are a n al yze d, K RI or its desi g n ee will pre pare 
a fi nal cli nical r e p ort.  


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 5  of 6 2  
1 4. 0  R E F E R E N C E S  
 
1.  Lai ne L. N o nster oi d al a nti -i nfla m mat or y dr u g gastr o pat h y. Gastr oi ntest E n d osc Cli n 
N A m 1 9 9 6, 6: 4 8 9 -5 0 4.  
2.  Bec ker J C, D o msc h k e W, P o hle T. C urre nt a p pr oac hes t o pre v e nt N S AI D -i n d uce d 
gastr o pat h y –  C O X sele cti vit y a n d be y o n d. Br J Cli n P har mac ol. 2 0 0 4 Dece m ber; 
5 8( 6):  5 8 7 – 6 0 0.  
3.  J ü ni P. Are selecti ve C O X 2 i n hi bit ors s u peri or t o tra diti o nal n o nster oi dal 
a ntii nfla m mat or y dr u gs? B MJ. 2 0 0 2 J u ne 1; 3 2 4( 7 3 4 9): 1 2 8 7 – 1 2 8 8.  
4.  Mas o n L, M o ore R A, E d war ds J E, Derr y S, Mc Q ua y HJ. T o pical N S AI Ds f or ac ut e 
pai n: a meta -a n al ysis. B M C Fa m Pract. 2 0 0 4 Ma y 1 7; 5: 1 0.  
5.  Oz M., El Ne brisi E. G., Ya n g, K -H. S., H o wart h F. C, a n d Al K ur y L T. C ell ular a n d 
M olec ular Tar gets of Me nt h ol Acti o ns. Fr o nt. P har mac ol.  2 0 1 7;  8: 4 7 2.  
6.  Ki m D H, Li m Y Y, Ki m H M, Ki m S Y, Ki m BJ . T he Safet y E val u ati o n of a P ote nt 
A n gi o ge nic Acti vat or, S y nt hetic Pe pti de S F K L R Y -N H 2, f or t he S ki n A p plicati o n.  
T o xic ol o gical Researc h. 2 0 1 2 ; 2 8: 5 1-5 6.  
7.  Gri mes D, L yssi kat os J. H u ma n Der m al Safet y T esti n g f or T o pical Dr u g Pr o d ucts . 
F D A W or ks h o p . 2 0 1 8. 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 6  of 6 2  
1 5. 0  A P P E N DI C E S  
 
1 5. 1  
A P P E N DI X 1  
VI S U A L A N A L O G S C A L E  ( E X A M P L E O F P A P E R V A S) 
 
 
Assess me nt of t he pai n i nte nsit y at rest a n d w hile sta n di n g  usi n g a  pa per  p ai n V A S .  
Please rec or d t he pai n i nt e nsit y w hile at rest/ w hil e st a n di n g  i n t he d o mi n a nt/ n o n -
d o mi n a nt le g  t hat y o u are e x peri e nci n g ri g ht n o w: 
 
 
 
Sc he matic is a re prese nt ati o n of t he pa per V A S i ma ge t hat will be pres e nte d t o s u bjects.  
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 7  of 6 2  
VI S U A L A N A L O G S C A L E  ( E X A M P L E O F E L E C T R O NI C  V A S)  
 
 
Assess me nt of t he pai n i nte nsit y of D O M S at rest a n d w hile sta n di n g  usi n g a pai n eV A S .  
Please rec or d t he pai n i nt e nsit y w hile at rest/ w hil e st a n di n g  i n t he st u d y le g/n o n -st u d y 
le g t hat y o u are e x peri e n ci n g ri g ht n o w d ue t o D O M S  ( dela ye d o nset m us cle s ore ness): 
 
 
 
 
Sc he matic is a re prese nt ati o n of t he eV A S i ma ge t hat will be prese nte d t o s u bjects.  
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 8  of 6 2  
1 5. 2  
A P P E N DI X 2  
 
 
 
  
 
 
   
 
   
 
  
 
 
 
 
 
 
  
 
 
  
 
   
 
  
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 5 9  of 6 2  
1 5. 3  
A P P E N DI X 3  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 6 0  of 6 2  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
 
 
 
 
 
 
 
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1, St u dy Pr ot oc ol  
 
 
 
 
 
 
 
 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 6 1  of 6 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
K o w a Rese arc h I nstit ute, I nc.  
K -2 8 5 -2 0 1 , St u dy Pr ot oc ol 
K -2 8 5  
 
 
Versi o n 2. 0 2 8 M ay  2 0 2 0  
P a ge 6 2  of 6 2  
 
1 5. 4  
A P P E N DI X 4  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

Prot_000.pdf: 
C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
A P h ase II, R a n d o mize d, D o u ble- bli n d, Acti ve C o m p ar at or, P a r all el 
Gr o u p St u d y t o E v al u ate t he Effi c a c y a n d S afet y of K- 2 8 5 C o m p a re d 
wit h
Me nt h ol Gel f or t he Tre at me nt of Del a ye d O nset M uscle S o re ness 
( D O M S) i n t he L o wer E xtre mit y 
Cli ni c al St u d y P r ot oc ol 
Dr u g N a me:  
K- 2 8 5
St u d y N u m ber:
U. S. I N D N u m ber: 
Pr ot oc ol Versi o n D ate: 
Versi o n #:
N a me of S p o ns or:
A d dress:
M a n a gi n g C o ntr act Rese arc h 
Or g a niz ati o n ( C R O):
A d dress:
C o nt act N u m bers:
K- 2 8 5- 2 0 1
I N D 1 3 5 3 4 8 
1 0 A pril 2 0 2 0 
1. 0 
K o w a Rese arc h I nstit ute, I nc. 
 
 
 
 
 
P r o pert y of K o w a Rese a rc h I nstit ute, I nc. 
C o nfi de nti al 
M a y n ot be use d, di v ul g e d, p u blis he d, o r ot her wise discl ose d 
wit h o ut t he c o nse nt of K o w a Rese arc h I nstit ute, I nc. 
Cli nic al Tri als. g o v                            N C T 0 4 4 8 4 4 2 8
Cli nic al Tri als. g o v                            N C T 0 4 4 8 4 4 2 8
ClinicalTrials.gov                            NCT04484428


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
ii1 6
I N V E S TI G A T O R’ S S T A T E M E N T 
I, t he i n vesti gat or, u n dersta n d t hat all i nf or mati o n c o ncer ni n g t he pr o d uct s u p plie d t o me 
b y 
K o wa 
Researc h I nstit ute, I nc. ( K RI) a n d  
 i n 
c o n necti o n wit h t his st u d y a n d n ot pre vi o usl y p u blis he d is c o nfi de ntial i nf or mati o n. 
T his i nf or mati o n i ncl u des t h e I n vesti gat ors’ Br oc h ure, pr ot oc ol, case re p ort f or ms, assa y 
met h o ds, tec h nical met h o d ol o g y a n d basic scie ntific data. 
I u n dersta n d t hat a n y c ha n ges t o t he pr ot oc ol m ust be a p pr o ve d i n writi n g b y K RI,  
 
 a n d t he I nstit uti o nal Re vie w B oar d/I n de pe n d e nt Et hics C o m mittee 
(I R B/I E C) bef ore i m ple me ntati o n, e xce pt 
w h ere ne cessar y t o eli mi nate a p pare nt 
i m m e diate h azar ds t o t h e s u bjects. 
I c o nfir m t h at I will re p ort all a d verse e ve nts ( A Es) f oll o wi n g t he re g ulati o ns i n di cate d i n 
t he pr ot oc ol. 
I c o nfir m t hat I will c o n d uct t his st u d y i n c o nf or ma nce wit h t he pri n ci ples of t h e 
Decl arati o n of Helsi n ki, Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A), 
G o o d Cli nical Practi ce ( G C P), a n d t he la ws a n d r e g ulati o ns of t he c o u ntr y w here t he st u d y 
is t o be c o n d ucte d. 
I c o nfir m t h at I a m i nf or me d of t h e n ee d f or rec or d ret e nti o n a n d t hat n o data ca n b e 
destr o ye d. 
B y m y si g nat ure bel o w, I here b y attest t hat I h a ve rea d, u n d erst o o d a n d a gr ee t o a bi d e b y 
all c o n diti o ns, i nstr ucti o ns a n d restricti o ns c o ntai ne d i n t his versi o n of t he pr ot oc ol 
date d 
 A pril 2 0 2 0. 
I n v esti g at or’s Si g n at ure:
Date:
m m/ d d/yyyy
Pri nte d N a me:


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
iii1 6 
SI G N A T U R E P A G E


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
i v1 6
P R O T O C O L S Y N O P SI S
N a me of S p o ns or C o m p a n y:
K o wa Researc h I nstit ut e, I nc. 
Dr u g U n der St u d y:
K- 2 8 5
Title of Pr ot o c ol: 
A P hase II, Ra n d o mize d, D o u ble- bli n d, Acti v e C o m parat or, Parallel Gr o u p St u d y t o E val uate 
t h e Efficac y a n d Safet y of K- 2 8 5 C o m pare d wit h M e nt h ol Gel f or t h e Treat m e nt of Dela ye d 
O nset M uscl e S ore ness ( D O M S) i n t he L o wer E xtre mit y
Pr ot oc ol N u m ber:
K- 2 8 5- 2 0 1
P h as e:
II
I n dic ati o n:
Ac ute pai n relief
St u d y Desi g n:
T his is a p hase II, ra n d o mize d, d o u ble- bli n d, acti ve c o m parat or, parallel gr o u p st u d y t o e val uat e 
t h e efficac y a n d safet y of K- 2 8 5 c o m pare d wit h me nt h ol gel f or t he treat me nt of dela ye d o nset 
m uscl e s ore ness ( D O M S) i n t he l o wer e xtre mit y. T he st u d y will c o nsist of scree ni n g, a n e xercise 
visit ( D O M S i n d ucti o n), i n- patie nt a n d o ut- pati e nt peri o ds u p t o 3 wee ks, a n d a f oll o w- u p 
tele p h o ne call. 
D uri n g t he Scree ni n g Visit, s u bjects will pr o vi de i nf or me d c o nse nt a n d c o m plete scree ni n g 
assess m e nts i ncl u di n g me dical hist or y, i d e ntificati o n of t he d o mi na nt le g, p h ysical a n d s ki n 
e xa mi n ati o ns, bl o o d a n d uri ne t ests, vit al si g ns meas ure me nts, el ectr ocar di o gra m ( E C G), a n d 
ot h er scree ni n g pr oce d ures. S u bjects w h o are a ble t o partici pate i n t he st u d y ( Peri o d 1 a n d 2) 
a n d w h o meet t he pre-e xercis e i ncl usi o n a n d e xcl usi o n criteri a will be e nr oll e d i nt o t he st u d y 
a n d ret ur n t o t he cli nic o n Da y - 1. 
Eli gi bilit y will be c o nfir me d a n d e nr oll e d s u bjects will perf or m a sta n dar dize d re petiti ve 
q ua dri ce ps m uscle e xercise t o creat e D O M S t o b ot h le gs ( Da y - 1). T he e xercise re gi me n will 
c o nsist of a war m- u p, deter mi nati o n of ma xi m u m t olerat e d wei g ht, a n d ti me d a n d u n-ti m e d 
w or k o ut p hases. Wit hi n 2 4 t o 3 0 h o urs after t he e xercise sessi o n ( Da y 1), s u bjects will rate t he 
pai n of b ot h le gs usi n g a cate g orical s cale a n d rec or d pai n i nte nsit y of b ot h le gs at rest a n d w hil e 
st a n di n g usi n g a 0- 1 0 0 p oi nt electr o ni c vis ual a nal o g scale (e V A S) (a ca pt ure pr o gra m will 
li nearl y c o n vert t he pi x el t o uc he d t o a n i nt e ger bet wee n 0 a n d 1 0 0) t o deter mi ne eli gi bilit y f or 
ra n d o mizati o n. 
 
 
 
 If b ot h l e gs meet p ost-e xercise i ncl usi o n criteri a, t he st u d y le g will b e t h e 
d o mi na nt le g, base d o n ha n d d o mi n a nce. S u bjects n ot q ualif yi n g f or ra n d o mizati o n will b e gi ve n 
a p pr o priate sta n dar d of care. 
A t otal of 2 4 0 s u bjects w h o meet p ost-e xercis e i ncl usi o n criteria will be ra n d o ml y assi g ne d i n a 
1: 1 rati o t o Treat me nt Ar m A ( K- 2 8 5 gel) or Treat me nt Ar m B ( Me nt h ol gel). 
 
 
 
 
.  


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
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Versi o n 1. 0 1 0 A pril 2 0 2 0 
v 1 6
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n Peri o d 1 (
 st u d y gels will be a p plie d t o ra n d o mize d s u bjects o n a
 
 o n t he st u d y le g as f oll o ws:  
Treat me nt Ar m A: Eac h s u bject will a p pl y K- 2 8 5 t o t he st u d y le g.
Treat me nt Ar m B: Eac h s u bject will a p pl y me nt h ol gel t o t h e st u d y le g.
T he first st u d y gel a p pli cati o n t o t he st u d y le g will be a p plie d b y t he s u bj ect wit h i n vesti gat or 
( or desi g nee) o versi g ht t o e ns ure pr o per a p plicati o n at t h e cli nic o n Da y 1 wit hi n 2 4 t o 3 0 h o urs 
after D O M S i n d ucti o n. S u bse q ue nt st u d y g el a p pli cati o ns at t he cli ni c will be a p plie d t o t he 
st u d y le g b y t he s u bject wit h i n vesti gat or ( or desi g nee) o versi g ht t o e ns ure pr o per a p pli cati o n. 
O n Da y 2, p h ot o gra p hic a n d resi d ue e val uati o n of t h e a p plicati o n site will be perf or me d pri or t o 
eac h st u d y gel a p pli cati o n. S u bj ects will re mai n i n t he cli nic u ntil t he y are disc har ge d f oll o wi n g 
c o m pleti o n of st u d y assess me nts o n Da y 2.  
Pai n i nte nsit y assess m e nts will be perf or me d f or t he st u d y le g a n d n o n-st u d y le g at rest a n d 
w hile sta n di n g usi n g a  0- 1 0 0 p oi nt e V A S o n Da y 1 at Baseli n e ( 0 h o urs ) a n d at 
 
 
after t he first st u d y gel a p plicati o n. Pai n assess m e nts sc he d ule d bet wee n mi d ni g ht a n d 6 a m m a y 
be s ki p pe d if s u bjects are aslee p b ut s u bj ects ma y n ot s ki p m ore t ha n t w o se q ue nti al assess me nts. 
A ti me wi n d o w of + 3 0 mi n ut es will be all o we d bet wee n q ualificati o n ( baseli ne assess m e nt) a n d 
first gel a p plicati o n ( 0 h o ur). T he f oll o wi n g ti me wi n d o ws will be all o we d f or eac h pai n 
assess m e nt ti me p oi nt: 
 
 
 
F oll o wi n g disc har ge fr o m t he cli nic o n Da y 2, s u bse q ue nt st u d y gel a p plicati o ns a n d pai n 
i nte nsit y assess me nts will be perf or me d b y t he s u bject o n a n o ut- pati e nt basis ( Da y 2 t hr o u g h 
Da y 8 ). S u bjects will be i nstr ucte d n ot t o s h o wer or bat he f or at least 3 0 mi n utes bef ore a n d at 
least 1 h o ur after gel a p plicati o n. All pai n i nte nsit y assess me nts will be rec or de d i n e- di aries 
t hr o u g h Da y 8 ( Peri o d 1), a n d all st u d y gel a p plicati o ns will be rec or de d i n e-diaries b y t he 
s u bj ect t hr o u g h Da y 2 2 ( Peri o d 1 a n d 2). A t ele p h o ne call will be c o n d ucte d b y st u d y staff o n 
Da y 5 ( ± 1 da y) t o assess safet y. S u bj ects will ret ur n t o t he cli nic f or assess me nts o n Da y 8 
( ± 1 da y). F or s u bjects w h o are assi g ne d t o recei ve st u d y gel f or 1 wee k, Da y 8 e n d of st u d y 
( E O S) ( + 1 da y) will be a cli nic visit a n d a f oll o w-u p tele p h o ne call t o assess safet y will be 
c o n d uct e d b y st u d y staff o n Da y 1 5 ( ± 1 da y). S u bjects w h o are assi g ne d t o recei ve st u d y gel f or 
3 wee ks will c o nti n ue t o a p pl y st u d y gel o n a n o ut- patie nt basis fr o m Da y 8 t o Da y 2 2 ( Peri o d 2) 


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
vi 1 6
acc or di n g t o t h eir assi g ne d d osi n g re gi me n (
 ( Ta ble 1 
). F or s u bjects w h o are 
d osi n g i n P eri o d 2, tele p h o n e calls t o assess safet y will be c o n d ucte d b y st u d y staff o n Da y 1 1 
( ± 1 da y) a n d Da y 1 8 ( ± 1 da y), st u d y gel a p pli cati o ns a n d use of a n y resc ue m e dicati o ns will 
be rec or de d i n e- diaries b y t he s u bjects t hr o u g h Da y 2 2, a n d a n e n d of st u d y ( E O S) cli nic visit 
will occ ur o n Da y 2 2 ( + 1 da y). A f oll o w- u p t ele p h o ne call t o assess safet y will be c o n d ucte d 
b y st u d y st aff o n Da y 2 9 ( ± 1 da y). 
Use of a n y res c ue m e dicati o n f or D O M S is str o n gl y dis c o ura ge d u ntil 1 6 8 h o urs ( Da y 8) after 
t h e first st u d y g el a p plicati o n, at w hic h ti me o ver-t he-c o u nter ( O T C) aceta mi n o p he n ( o ne 
5 0 0 m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue m e dicati o n f or 
D O M S is per mitte d if re q uire d. S u bjects e x perie nci n g se vere pai n or i na bilit y t o m o ve or wal k 
d ue t o pai n ma y be per mitte d t o use resc ue me dicati o n ( o ne 5 0 0 m g O T C aceta mi n o p he n ta blet 
t wice dail y, n ot m ore t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs after t he first st u d y gel a p plicati o n. 
If s u bjects ta ke resc ue me dicati o n bef ore t he first 1 6 8 h o urs, it will be ca pt ure d as a c o nc o mita nt 
me dicati o n, a n d s u bjects will rec or d t heir pai n i nte nsit y i n t he e- di ar y bef ore ta ki n g t he resc ue 
me dicati o n. T he n u m ber of ta blets ta ke n a n d t h e date a n d ti me will be rec or de d i n t h e e- di ar y.  
 
 
. T he i nteri m a nal ysis 
will assess f utilit y of t he trial (c o n diti o nal p o wer < 0. 0 5). If f utilit y is deter mi ne d, t h e st u d y will 
be ter mi nate d. If c o nti n uati o n of t he trial is deter mi ne d, s u bject e nr oll me nt will be res u me d. 
Pri m ar y O bjecti v e: 
T o e val uat e t he efficac y of K- 2 8 5 c o m pare d wit h m e nt h ol gel bet wee n 0 t o 2 4 h o urs aft er
t h e first gel a p plicati o n f or t he treat me nt of D O M S
Sec o n d ar y O bjecti ves: 
T o e val u at e t he efficac y of K- 2 8 5 c o m pare d wit h me nt h ol gel after t he first gel a p plicati o n
f or t he treat me nt of D O M S
T o e val uate t he s afet y a n d t olera bilit y of K- 2 8 5 c o m pare d wit h me nt h ol gel aft er t h e first
gel a p plicati o n f or t h e treat me nt of D O M S
S u bject P o p ul ati o n: 
T he st u d y p o p ulati o n will be a d ult m al e a n d fe male s u bjects a ge d 1 8 t o 3 5 years, i ncl usi ve, wit h 
a b o d y mass i n de x ( B MI) bet wee n 1 8 a n d 3 2 k g/ m 2, i ncl usi ve. 
N u m ber of S u bjects: 
T otal 2 4 0 s u bjects wit h 1 2 0 s u bjects i n eac h of t he 2 
treat m e nt ar ms (Ta ble 1 
).  
N u m ber of Ce nters:
1 sit e i n t he U nite d St at es 
D ose Le vels:
K- 2 8 5: 
Me nt h ol gel:
R o ute of A d mi nistr ati o n:
T o pical gel 
D ur ati o n of Tre at me nt: 
1 wee k d osi n g ( Peri o d 1): Eac h s u bject will a p pl y 
. 
 ( Peri o d 1 a n d 2): Eac h s u bject will a p pl y 
 
. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
vii
1 6   
 
Criteri a f or E v al u ati o n: 
Effic ac y:
Pri mar y E n d p oi nt: 
 
T he s u m of p ai n i nte nsit y differe nce ( S PI D) bet wee n 
) 
f or t h e st u d y le g after t h e first st u d y gel a p plicati o n w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S 
Sec o n dar y E n d p oi nts:
F or b ot h t he st u d y le g a n d t he n o n-st u d y le g 
 
S PI D 0- 2 4 h o urs after t he first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D bet wee n 0 ( Baseli ne) t o 1 2 h o urs ( S PI D 0- 1 2) after t he first st u d y gel a p pli cati o n w hile 
st a n di n g usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D 0- 1 2 h o urs after t he first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D bet wee n 0 ( Baseli ne) t o 4 8 h o urs ( S PI D 0- 4 8) after t he first st u d y gel a p pli cati o n w hile 
st a n di n g usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D 0- 4 8 h o urs after t he first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D bet wee n 0 ( Baseli ne) t o 7 2 h o urs ( S PI D 0- 7 2) after t he first st u d y gel a p pli cati o n w hile 
st a n di n g usi n g a 0- 1 0 0 p oi nt e V A S  
 
S PI D 0- 7 2 h o urs after t he first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
S afet y: 
Safet y assess me nts will i ncl u de a d verse e ve nts ( A Es), vital si g n m eas ure m e nts (s yst olic bl o o d 
press ure, diast olic bl o o d press ure, p ulse rate, res pirat or y rate, a n d oral b o d y t e m perat ure), E C G, 
p h ysical e xa mi nati o n fi n di n gs i ncl u di n g wei g ht, st u d y gel a p plicati o n site reacti o ns, cli ni cal 
la b orat or y t est res ults, st u d y gel use, a n d c o nc o mit a nt m e dicati o n use. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
viii
1 6
Criteri a f or I ncl usi o n: 
Pre-e xercise Criteri a f or I ncl usi o n:
1.
S u bject 
m ust pr o vi de i nf or me d c o nse nt bef ore a n y st u d y- s pecific e val uati o n is 
perf or me d. 
2.
S u bject is m al e a n d fe m al e a ge d 1 8 t o 3 5 years, i ncl usi ve. 
3.  S u bject has a b o d y mass i n d e x of 1 8 t o 3 2 k g/ m 2, i ncl usi ve  
 
 
 
 
6.
S u bject he mat ol o g y, ser u m c he mistr y, uri nal ysis, vit al si g n meas ure me nts (s yst olic 
bl o o d press ure, diast olic bl o o d press ure, p ulse rate, a n d oral b o d y te m perat ure) a n d 
1 2-lea d E C G res ults s h o w n o cli nicall y rele va nt a b n or malities, as j u d ge d b y t he 
i n vesti g at or at t h e Scree ni n g Visit. 
7.
All fe m ale s u bjects m ust ha ve a ne gati v e ser u m pre g na nc y test res ult at scree ni n g a n d 
ne gati v e uri ne pre g na nc y t est o n Da y - 1 pri or t o a d missi o n t o t he cli nic. Fe male s u bjects 
of c hil d beari n g p ote ntial m ust us e o ne of t he f oll o wi n g acce pta ble birt h c o ntr ol m et h o ds 
as s pecifie d bef ore e nr oll me nt a n d t hr o u g h o ut t he st u d y: 
a. S ur gical sterilizati o n ( bilateral t u bal li g ati o n, 
h ysterect o m y, 
bil ateral 
o o p h orect o m y) at least 6 m o nt hs bef ore t he first d ose of st u d y gel; 
b.
I ntra uteri ne de vice i n place f or at least 3 m o nt hs bef ore t he first d ose of st u d y 
gel a n d t hr o u g h o ut t he st u d y; 
c. Barrier met h o d (c o n d o m or dia p hra g m) wit h s per mici d e f or at least 1 4 da ys 
bef ore t h e first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y; 
d.
S ur gical sterilizati o n of t he male part ner ( vasect o m y at least 6 m o nt hs bef ore 
t h e first d ose of st u d y gel); 
e. H or m o nal c o ntrace pti ves f or at least 3 m o nt hs wit h a barrier met h o d 1 4 da ys 
bef ore t h e first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y; 
f. A bsti n e nce. 
8.  S u bject is a bl e a n d willi n g t o c o m pl y wit h t h e pr ot o c ol a n d st u d y pr oce d ures. 
9.
S u bject has n e gati ve test res ults f or dr u gs a n d al c o h ol at scree ni n g a n d is a ble a n d 
willi n g t o a bstai n fr o m marij ua na a n d alc o h ol use f or 4 da ys b ef ore Da y 1 a n d 
t hr o u g h o ut t he st u d y. N ot e t hat a p ositi v e scree ni n g res ult f or marij ua na is acce pta ble 
pr o vi de d t he s u bject will a bst ai n f or t h e st u d y as descri be d a b o ve. 
1 0. S u bject d oes n ot use nic oti ne or has q uit usi n g nic oti ne f or at least 6 m o nt hs bef ore t he 
first d ose of st u d y gel a n d will n ot use nic oti ne t hr o u g h o ut t he st u d y. 
 
 
 
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
i x
1 6   
 
Criteri a f or E xcl usi o n:
Pre-e xercise Criteri a f or E xcl usi o n:
 
 
 
 
 
3.
S u bject has recei ve d oral or t o pical a nal gesic me di cati o ns wit hi n 1 4 da ys bef ore t he 
Scree ni n g Visit.
4.
S u bject has use d a s yste mic c ortic oster oi d wit hi n 3 0 da ys bef ore t he Scree ni n g Visit. 
5.
S u bject has a me di cal hist or y t hat i n cl u des a c o ntrai n di cati o n f or t he use of me nt h ol or 
n o nster oi dal 
a nti- i nfl a m mat or y 
dr u gs ( N S AI Ds) (e. g., 
gastr oi ntesti n al 
ulcer, 
gastr oi ntesti n al blee di n g). 
6.
S u bject is ta ki n g me dicati o ns or ot her s u bst a nces c o ntrai n di cat e d beca use of t he nat ure 
of t he st u d y gel or t he p ote ntial f or dr u g i nteracti o ns. T his i ncl u des s u bjects wit h 
aller gies t o prescri pti o n or O T C pr o d ucts c o ntai ni n g me nt h ol or N S AI Ds. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 4.  S u bject is pre g na nt or n ursi n g. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
x
1 6
1 5. S u bject h as parti ci pate d i n a n i n vesti gati o nal dr u g st u d y wit hi n 3 0 da ys bef ore 
Scree ni n g. 
1 6. S u bject is a me m ber or a fa mil y me m ber of t he pr ofessi o nal or a ncillar y pers o n nel 
i n v ol ve d i n t h e st u d y. 
1 7. S u bject has partici pat e d i n ot her cli ni cal trials f or K- 2 8 5. 
1 8.  S u bject has a b n or mal fi n di n gs or assess m e nts t hat are cli nicall y n ot e w ort h y. 
1 9. S u bject w h o, i n t he o pi ni o n of t he i n vesti gat or, s h o ul d n ot partici pate i n t he st u d y.
St atisti c al A n al ysis:
I n g e neral, assess m e nts wit h c o nti n u o us o utc o m es will be s u m mari ze d usi n g t he descri pti ve 
st atisti cs n, mea n, st a n dar d de viati o n ( S D), me dia n, mi ni m u m a n d m a xi m u m. F or assess m e nts 
wit h cate g orical o utc o mes, fre q ue nc y c o u nts a n d perce nt a ge will be calc ulate d. Detaile d 
st atisti cal met h o d ol o g y will be prese nte d i n a se parate statistical a nal ysis pla n.  
St u d y P o p ul ati o ns: 
T hree a nal ysis p o p ulati o ns will be e val uate d:  
 
T he f ull a nal ysis set ( F A S) will i ncl u de all ra n d o mi ze d s u bjects w h o ha ve a b aseli ne pai n 
sc ore, a n d at least 1 st u d y gel a p pli e d  
 
T he p er- pr ot oc ol set ( P P S) will i ncl u de all ra n d o mize d s u bjects w h o ha ve a baseli ne pai n 
sc ore, at least 1 st u d y gel a p plie d, a n d n o maj or pr ot oc ol vi olati o ns. 
 
T he safet y set will i n cl u de all s u bjects w h o ha ve at least 1 st u d y gel a p plie d. 
Pri m ar y Effic ac y A n al ysis:   
T he pri m ar y a nal ysis p o p ulati o n is t he F A S. T he pri m ar y a nal ysis will be re pe ate d usi n g t he 
P P S. 
 
 
 
. If t here e xist missi n g V A S val u es t o be i m p ute d, a n y s uc h 
val ues will be i m p ute d bef ore cal c ulati n g t he S PI D. Aft er calc ulati n g t he S PI D, a n a nal ysis of 
c o varia nce ( A N C O V A) m o del will be a p plie d f or t he pri mar y e n d p oi nt wit h ge n der a n d 
treat me nt as mai n effects a n d baseli n e pai n as a c o variate.  
Sec o n d ar y Effic ac y A n al yses:  
A mi xe d effect m o del re peate d- meas ures ( M M R M) wit h t h e sa me m ai n effects a n d c o variate 
will be a p pli e d t o t he PI D w hile st a n di n g a n d PI D at rest t o i n vesti gate treat me nt differe nces. 
 
. T he ti me t o first d ose of resc ue me dicati o n, will be a nal yze d usi n g t he Ka pla n- Meier 
met h o d t o esti mate t he s ur vi val distri b uti o n f u ncti o n.  
S afet y: 
T he safet y e n d p oi nt data will be s u m marize d f or t he safet y set. A d verse e ve nts will be c o de d 
usi n g t h e latest versi o n of t he M e dical Di cti o nar y f or Re g ul at or y Acti vities ( Me d D R A). A d vers e 
e ve nts a n d s eri o us A Es ( S A Es) will be s u m marize d b y treat me nt gr o u p f or o verall n u m b er of 
A Es, se verit y, a n d rel ati o ns hi p t o st u d y gel. T he i nci de nce of A Es will be s u m m ari ze d b y b o d y 
s yste m a n d treat me nt gr o u p. T he i nci de nce of treat me nt-e mer ge nt A Es ( T E A Es) will als o be 
s u m marize d b y s yst e m or ga n cl ass a n d preferre d ter m. Cli nical la b orat or y res ults will be 
s u m marize d b y treat me nt gr o u p al o n g wit h c ha n ge fr o m Bas eli ne. Vital si g n meas ure m e nts will 
be s u m marize d b y gr o u p a n d ti me p oi nt al o n g wit h c ha n ge fr o m Baseli ne. All A E, cli nical 
la b orat or y, vital si g n, p h ysical e xa mi nati o n, st u d y gel a p plicati o n site reacti o n, st u d y gel use 
a n d c o nc o mita nt me dicati o n use will be prese nte d i n data listi n gs. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
xi
1 6   
 
 
 
 
 
 
 
 
.
S a m ple Size C alc ul ati o n:
T he para meters are c o nser vati vel y esti mate d base d o n t he D O M S st u d y wit h   
 gel. T he 
bet wee n- gr o u p differe nce i n t he m ea n   
 is 1 1. 0 7 wit h a S D of 2 5. 6 2. T o ha ve statistical 
p o wer of 9 0 %, 
. Ta ki n g i nt o acc o u nt i nf or mati o n l oss ca use d 
b y missi n g data, it is esti m at e d t hat 1 2 0 s u bjects nee d t o be treate d wit h eac h st u d y gel.  


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
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1 6
T A B L E O F C O N T E N T S
1. 0  
I N T R O D U C TI O N A N D R A TI O N A L E F O R D O S E S E L E C TI O N ............................ 1
1. 1   
B A C K G R O U N D I N F O R M A TI O N ................................................................................... 1  
1. 2   
R A TI O N A L E F O R S T U D Y A N D D O S E S E L E C TI O N ................................................... 2  
2. 0   
S T U D Y O B J E C TI V E S ..................................................................................................... 4  
2. 1   
P RI M A R Y O BJ E C TI V E .................................................................................................... 4  
2. 2   
S E C O N D A R Y O BJ E C TI V E S............................................................................................ 4  
2. 3   
P RI M A R Y E F FI C A C Y E N D P OI N T ................................................................................. 4  
2. 4   
S E C O N D A R Y E F FI C A C Y E N D P OI N T S ......................................................................... 4  
2. 5   
S A F E T Y E N D P OI N T S ...................................................................................................... 5  
3. 0   
S T U D Y D E S C RI P TI O N .................................................................................................. 6  
3. 1   
S T U D Y D E SI G N ............................................................................................................... 6  
4. 0   
S U B J E C T E LI GI BI LI T Y A N D WI T H D R A W A L C RI T E RI A ................................. 1 4  
4. 1   
I N C L U SI O N C RI T E RI A ................................................................................................. 1 4 
4. 1. 1  
Pre-e xercise I ncl usi o n Criteria .......................................................................................... 1 4  
4. 1. 2  
P ost-e xercis e Ra n d o mizati o n I ncl usi o n Criteria: .............................................................. 1 5  
4. 2   
E X C L U SI O N C RI T E RI A ................................................................................................ 1 5  
4. 3   
DI S C O N TI N U A TI O N A N D WI T H D R A W A L C RI T E RI A ............................................ 1 6  
4. 3. 1  
Disc o nti n uati o n d ue t o a n A p plicati o n Site Reacti o n ....................................................... 1 7  
5. 0   
P R O C E D U R E S F O R E F FI C A C Y A N D S A F E T Y E V A L U A TI O N S ....................... 1 8  
5. 1   
E F FI C A C Y E V A L U A TI O N S .......................................................................................... 1 8  
5. 1. 1  
Pai n I nte nsit y .................................................................................................................... 1 8  
5. 1. 1. 1  Vis ual A nal o g Scale .......................................................................................................... 1 8  
5. 1. 1. 2  Cate g orical Scal e .............................................................................................................. 1 8  
5. 1. 2  
Use of Resc ue Me dicati o n ................................................................................................ 1 8  
5. 1. 3  
Ti me t o O nset of First Perce pti ble a n d Mea ni n gf ul Pai n Relief ....................................... 1 9  
5. 1. 3. 1  O nset of Perce pti ble Pai n Relief ....................................................................................... 1 9  
5. 1. 3. 2  O nset of Mea ni n gf ul Pai n Relief ...................................................................................... 1 9  
5. 2   
S A F E T Y E V A L U A TI O N S .............................................................................................. 1 9  
5. 2. 1  
A d verse E ve nts ................................................................................................................. 1 9  
5. 2. 2  
Cli ni cal La b orat or y Tests .................................................................................................. 2 0  
5. 2. 2. 1  Ele vat e d Le vels of Ser u m Creati n e Ki nase....................................................................... 2 0  
5. 2. 3  
Vital Si g ns......................................................................................................................... 2 1  
5. 2. 4  
Electr ocar di o gra m ............................................................................................................. 2 1  
5. 2. 5  
P h ysical E xa mi nati o n ....................................................................................................... 2 1  
5. 2. 6  
S ki n E xa mi nati o n ( A p plicati o n Site Reacti o n) ................................................................. 2 1  
5. 2. 7  
C o nc o mita nt Me dicati o ns ................................................................................................. 2 2  
5. 3   
O T H E R E V A L U A TI O N S ................................................................................................ 2 2  
5. 3. 1  
De m o gra p hics, Me di cal Hist or y a n d Ot her Baseli ne C haracteristics ............................... 2 2  
5. 3. 2  
Dr u g a n d Al c o h ol Scree ni n g ............................................................................................. 2 2  
5. 3. 3  
Pre g na nc y.......................................................................................................................... 2 3  
5. 3. 4  
Sta n dar di ze d E xercise Re gi me n ....................................................................................... 2 3  
5. 3. 5  
P h ot o gra p h a n d Resi d ue E val uati o n ................................................................................. 2 3  
5. 3. 5. 1  P h ot o gra p hic A nal ysis ...................................................................................................... 2 3  
5. 3. 5. 2  Resi d ue E val u ati o n ........................................................................................................... 2 4  
5. 4   
T O T A L B L O O D V O L U M E............................................................................................. 2 4  
6. 0   
C O N D U C T O F S T U D Y ................................................................................................. 2 4  


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
xiii
1 6
6. 1  
S T U D Y B LI N DI N G A N D R A N D O MI Z A TI O N ............................................................ 2 4
6. 2   
S U BJ E C T I N F O R M E D C O N S E N T ................................................................................ 2 5  
6. 3   
S T U D Y VI SI T S ................................................................................................................ 2 6  
6. 4   
C O M P LI A N C E WI T H T H E P R O T O C O L ...................................................................... 3 2  
6. 5   
T E R MI N A TI O N O F T H E S T U D Y.................................................................................. 3 2  
7. 0   
S T U D Y M E DI C A TI O N ................................................................................................. 3 2  
7. 1   
D E S C RI P TI O N O F S T U D Y M E DI C A TI O N .................................................................. 3 2  
7. 2   
D R U G P A C K A GI N G ....................................................................................................... 3 3  
7. 3   
D R U G L A B E LI N G .......................................................................................................... 3 3  
7. 4   
D R U G S T O R A G E ............................................................................................................ 3 4  
7. 5   
DI S P E N SI N G A N D A D MI NI S T R A TI O N O F T R E A T M E N T ....................................... 3 4  
7. 5. 1  
Dis pe nsi n g of St u d y Gel ................................................................................................... 3 4  
7. 5. 2  
A p plicati o n Trai ni n g ......................................................................................................... 3 4  
7. 5. 3  
Dr u g A d mi nistrati o n ......................................................................................................... 3 4  
7. 5. 4  
e- Diar y .............................................................................................................................. 3 6  
7. 5. 5  
P h ysical E xercise .............................................................................................................. 3 6  
7. 6   
C O M P LI A N C E WI T H P R E S C RI B E D S T U D Y G E L D O SI N G R E GI M E N .................. 3 6  
7. 7   
D R U G A C C O U N T A BI LI T Y ........................................................................................... 3 6  
7. 8   
P R O C E D U R E F O R U N B LI N DI N G ................................................................................ 3 6  
8. 0   
C O N C O MI T A N T M E DI C A TI O N ............................................................................... 3 8  
8. 1   
G E N E R A L C O N SI D E R A TI O N S .................................................................................... 3 8  
8. 2   
P R O HI BI T E D M E DI C A TI O N A N D T H E R A PI E S ........................................................ 3 8  
8. 3   
P E R MI T T E D M E DI C A TI O N .......................................................................................... 3 8  
9. 0   
A D V E R S E E V E N T S ...................................................................................................... 3 9  
9. 1   
A D V E R S E E V E N T D E FI NI TI O N .................................................................................. 3 9  
9. 2   
R E P O R TI N G A D V E R S E E V E N T S ................................................................................ 3 9  
9. 3   
F O L L O W- U P O F A D V E R S E E V E N T S .......................................................................... 4 1  
1 0. 0  
S E RI O U S A D V E R S E E V E N T S .................................................................................... 4 2  
1 0. 1  
LI F E- T H R E A T E NI N G A D V E R S E E V E N T ................................................................... 4 2  
1 0. 2  
H O S PI T A LI Z A TI O N ....................................................................................................... 4 2  
1 0. 3  
I M P O R T A N T M E DI C A L E V E N T .................................................................................. 4 2 
1 0. 4  
P R E G N A N C Y .................................................................................................................. 4 2  
1 0. 5  
S U BJ E C T DI S C O N TI N U A TI O N A N D WI T H D R A W A L ............................................. 4 3  
1 0. 6  
S E RI O U S U N E X P E C T E D S U S P E C T E D A D V E R S E R E A C TI O N S............................. 4 3  
1 0. 7  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G ................................................................. 4 4  
1 1. 0  
S T A TI S TI C A L M E T H O D S A N D D A T A A N A L Y SI S ............................................... 4 5  
1 1. 1  
S A M P L E SI Z E J U S TI FI C A TI O N ................................................................................... 4 5  
1 1. 2  
S T U D Y P O P U L A TI O N S ................................................................................................. 4 5  
1 1. 3  
DI S P O SI TI O N .................................................................................................................. 4 5  
1 1. 4  
D E M O G R A P HI C/ B A S E LI N E I N F O R M A TI O N ............................................................ 4 5  
1 1. 5  
A N A L Y SI S O F E F FI C A C Y P A R A M E T E R S ................................................................. 4 5  
1 1. 5. 1  Pri mar y Efficac y Para meters ............................................................................................ 4 5  
1 1. 5. 2  Sec o n dar y Effi cac y Para met ers ........................................................................................ 4 6  
1 1. 6  
A N A L Y SI S O F S A F E T Y D A T A .................................................................................... 4 6  
1 1. 7  
I N T E RI M A N A L Y SI S ..................................................................................................... 4 7 
1 2. 0  
S T U D Y M A N A G E M E N T A N D D A T A C O L L E C TI O N ............................................ 4 8  
1 2. 1  
E T HI C A L C O N D U C T O F T H E T RI A L ......................................................................... 4 8  
1 2. 2  
I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T E T HI C S C O M MI T T E E ........ 4 8 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
xiv
1 6   
 
1 2. 3 
S U BJ E C T I N F O R M E D C O N S E N T ................................................................................ 4 8
1 2. 4  
A M E N D M E N T S T O T H E P R O T O C O L ......................................................................... 4 9  
1 2. 5  
S T U D Y I NI TI A TI O N ...................................................................................................... 4 9  
1 2. 6  
S T U D Y M O NI T O RI N G .................................................................................................. 4 9  
1 2. 7  
C A S E R E P O R T F O R M .................................................................................................... 5 0  
1 2. 8  
V E RI FI C A TI O N P R O C E D U R E S.................................................................................... 5 0  
1 2. 9  
R E T E N TI O N O F R E C O R D S........................................................................................... 5 0  
1 2. 1 0  I N S U R A N C E A N D I N D E M NI T Y .................................................................................. 5 1 
1 2. 1 1  A U DI T .............................................................................................................................. 5 1  
1 3. 0  
U S E O F I N F O R M A TI O N ............................................................................................. 5 2  
1 3. 1  
G E N E R A L A S P E C T S ...................................................................................................... 5 2  
1 3. 2  
S U BJ E C T C O N FI D E N TI A LI T Y A N D D A T A P R O T E C TI O N ..................................... 5 2  
1 3. 3  
FI N A L R E P O R T A N D P U B LI C A TI O N P O LI C Y .......................................................... 5 2  
1 4. 0  
R E F E R E N C E S ................................................................................................................ 5 4  
1 5. 0  
A P P E N DI C E S ................................................................................................................. 5 5  
1 5. 1  
A P P E N DI X 1 ................................................................................................................... 5 5  
VI S U A L A N A L O G S C A L E ( E X A M P L E O F P A P E R V A S) ...................................................... 5 5  
VI S U A L A N A L O G S C A L E ( E X A M P L E O F E L E C T R O NI C V A S) .......................................... 5 6  
1 5. 2  
A P P E N DI X 2 ................................................................................................................... 5 7  
C A T E G O RI C A L P AI N S C A L E A S S E S S M E N T ......................................................................... 5 7  
1 5. 3  
A P P E N DI X 3 ................................................................................................................... 5 8  
K- 2 8 5- 2 0 1 A P P LI C A TI O N I N S T R U C TI O N S ............................................................................. 5 8  
1 5. 4  
A P P E N DI X 4 ................................................................................................................... 6 0  
E X A M P L E I M A G E S O F A P P LI C A TI O N SI T E R E A C TI O N S .................................................. 6 0  
 
List of T a bles 
Ta ble 1: Treat me nt Assi g n m e nt ....................................................................................................... 7  
Ta ble 2: Cli nical E val u ati o n Sc he d ule ........................................................................................... 1 0  
Ta ble 3. Cli nical La b orat or y Test Para meters ............................................................................... 2 0  
 
List of Fi g ures
Fi g ure 1. St u d y Sc he m a ................................................................................................................... 9  
Fi g ure 2. St u d y Gel All ocati o n ...................................................................................................... 3 3  
Fi g ure 3: Meas uri n g St u d y Gel ...................................................................................................... 3 5  
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
x v
1 6
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S
A PI  
acti v e p har m ace utical i n gre di e nts 
A E  
a d v erse e ve nt
A L T  
ala ni ne a mi n otra nsferas e
A N C O V A
a nal ysis of c o varia nce
A S T  
as partate a mi n otra nsferas e
A U C  
area u n d er t h e c ur ve 
B MI  
b o d y mass i n de x
C F R  
C o de of Fe d eral Re g ulati o ns
C K  
creati ne ki n ase
C K- M B  
creati ne ki n ase- m y ocar di al ba n d 
C K- M M  
creati ne ki n ase i n s k eletal m uscle 
C ma x
ma xi m u m c o nce ntrati o n 
C O X(- 2)  
c ycl o o x y ge nase i n hi bit ors
C R F  
case re p ort/rec or d f or m 
C R O  
C o ntract R esearc h Or ga nizati o n
D O M S  
dela ye d o nset m uscle s ore ness
E C G  
electr ocar di o gra m
e C R F  
electr o nic Cas e Re p ort/ R ec or d F or m 
e- diar y  
electr o nic diar y de vic e 
e V A S  
electr o nic vis ual a nal o g s cale 
E T  
earl y ter mi nati o n 
F A S  
f ull a nal ysis set
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P   
G o o d Cli nical Practi ce 
GI  
gastr oi ntesti nal
I C F  
i nf or me d c o nse nt f or m
I C H  
I nter nati o nal C o u ncil f or Har m o nis ati o n 
I E C  
I n d e pe n de nt Et hics C o m mittee
I R B   
I nstit uti o nal Re vie w B o ar d


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0   
   
   
   
   
   
   
   
   
x vi
1 6   
 
K RI   
K o wa Researc h I nstit ute, I n c.
L D H  
lactate de h y dr o ge nase 
L O C F  
last o bser vati o n carrie d f or war d
M A R   
missi n g at ra n d o m
M D M A  
3, 4- met h yle ne di o x y- met ha m p heta mi ne ( E cstas y)
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities 
MI   
m ulti ple i m p utati o n
M T W   
Ma xi m u m t olerate d wei g ht
N S AI D  
n o n-ster oi dal a nti-i nfla m mat or y dr u g
O T C  
o ver-t he-c o u nter
P C P  
p he nc ycli di ne
PI D  
pai n i nte nsit y differe n ce
P K  
p har mac o ki n etics 
P P S   
per- pr ot oc ol s et 
S A E  
Seri o us A d verse E v e nt 
S D  
sta n dar d de viati o n 
S O P  
St a n dar d O perati n g Pr oce d ure/s
S PI D   
s u m of pai n i nte nsit y differe nce
S PI D 0- 1 2 
s u m of pai n i nte nsit y differe nce o v er 1 2 h o urs after t he first gel a p plicati o n  
S PI D 0- 2 4 
s u m of pai n i nte nsit y differe n ce o v er 2 4 h o urs after t he first gel a p plicati o n
S PI D 0- 4 8 
s u m of pai n i nte nsit y differe nce o ver 4 8 h o urs after first gel a p plicati o n
S PI D 0- 7 2 
s u m of p ai n i nte nsit y differe nce o ver 7 2 h o urs after first gel a p plicati o n
S T E  
s h ort ti me e x p os ure
S U S A R  
Seri o us U ne x pect e d S us pect e d A d v erse Re acti o n
T E A E  
Treat me nt-e mer ge nt A E 
T R P  
tra nsie nt rec e pt or p ote nti al
(e) V A S  
(electr o ni c) vis ual a nal o g scale
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 of 6 0 
 
1. 0
I N T R O D U C TI O N A N D R A TI O N A L E F O R D O S E S E L E C TI O N
1. 1  
B A C K G R O U N D I N F O R M A TI O N 
N o n-ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds), i ncl u di n g n o n-selecti ve N S AI Ds a n d 
t he m ore selecti ve c ycl o o x y ge nase ( C O X- 2) i n hi bit ors, are e xte nsi vel y use d i n t he U nite d 
States a n d rest of w orl d f or t h e relief of pai n a n d t he re d u cti o n of i nfla m mati o n. T his class 
of me dicati o ns is t he m ost wi d el y use d w he n prescri pti o n a n d o ver-t h e-c o u nter ( O T C) 
pr o d ucts are c o nsi dere d. H o we v er, its oral us e is n ot wit h o ut ris k, w hi c h m ost n ota bl y 
i ncl u des t o xicit y ass ociate d wit h gastr oi ntesti nal ( GI) i nfla m mati o n a n d blee di n g. 
Half of patie nts ta ki n g N S AI Ds re g ularl y ha v e e n d osc o picall y c o nfir me d g astric er osi o ns, 
a n d 1 0 %- 3 0 % h a ve ulc ers. 1 T hese ris ks are a m plifie d i n hi g h ris k gr o u ps, i ncl u di n g t he 
el derl y, t h ose 
wit h pre-e xisti n g gastr o pat h y, c hr o nic a d mi nistrati o n, c o nc o mit a nt 
c ortic oster oi d use a n d Helic o bacter p yl ori i nfecti o n pri or t o N S AI D t hera p y. 2 T he use of 
selecti v e C O X- 2 i n hi bit ors, pr u de nt use of pr ot o n p u m p i n hi bit ors, a n d alter nati ve 
me dicati o ns ha ve i m pr o ve d t he i nci de nce of g astr o pat h y, b ut ha ve n ot eli mi n ate d it.
C O X- 2 i n hi bit ors still de m o nstrate a si g nifica nt ris k of GI c o m plicati o ns. 3  
T he wi d es prea d use of O T C N S AI Ds, w hic h i ncl u des all n o n-selecti ve C O X i n hi bit ors, 
p oses a great ris k of GI c o m plicati o ns. Rece nt acti vit y has als o s h o w n t he p ote ntial f or 
car di o vasc ular ris k fr o m t he s yste mic use of C O X- 2 i n hi bit ors, w hic h was hi g hli g hte d b y 
t he 2 0 0 4 wit h dra wal of r ofec o xi b ( Vi o x x® ). Wit h t his bac k gr o u n d, t here is a nee d f or safer 
alter nati ves t o orall y a d mi nistere d N S AI Ds, es peciall y f or t h ose i n hi g her ris k gr o u ps, or 
t h ose i nt olera nt of orall y a d mi nistere d N S AI Ds.  
T o pical a nal g esics offer a n alter n ati v e t o t he us e of s yste mic N S AI Ds f or relief of f ocal
pai n a n d i nfla m mati o n. T hese fall i nt o se veral cate g ories, i ncl u di n g a nest hetics, 
c o u nterirrita nts a n d a nal gesics. T he first t w o cate g ories are ill ustrate d b y t h e a p pr o v e d 
li d ocai n e 5 % p atc h ( Li d o der m® ), a n d ca psaici n, res pecti vel y. Fle ct or ®  ( dicl ofe nac 
e p ola mi ne t o pical p atc h 1. 3 %) is a n e x a m ple of a prescri pti o n N S AI D a nal gesic patc h. A 
meta-a n al ysis of 2 6 d o u ble- bli n d place b o-c o ntr olle d 
N S AI Ds trials t hat e nr olle d
2, 8 5 3 patie nts de m o nstrate d t hat i n 1 9/ 2 6 tri als t h e N S AI D was s u peri or t o place b o a n d 
was s h o w n t o be safe. 4
l- Me nt h ol is a nat urall y occ urri n g c yclic m o n oter pe ne alc o h ol of pla nt ori gi n. Its use 
e xte n ds fr o m c uli nar y ite ms t o c os metic pr o d ucts t o p har mace utic al i n gre die nts. 
Wit h 
re gar ds t o its 
me dici n al p ur p oses, b ot h pres cri b e d a n d 
O T C 
me nt h ol c o ntai ni n g 
me dicati o ns are c urre ntl y a vaila ble t hr o u g h o ut t he w orl d f or a h ost of c o n diti o ns, i ncl u di n g 
res pirat or y dise ases, GI dis or ders, c o m m o n c ol d, a n d m usc ul os keletal pai n. It is als o 
c o m m o nl y use d as part of a nal g esic, a ntis e pti c, t o pical a nti pr uritic, a n d c o u nterirrita nt 
pr o d ucts. Its a bilit y t o m o d ulate Tra nsie nt Rece pt or P ote ntial ( T R P) cati o n c ha n nels a n d 
n u mer o us 
ot her i o n 
c ha n nels 
m a y 
u n derlie its 
re p ute d 
a nal gesic 
effects. 5
Me nt h ol-c o ntai ni n g O T C 
m e dicati o ns are c urre ntl y 
mar kete d i n t h e U S as t o pical 
a nal gesics at c o n ce ntr ati o ns u p t o 1 6 % l- me nt h ol i n t he U S.  


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 of 6 0 
 
1. 2   
R A TI O N A L E F O R S T U D Y A N D D O S E S E L E C TI O N
K o wa C o m pa n y Lt d. h as de vel o pe d K- 2 8 5, a pr o d uct c o ntai ni n g 
 
 f or relief of p ai n d ue t o m uscle 
s ore ness, s prai ns a n d strai ns. 
T he acti ve p h ar mace utical i n gre die nts ( A PI) i n K- 2 8 5 t o pical gel are 
 
 T he m e nt h ol gel c o ntai ns 
.  
 
 
 
 
 
 
 
 
 
 
 
.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 of 6 0 
 
T he 
m ost c o m m o nl y re p orte d treat me nt-relate d, treat m e nt-e mer g e nt a d v erse e v e nts 
( T E A Es) (i. e., t h ose re p orte d b y m ore t h a n 2 s u bj ects o verall) were a p plicati o n sit e pai n, 
a p plicati o n site er yt h e ma, a p plicati o n site disc ol orati o n, a p plicati o n site e xf oli ati o n, 
a p plicati o n site pr urit us, a n d a p plicati o n site dr y n ess. All T E A Es re p ort e d were mil d i n 
se verit y. T here were n o m o derate or se v ere T E A Es, seri o us a d verse e ve nts ( S A Es), or 
deat hs re p orte d d uri n g t h e st u d y. O ne s u bject ( 6. 7 %) disc o nti n ue d fr o m t he st u d y d ue t o a 
treat me nt-relate d T E A E of a p plicati o n site disc har ge. All T E A Es were res ol ve d b y t he e n d 
of t he st u d y. Der mat ol o gical fi n di n gs relate d t o t he a p plicati o n site were re p orte d as 
T E A Es, b ut t hese e ve nts a n d cli nical l a b orat or y ass ess me nts, vital si g n meas ure me nts, 
electr ocar di o gra m ( E C G) assess me nts, a n d p h ysical e x a mi n ati o ns were n ot c o nsi dere d 
cli nicall y si g nifica nt. M ulti ple a p plicati o ns of K- 2 8 5 were s afe a n d g e nerall y well t olerate d 
b y healt h y s u bjects i n t his st u d y.  
Base d o n t he P h ase 1 st u d y res ults, t h e d os a ge of K- 2 8 5, 
 
s h o we d hi g her 
, a n d t h us was s electe d t o e val uate effic ac y a n d s afet y at 
1 wee k ( Peri o d 1). F or P eri o d 2, b ot h t he 
) 
d osi n g re gi me ns were selecte d t o e val uate t he a d diti o nal safet y pr ofile at 2 wee ks. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 of 6 0 
 
2. 0
S T U D Y O B J E C TI V E S
2. 1  
P RI M A R Y O B J E C TI V E
T he pri m ar y o bjecti v e is t o e val uate t he efficac y of K- 2 8 5 c o m pare d wit h me nt h ol gel 
bet wee n 0 t o 2 4 h o urs after t he first g el a p plicati o n f or t he treat me nt of dela ye d o ns et 
m uscle s ore ness ( D O M S). 
2. 2  
S E C O N D A R Y O B J E C TI V E S 
T he sec o n d ar y o bjecti v es are: 
 
T o e val uat e t he effi cac y of K- 2 8 5 c o m pare d wit h me nt h ol gel aft er t he first gel 
a p plicati o n f or t he treat m e nt of D O M S
T o e val u ate t he safet y a n d t olera bilit y of K- 2 8 5 c o m pare d wit h me nt h ol g el aft er first 
gel a p pli cati o n f or t he treat me nt of D O M S 
2. 3  
P RI M A R Y E F FI C A C Y E N D P OI N T 
Pri mar y E n d p oi nt: 
 
T he s u m of pai n i nte nsit y differe nce 
 
 f or t h e st u d y le g after t h e first st u d y gel a p plicati o n w hile sta n di n g usi n g a 
0- 1 0 0 p oi nt electr o nic vis ual a nal o g scale (e V A S) 
2. 4  
S E C O N D A R Y E F FI C A C Y E N D P OI N T S
Sec o n dar y E n d p oi nts: 
F or b ot h t he st u d y le g a n d t he n o n-st u d y le g 
 
S PI D 0- 2 4 h o urs after t h e first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S
 
S PI D bet wee n 0 ( Baseli n e) t o 1 2 h o urs ( S PI D 0- 1 2) after t h e first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S 
S PI D 0- 1 2 h o urs after t h e first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S
 
S PI D bet wee n 0 ( Baseli n e) t o 4 8 h o urs ( S PI D 0- 4 8) after t h e first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S 
 
S PI D 0- 4 8 h o urs after t h e first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S
 
S PI D bet wee n 0 ( Baseli n e) t o 7 2 h o urs ( S PI D 0- 7 2) after t h e first st u d y gel a p plicati o n 
w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S 
 
S PI D 0- 7 2 after t h e first st u d y gel a p plicati o n at rest usi n g a 0- 1 0 0 p oi nt e V A S 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 of 6 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
2. 5  
S A F E T Y E N D P OI N T S 
Safet y assess m e nts will i ncl u de a d v erse e ve nts ( A Es), vit al si g n meas ure me nts (s yst olic 
bl o o d press ure, diast oli c bl o o d press ure, p ulse rate, res pirat or y rate, a n d oral b o d y 
te m perat ure), E C G, p h ysical e xa mi nati o n fi n di n gs i ncl u di n g wei g ht, st u d y gel a p plicati o n 
site reacti o ns (i ncl u di n g via a n irrit ati o n rati n g scal e), cli nical la b orat or y test res ults, st u d y 
gel use, a n d c o n c o mita nt me dicati o n use. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 6 of 6 0 
 
3. 0  
S T U D Y D E S C RI P TI O N
3. 1  
S T U D Y D E SI G N
T his is a p has e II, ra n d o mize d, d o u ble- bli n d, acti ve c o m parat or, p arall el gr o u p st u d y t o 
e val uate t he effi cac y a n d safet y of K- 2 8 5 c o m p are d wit h me nt h ol gel f or t h e treat m e nt of 
D O M S i n t h e l o wer e xtre mit y.
T he st u d y will c o nsist of scree ni n g, a n e xercise visit ( D O M S i n d ucti o n), i n- patie nt a n d 
o ut- patie nt peri o ds u p t o 3 wee ks, a n d a f oll o w- u p tele p h o ne call. D uri n g t h e S cree ni n g 
Visit, s u bjects will pr o vi de i nf or me d c o nse nt a n d c o m plete s cree ni n g assess me nts 
i ncl u di n g m e dical hist or y, i de ntificati o n of t he d o mi na nt le g as deter mi n e d b y ha n d 
d o mi n a nce, p h ysical a n d s ki n e xa mi nati o ns, bl o o d a n d uri ne tests, vital si g ns 
meas ure me nts, E C G, a n d ot her scree ni n g pr oce d ures. S u bjects w h o are a ble t o parti ci pate 
i n t h e st u d y ( Peri o d 1 a n d 2) a n d w h o meet t he pre-e xercis e i ncl usi o n a n d e xcl usi o n crit eria 
will be e nr olle d i nt o t h e st u d y a n d ret ur n t o t h e cli nic o n Da y - 1. Eli gi bilit y will b e 
c o nfir me d a n d e nr olle d s u bjects will perf or m a sta n dar dize d re petiti ve q ua drice ps m uscl e 
e xercis e t o creat e D O M S t o b ot h le gs ( Da y - 1). T he e xercise re gi m e n will c o nsist of a 
war m- u p, d eter mi nati o n of ma xi m u m t olerate d wei g ht, a n d ti me d a n d u n-ti me d w or k o ut 
p hases. 
Wit hi n 2 4 t o 3 0 h o urs aft er t h e e x ercis e sessi o n ( Da y 1), s u bjects will rat e t he pai n of b ot h 
le gs usi n g a cate g orical scale a n d rec or d p ai n i nte nsit y of b ot h le gs at rest a n d w hile 
sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S (a ca pt ure pr o gra m will li nearl y c o n vert t he pi xel 
t o uc he d t o a n i nte ger b et wee n 0 a n d 1 0 0) t o d eter mi n e eli gi bilit y f or ra n d o mizati o n. T he 
s pecific p ost-e x ercise   
 i ncl usi o n crit eri o n will be mas ke d t o s u bjects.  
 
 
 
 If b ot h le gs meet p ost-e xercise i ncl usi o n criteria, t he st u d y le g will be t he 
d o mi n a nt l e g, base d o n h a n d d o mi na nce. S u bjects n ot q ualif yi n g f or ra n d o mizati o n will be 
gi ve n a p pr o priate sta n d ar d of care. A t otal of 2 4 0 s u bjects w h o meet p ost-e xercise 
i ncl usi o n criteria will be ra n d o ml y assi g ne d i n a 1: 1 rati o t o Treat m e nt Ar m A ( K- 2 8 5 gel) 
or Treat me nt Ar m B ( Me nt h ol gel). 
 
 
 
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 7 of 6 0 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 o n t he st u d y le g as f oll o ws:
 
Treat m e nt Ar m A: Eac h s u bject will a p pl y K- 2 8 5 t o t he st u d y le g.  
 
Treat m e nt Ar m B: Eac h s u bject will a p pl y me nt h ol gel t o t he st u d y le g. 
T he first st u d y gel a p plicati o n t o t he st u d y le g
will b e a p plie d b y t he s u bject wit h 
i n vesti gat or ( or d esi g nee) o versi g ht t o e ns ure pr o per a p pli cati o n at t he cli nic o n Da y 1 
wit hi n 2 4 t o 3 0 h o urs after D O M S i n d ucti o n. S u bse q ue nt st u d y gel a p plicati o ns at t h e cli nic 
will b e a p plie d t o t h e st u d y le g b y t he s u bject wit h i n vesti gat or ( or d esi g nee) o versi g ht t o 
e ns ure pr o p er a p plicati o n. O n Da y 2, p h ot o gra p hic a n d resi d ue e val uati o n of t he 
a p plicati o n site will be p erf or me d pri or t o eac h st u d y gel a p plicati o n. S u bj ects will re mai n 
i n t h e cli nic u ntil t h e y are disc har ge d f oll o wi n g c o m pleti o n of st u d y assess me nts o n Da y 2. 
Pai n i nte nsit y assess me nts will be p erf or me d f or t he st u d y le g a n d n o n-st u d y le g at rest a n d 
w hile sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S o n Da y 1 at Baseli ne ( 0 h o urs) a n d at   
 
 
after t h e first st u d y gel a p plicati o n. Pai n assess m e nts sc he d ule d bet wee n mi d ni g ht 
a n d 6 a m ma y be s ki p pe d if s u bjects are aslee p b ut s u bjects ma y n ot s ki p m ore t ha n t w o 
se q ue nti al assess me nts. A ti m e wi n d o w of + 3 0 mi n utes will be all o we d b et wee n q u alif yi n g 
pai n assess m e nts a n d first st u d y gel a p plicati o n ( 0 h o urs).  
T he f oll o wi n g ti me wi n d o ws will be all o we d f or eac h pai n assess m e nt ti m e p oi nt: 
± 1 5 mi n utes f or assess me nts fr o m 1 t o 1 2 h o urs ( Da y 1), ± 3 0 mi n utes f or assess me nts at 
1 8 t hr o u g h 2 4 h o urs ( Da y 2), a n d ± 1 h o ur f or ass ess me nts at 3 6 t o 1 6 8 h o urs ( Da y 2 t o 
Da y 8). F oll o wi n g disc h ar ge fr o m t he cli nic o n Da y 2, s u bse q ue nt st u d y gel a p plicati o ns 
a n d pai n i nte nsit y assess me nts will be perf or me d b y t he s u bject o n a n o ut- patie nt basis 
( Da y 2 t hr o u g h Da y 8). S u bjects will be i nstr ucte d n ot t o s h o wer or bat he f or at least 
3 0 mi n utes b ef ore a n d at least 1 h o ur after gel a p plicati o n.  
All pai n i nte nsit y assess me nts will b e rec or d e d i n e- diaries t hr o u g h Da y 8 ( Peri o d 1), a n d 
all st u d y gel a p plicati o ns will be rec or de d i n t he e- diar y b y t he s u bject t hr o u g h Da y 2 2 
( Peri o d 1 a n d 2). A tele p h o ne call will be c o n d ucte d b y st u d y staff o n Da y 5 ( ± 1 da y) t o 
assess safet y. S u bjects will ret ur n t o t he cli nic f or assess me nts o n Da y 8 ( ± 1 da y). F or 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 8 of 6 0 
 
s u bjects w h o are assi g ne d t o recei ve st u d y gel f or 1 wee k, Da y 8 ( + 1 da y) will be a n e n d 
of st u d y ( E O S) cli nic visit a n d a f oll o w- u p t ele p h o ne call t o assess s afet y will be c o n d ucte d 
b y st u d y staff o n Da y 1 5 ( ± 1 da y). S u bjects w h o are assi g ne d t o recei v e st u d y gel f or 
3 wee ks will c o nti n ue t o a p pl y st u d y gel o n a n o ut- patie nt basis fr o m Da y 8 t o Da y 2 2 
( Peri o d 2) acc or di n g t o t heir assi g ne d d osi n g re gi me n (  
) (Ta bl e 1 : Treat me nt 
Assi g n me nt). F or s u bjects w h o are d osi n g i n Peri o d 2, tele p h o ne calls t o ass ess safet y will 
be c o n d ucte d b y st u d y staff o n Da y 1 1 ( ± 1 da y) a n d Da y 1 8 ( ± 1 d a y), st u d y gel a p plicati o ns 
a n d use of a n y resc u e m e dicati o ns will be rec or d e d i n e- diaries b y t he s u bjects t hr o u g h 
Da y 2 2, a n d a n e n d of st u d y ( E O S) cli nic visit will occ ur o n Da y 2 2 ( + 1 d a y). A f oll o w- u p 
tele p h o ne call t o assess safet y will be c o n d u cte d b y st u d y staff o n Da y 2 9 ( ± 1 da y). 
Use of a n y resc ue me di cati o n f or D O M S is str o n gl y disc o ura ge d u ntil 
) 
after t he first st u d y gel a p plicati o n, at w hic h ti me o ver-t he-c o u nter ( O T C) aceta mi n o p he n 
( o ne 5 0 0 m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t h a n e ver y 6 h o urs) as resc ue 
me dicati o n f or D O M S is per mitte d if re q uire d. S u bjects e x perie nci n g se vere p ai n or 
i na bilit y t o m o ve or wal k d ue t o pai n m a y b e per mitte d t o use res c ue me dicati o n 
( o ne 5 0 0 m g O T C aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) pri or t o 
1 6 8 h o urs after t he first st u d y gel a p plicati o n. If s u bjects ta ke res c ue me dicati o n bef ore t he 
first 1 6 8 h o urs, it will be ca pt ure d as a c o n c o mita nt me dicati o n, a n d s u bjects will rec or d 
t heir pai n i nte nsit y i n t he e- diar y b ef ore ta ki n g t he resc u e me dicati o n. T he n u m ber of 
ta blets ta ke n a n d t he d ate a n d ti me will be rec or de d i n t h e e- diar y. 
W he n 
 
 
. T he 
i nteri m a nal ysis will ass ess f utilit y of t he trial (c o n diti o nal p o wer < 0. 0 5). If f utilit y is 
deter mi n e d, t h e st u d y will be ter mi nate d. If c o nti n uati o n of t h e trial is deter mi n e d, s u bject 
e nr oll me nt will be res u m e d. 
A st u d y sc he matic is s h o w n i n Fi g ure 1 . T he s c he d ule of assess me nts is s h o w n i n Ta ble  2 .  
 


C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 9 of 6 0
 
 
 
 
 
 
 


C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 0 of 6 0
 
T a ble 2: Cli nic al E v al u ati o n Sc he d ule
A S S E S S M E N T S 
P E R F O R M E D 
Scree ni n g 
Visit 
E xercise 
Visit 
Peri o d 1 
Peri o d 2 
E O S 
Visit/ E T j 
F oll o w- 
u p call 
I n
p atie nt 
O ut
p atie nt 
Safet y 
Visit 
O ut
p atie nt 
Safet y
Visit 
O ut
p atie nt
Da y 
- 3 0 t o - 2 
- 1 
1 
2 
3- 8 
8 
( ± 1 d a y)
9- 1 4 
1 5 
( ± 1 d a y)
1 6- 2 2 
8 or 2 2 
( + 1 da y) 
1 5 or 2 9 
( ± 1 d a y)  
I nf or me d c o nse nt
X
De m o gra p h y 
X 
 
 
 
 
 
 
 
 
 
 
Me dical/ m e dicati o n 
hist or y 
X 
X 
 
 
 
 
 
 
 
 
 
Pre-e x ercise i n cl usi o n 
criteria, e x cl usi o n 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
A d missi o n t o cli nic a
X 
 
 
 
 
 
Disc h ar ge fr o m cli nic a 
 
 
 
X 
 
 
 
 
 
 
 
Visit t o cli nic ( o ne 
d a y) 
X 
X 
 
 
 
X 
 
X 
 
X 
 
T ele p h o ne Call ( Da ys 
5, 1 1, 1 8, a n d Da y 1 5 
or 2 9) b
 
 
 
 
X 
 
X
 
 
X 
 
 
X 
Pre-e x ercise pai n 
assess me nt ( pa p er 
V A S) 
 
X 
 
 
 
 
 
 
 
 
 
D O M S i n d u cti o n 
e xercise 
 
X 
 
 
 
 
 
 
 
 
 
e- diar y, st u d y trai ni n g
X
Iss u e e- diar y
X
V A S Q u alif yi n g Pai n 
assess me nts c
 
 
X 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 1 of 6 0
A S S E S S M E N T S 
P E R F O R M E D 
Scree ni n g 
Visit 
E xercise 
Visit 
Peri o d 1 
Peri o d 2 
E O S 
Visit/ E T j 
F oll o w- 
u p call 
I n  
p atie nt 
O ut 
p atie nt 
Safet y 
Visit 
O ut 
p atie nt 
Safet y 
Visit 
O ut 
p atie nt
Da y 
- 3 0 t o - 2 
- 1 
1 
2 
3- 8 
8 
( ± 1 d a y)
9- 1 4 
1 5 
( ± 1 d a y)
1 6- 2 2 
8 or 2 2 
( + 1 da y) 
1 5 or 2 9 
( ± 1 d a y)  
Cate g orical 
Q u alif yi n g Pai n 
assess me nts c  
 
 
X 
 
 
 
 
 
 
 
 
P ost-e x ercise 
i ncl usi o n criteria 
 
 
X 
 
 
 
 
 
 
 
 
Ra n d o mizati o n
X
 
 
 
 
Hei g ht a n d wei g ht
X
Vital si g ns d
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Electr o car di o gra m
X
X
 
 
 
X  
 
P h ysical e x a mi n ati o n 
X 
X 
 
 
 
X
X
X
S ki n e xa mi n ati o n /
assess me nt at st u d y 
g el site
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Pre g na n c y test e 
X
X
X
Uri n e dr u g scree n a n d 
alc o h ol test 
X 
X 
 
 
 
 
 
 
 
 
 
Cli nical la b orat or y 
tests ( he mat ol o g y, 
ser u m c h e mistr y, a n d 
uri n al ysis)
X
X
V A S pai n i nte nsit y 
assess me nt c
 
 
X 
X 
X 
X 
 
 
 
( X) k
Perce pti ble a n d 
Mea ni n gf ul p ai n relief 
assess me nts c
 
 
X 
X 
X 
X 
 
 
 
( X) k
P h ot o gra p hic a n d 
resi d ue e v al u ati o nf
X


C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 2 of 6 0
A S S E S S M E N T S 
P E R F O R M E D 
Scree ni n g 
Visit 
E xercise 
Visit 
Peri o d 1 
Peri o d 2 
E O S 
Visit/ E T j 
F oll o w- 
u p call 
I n  
p atie nt 
O ut 
p atie nt 
Safet y 
Visit 
O ut 
p atie nt 
Safet y 
Visit 
O ut 
p atie nt
Da y 
- 3 0 t o - 2 
- 1 
1 
2 
3- 8 
8 
( ± 1 d a y)
9- 1 4 
1 5 
( ± 1 d a y)
1 6- 2 2 
8 or 2 2 
( + 1 da y) 
1 5 or 2 9 
( ± 1 d a y)  
P h ot o gra p hic
e val uati o n of 
a p plicati o n site 
reacti o nsg
 
 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
( X) 
 
Dis p e nse st u d y g el 
 
 
 
X 
 
X 
 
X 
 
 
 
A p pl y st u d y g el h
X
X
X
X
X
X
X
( X)  
Rec or d a d verse e v e nts  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rec or d c o nc o mita nt 
me dicati o ns i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Rec or d resc u e 
me dicati o n use 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C ollect st u d y g el
X
C ollect s u bject e- diar y 
 
 
 
 
 
 
 
 
 
X 
 
; D O M S, d ela y e d o nset m uscle s ore ness; e- diar y, electr o nic diar y d e vice; E O S, e n d of st u d y; E T, earl y ter mi n ati o n; 
; V A S, vis u al a nal o g 
scale; ( X), p erf or me d as i n dicate d i n t h e f o ot n ote.  
a S u bjects will e nter t h e cli nic o n Da y 1 a n d will b e disc h ar g e d o n Da y 2 after st u d y assess me nts at 
 g el a p pli cati o n are c o m plete d.
b St u d y staff will c o ntact s u bjects b y tele p h o n e f or assess me nt of A Es, s ki n c o n diti o n a n d c o nc o mit a nt me dicati o ns, a n d use of resc ue me dicati o n. All s u bjects will b e c o ntacte d 
o n Da y 5 ( ± 1 da y). S u bjects p artici p ati n g i n P eri o d 1 will b e c o ntacte d o n Da y 1 5 ( ± 1 d a y). S u bjects p artici p ati n g i n Peri o d 2 will be c o ntacte d o n Da y 1 1 ( ± 1 d a y), Da y 1 8 
( ± 1 d a y), a n d Da y 2 9 ( ± 1 d a y). 
c V A S a n d cate g orical q u alif yi n g pai n assess me nts will b e p erf or me d o n b ot h le gs wit hi n 2 4- 3 0 h o urs of e x ercise t o i n d uce D O M S. Pai n i nte nsit y assess me nts will be p erf or me d 
f or t h e st u d y le g a n d n o n-st u d y le g at rest a n d w hil e sta n di n g usi n g a 0- 1 0 0 p oi nt e V A S o n Da y 1 at Baseli n e ( 0 h o urs) a n d at 
 
 after t h e first st u d y g el a p plicati o n. Baseli ne ( 0 h o urs) is t h e ti me p oi nt f or t h e first st u d y g el a p plicati o n; a ti me 
wi n d o w of + 3 0 mi n utes will b e all o we d b et wee n q u alif yi n g p ai n assess me nts ( q u alif yi n g p ost-e x ercise i n cl usi o n criteria) a n d first st u d y g el a p plicati o n ( 0 h o ur). T h e f oll o wi n g 
ti me wi n d o ws will b e all o we d f or eac h p ai n assess me nt ti me p oi nt: ± 1 5 mi n utes f or assess me nts fr o m 1 t o 1 2 h o urs ( Da y 1), ± 3 0 mi n utes f or assess me nts at 1 8 t hr o u g h 
2 4 h o urs ( Da y 2), a n d ± 1 h o ur f or assess me nts at 3 6 t o 1 6 8 h o urs ( Da y 2 t o 8). Ti me t o p erce pti bl e a n d mea ni n gf ul p ai n relief will be rec or de d b y s u bjects i n t h eir e- diar y. 
W h e n st u d y gel a p plicati o n a n d pai n assess me nt o cc ur at t h e sa me ti me p oi nt, pai n assess me nts will be p erf or me d b ef ore st u d y gel a p plicati o n. 
d Vital si g n meas ure me nts will i n cl u d e s yst olic bl o o d press ure, diast olic bl o o d press ure, p ulse rate, a n d oral b o d y te m p erat ure. Bl o o d press ure a n d p ulse rat e will b e meas ure d 
aft er t h e s u bject h as b ee n resti n g i n t h e s u pi n e p ositi o n f or at least 5 mi n utes. 
e Ser u m pre g n a n c y test at S cree ni n g a n d uri n e pre g n a n c y t est at E x ercise visit, E O S Visit ( Da y 8 or Da y 2 2) (fe males o nl y). 
f P h ot o gra p hic a n d resi d ue e v al u ati o ns of t h e a p plicati o n site will b e p erf or me d bef ore t h e 
 st u d y gel a p plicati o ns o n Da y 2.  


C O N FI D E N TI A L
K o w a Rese arc h I nstit ute, I nc. 
K- 2 8 5- 2 0 1, St u dy Pr ot oc ol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 3 of 6 0
g
Be gi n ni n g wit h t h e 
, w he n a n a p plicati o n site reacti o n is o bser ve d at t h e cli nical site, p h ot o gra p hs of t h e a p plicati o n site will be ta k e n 
b y site staff t o vis u all y d o c u me nt t h e s ki n c o n diti o n at t h e site of gel a p pli cati o n. If n ee d e d, t h e p h ot o gra p hs will b e p eri o dicall y ta k e n t o f oll o w- u p t h e a p plicati o n site 
reacti o n. If a n a p plicati o n site reacti o n is o bser v e d at h o me, p h ot o gra p hs of t h e a p plicati o n site will b e ta k e n b y site staff w h e n s u bject ret ur ns t o t he cli nical site. All 
p h ot o gra p hs s h o ul d be ta k e n pri or t o gel a p plicati o n. 
h
 
 
 
T h e f oll o wi n g ti me wi n d o ws will b e all o we d f or eac h st u d y g el a p plicati o n ti me p oi nt: + 3 0 mi n utes f or first st u d y g el a p plicati o n ( 0 h o ur) after q u alif yi n g p ai n assess me nts, 
± 1 5 mi n utes f or t h e 
 a p plicati o ns, ± 3 0 mi n utes f or t h e 
 a p plicati o ns, a n d ± 1 h o ur f or ot her a p plicati o n ti me p oi nts.  
At t h e site, st u d y g el is a p plie d t o t h e st u d y le g b y t h e s u bject wit h i n v esti gat or ( or d esi g n ee) o v ersi g ht t o e ns ure pr o p er a p plicati o n. F oll o wi n g disc h ar g e fr o m t h e cli nic o n 
Da y 2, s u bse q u e nt st u d y gel a p plicati o ns will be p erf or me d b y t h e s u bject. F or s u bjects p artici pati n g o nl y i n Peri o d 1, t h e last a p plicati o n of st u d y g el is a p plie d at 6 a m o n 
Da y 8. F or s u bjects partici pati n g i n Peri o d 2, t h e last a p plicati o n of st u d y g el is a p plie d at 6 a m o n Da y 2 2. 
i
All me dicati o ns a n d ot h er treat me nts ta k e n b y s u bjects wit hi n 3 0 d a ys b ef ore d osi n g a n d d uri n g t he st u d y will b e rec or d e d i n t h e C R F. A n y c h a n g es i n t h e c o nc o mit a nt 
me dicati o ns after disc h ar g e fr o m t h e cli nic o n Da y 2, eit h er prescri b e d or self-a d mi nistere d, will b e d o c u me nte d a n d re vie we d d uri n g tele p h o n e calls, Safet y visits a n d at t he 
E O S Visits. 
j F or s u bjects partici p ati n g o nl y i n Peri o d 1 E O S is o n Da y 8 ( + 1 d a y), f or s u bjects p artici pati n g i n Peri o d 2 E O S is o n Da y 2 2 ( + 1 d a y). N ote t h at E O S visits h a v e a wi n d o w 
of + 1 d a y w hereas Safet y visits ha ve a wi n d o w of ± 1 d a y. 
k F or Da y 8, Peri o d 1. 


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 4 of 6 0 
4. 0
S U B J E C T E LI GI BI LI T Y A N D WI T H D R A W A L C RI T E RI A
S u bjects w h o d o n ot meet eli gi bilit y criteria will be classifie d as s cree n fail ures a n d t h e 
reas o n(s) will be rec or de d i n t he case re p ort f or m ( C R F)/electr o ni c C R F (e C R F).
4. 1 
I N C L U SI O N C RI T E RI A
4. 1. 1 
Pre-e xercise I ncl usi o n Criteri a
S u bjects are eli gi ble f or t he st u d y if all of t he f oll o wi n g crit eria are met:
1.  S u bject 
m ust pr o vi de i nf or m e d c o nse nt bef ore a n y st u d y-s pecific e val uati o n is 
perf or me d. 
2.  S u bject is male a n d fe male a ge d 1 8 t o 3 5 years, i n cl usi v e. 
3.  S u bject has a b o d y mass i n de x ( B MI) of 1 8 t o 3 2 k g/ m 2, i ncl usi ve 
 
 
 
 
 
 
6.  S u bject  h e mat ol o g y, ser u m c he mistr y, uri nal ysis, vital si g n meas ure me nts (s yst olic 
bl o o d press ure, di ast olic bl o o d press ure, p ulse r ate, a n d oral b o d y te m perat ure) a n d 
1 2-lea d E C G res ults s h o w n o cli nicall y rel e va nt a b n or malities, as j u d ge d b y t he 
i n vesti gat or at t he Scree ni n g Visit. 
7.  All fe male s u bjects m ust ha ve a ne g ati ve ser u m pre g n a nc y test res ult at Scree ni n g a n d 
ne gati v e uri n e pre g na nc y test o n Da y - 1 pri or t o a d missi o n t o t he cli ni c. Fe male 
s u bjects of c hil d beari n g p ote ntial m ust use o ne of t h e f oll o wi n g acce pta ble birt h c o ntr ol 
met h o ds as s pecifie d b ef ore e nr oll me nt a n d t hr o u g h o ut t he st u d y: 
a. S ur gical 
sterilizati o n 
( bilateral 
t u bal 
li gati o n, 
h ysterect o m y, 
bilateral 
o o p h orect o m y) at le ast 6 m o nt hs bef ore t h e first d ose of st u d y gel; 
b.  I ntra uteri ne de vice i n place f or at least 3 m o nt hs b ef ore t he first d ose of st u d y gel 
a n d t hr o u g h o ut t he st u d y; 
c. Barrier met h o d (c o n d o m or dia p hra g m) wit h s per mici de f or at least 1 4 da ys bef ore 
t he first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y; 
d.  S ur gical sterilizati o n of t he male p art n er ( v asect o m y at least 6 m o nt hs bef ore t h e 
first d ose of st u d y gel); 
e. H or m o nal c o ntrace pti ves f or at least 3 m o nt hs wit h a barrier met h o d 1 4 da ys b ef ore 
t he first d ose of st u d y gel a n d t hr o u g h o ut t he st u d y; 
f. A bsti ne nce. 
8.  S u bject is a ble a n d willi n g t o c o m pl y wit h t he pr ot oc ol a n d st u d y pr oce d ures.
9.  S u bject h as ne g ati ve test res ults f or dr u gs a n d alc o h ol at scree ni n g a n d is a bl e a n d 
willi n g t o a bstai n fr o m marij u a na a n d alc o h ol use f or 4 da ys bef ore Da y 1 a n d 
t hr o u g h o ut t he st u d y. N ote t hat a p ositi ve scree ni n g res ult f or marij ua na is acce pta bl e 
pr o vi de d t he s u bject will a bstai n f or t h e st u d y as d escri b e d a b o ve. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 5 of 6 0 
1 0. S u bject d oes n ot use nic oti ne or has q uit usi n g nic oti ne f or at l east 6 m o nt hs bef ore t h e 
first d ose of st u d y gel a n d will n ot use nic oti ne t hr o u g h o ut t he st u d y. 
 
 
 
 
.
4. 2  
E X C L U SI O N C RI T E RI A
S u bjects are e x cl u de d fr o m t h e st u d y if a n y of t he f oll o wi n g criteria are m et: 
 
 
 
 
 
 
 
 
3.  
S u bject h as recei ve d oral or t o pical a nal gesic m e dicati o ns wit hi n 1 4 da ys bef ore t h e 
Scree ni n g Visit.
4.  
S u bject has use d a s yste mic c ortic oster oi d wit hi n 3 0 da ys bef ore t he Scree ni n g Visit.
5.  
S u bject has a me dical hist or y t hat i ncl u des a c o ntr ai n dicati o n t o t h e use of me nt h ol or 
N S AI Ds (e. g., g astr oi ntesti nal ulcer, gastr oi ntesti nal blee di n g).
6.  
S u bject is ta ki n g me dicati o ns or ot h er s u bsta nces c o ntrai n dicate d beca us e of t he nat ure 
of t he st u d y g el or t h e p ote ntial f or dr u g i nteracti o ns. T his i n cl u des s u bjects wit h 
aller gi es t o pres cri pti o n or O T C pr o d ucts c o ntai ni n g me nt h ol or N S AI Ds. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 6 of 6 0 
 
 
 
 
 
 
 
 bee n a de q uatel y treate d, a n d d o n ot i n v ol v e t h e i n vesti g ati v e 
sites are all o wa ble. 
1 4.
S u bject is pre g na nt or n ursi n g. 
1 5.
S u bject has partici pate d i n a n i n vesti gati o nal dr u g st u d y wit hi n 3 0 da ys bef ore 
Scree ni n g.
1 6.
S u bject is a me m ber or a fa mil y me m ber of t h e pr ofessi o nal or a ncillar y pers o n nel 
i n v ol v e d i n t he st u d y.  
1 7.
S u bject has partici pate d i n ot her cli nical trials f or K- 2 8 5. 
1 8.
S u bject has a b n or mal fi n di n gs or assess me nts t hat are cli nicall y n ote w ort h y. 
1 9.
S u bject w h o, i n t he o pi ni o n of t h e i n vesti g at or, s h o ul d n ot partici pate i n t he st u d y. 
4. 3   
DI S C O N TI N U A TI O N A N D WI T H D R A W A L C RI T E RI A 
S u bjects m a y v ol u ntaril y wit h dra w fr o m t he st u d y at a n y ti me a n d f or a n y reas o n wit h o ut 
prej u dice t o t heir f ut ure me di cal care b y t he i n vesti gat or or at t he st u d y site. T he 
i n vesti gat or ma y disc o nti n ue treat m e nt of a s u bject or wit h dra w a s u bject fr o m t he st u d y 
u n der s p ecific circ u msta nces, descri be d b el o w. T he pri mar y reas o n(s) f or disc o nti n uati o n 
or wit h dra wal ( b y t he s u bject or t h e i n vesti gat or) will be d oc u me nt e d a n d rec or d e d i n t he 
case re p ort f or m C R F/e C R F.  
T he s u bject will be dis c o nti n ue d fr o m st u d y gel if a n y of t h e f oll o wi n g occ ur: 
1.  
T here is a deteri orati o n i n t he s u bject’s si g ns/s y m pt o ms a n d/ or t he s u bject de vel o ps a 
disease or c o n diti o n t h at i n t he o pi ni o n of t h e i n vesti g at or, w o ul d c o m pr o mise t he 
s u bject’s safet y b y c o nti n ui n g i n t he st u d y. 
2.  
I n t he i n v esti gat or’s j u d g me nt, it is i n t he s u bject’s best i nterests. 
3.  
Vi olati o n of t he pr ot oc ol i ncl usi o n a n d e xcl usi o n criteria. 
4.  
T he s u bject be gi ns t o ta k e a n y me dicati o n(s) t hat is e xcl u de d b y t he pr ot o c ol. 
5.  
It is deter mi ne d t hat t here is disc ol orati o n, e xf oli ati o n or er osi o n, e d e ma, disc har ge, 
blisteri n g, e x u date, 
2 p oi nt o n der mal res p o nses sc ore ( Secti o n 5. 2. 6 ), a n d/ or a n y 
ot her der m al c ha n g e t h at i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o m pr o mise t he
s u bject’s safet y b y c o nti n ui n g i n t he st u d y at t h e a p pli cati o n site. T he pr ocess f or 
disc o nti n uati o n d ue t o a n a p plicati o n site reacti o n is descri b e d i n Secti o n 4. 3. 1 bel o w. 
6.  
Occ urre n ce of seri o us a d verse e v e nt(s). 
7.  
Pre g na nc y. 
T he s u bject will be wit h dra w n fr o m t he st u d y if a n y of t he f oll o wi n g occ ur: 
1.  
T he s u bject wit h dra ws c o nse nt. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 7 of 6 0 
2.  
T he s u bject is l ost t o f oll o w- u p. 
3.  
A n y of t he c o n diti o ns are met i n Secti o n 6. 5 , Ter mi n ati o n of t h e St u d y. 
4.  
T he s u bject is u na ble or u n willi n g t o c o o perate wit h st u d y staff. 
5.  
Deat h. 
 
S u bjects w h o disc o nti n ue or wit h dra w fr o m t he trial d ue t o t he a b o ve criteria or a n y ot her 
reas o n, will be e nc o ura g e d t o c o m plete t he fi nal e val uati o ns as detaile d i n Ta ble  2 . If a 
s u bject decli nes t o c o m pl ete earl y ter mi nati o n pr oce d ures, t his decisi o n will be rec or de d i n 
t he case re p ort f or m C R F/e C R F.  
If a s u bject dis c o nti n ues or wit h dra ws fr o m t he st u d y d ue t o a n A E, t he s u bject will be 
as ke d t o ret ur n t o t he cli nic f or, at a mi ni m u m, t h e e val u ati o ns sc he d ule d f or t he E O S/ E T 
Visit ( Da y 8/ Da y 2 2). If t he A E has still n ot res ol ve d, a d diti o nal f oll o w- u p will be 
perf or me d, as a p pr o priate, a n d d oc u me nte d i n t he s u bject’s me dical rec or ds. As a mi ni m u m 
re q uire me nt, A Es m ust b e f oll o we d f or 3 0 d a ys after t he s u bje ct’s last d ose of st u d y gel or 
u ntil res ol uti o n or u ntil u nres ol ve d A Es are j u d ge d b y t he i n vesti gat or ( or d esi g nee) t o h a ve 
sta bilize d.  
If s u bjects are l ost t o f oll o w- u p, atte m pts t o c o ntact t h e m m ust be ma de a n d d oc u m e nte d 
i n t h e me dical rec or ds. S u bjects w h o fail t o ret ur n f or a st u d y visit will be c o ntacte d directl y 
b y t he st u d y staff. A mi ni m u m of 2 d oc u me nte d p h o ne calls will be m a de. If t h e st u d y staff 
recei v es n o res p o nse, t h e y will se n d a certifie d l ett er re q u esti n g t hat t h e s u bject c o ntact t h e 
st u d y sit e re gar di n g his or her stat us i n t h e st u d y.  
Disc o nti n ue d or wit h dra w n s u bjects will n ot be re place d. 
4. 3. 1  Disc o nti n u ati o n d ue t o a n A p plic ati o n Site Re acti o n 
1.  D uri n g a cli nical site visit, t h e a p plicati o n site reacti o n will be assesse d b y st u d y 
staff. If t here are a n y si g nifica nt fi n di n gs, t he y will b e n ote d i n eac h s u bject’s 
s o urce d oc u m e nts.  
 
If t he a p plicati o n site reacti o n is j u d ge d t o meet t h e dis c o nti n uati o n crit eria 
(Secti o n 4. 3 ), t he s u bject will be dis c o nti n ue d fr o m t he st u d y. 
 
2.  D uri n g t he o ut- patie nt peri o d at h o me, a p pli cati o n site reacti o ns will be assesse d 
b y t he s u bject. If a n y a p plicati o n site reacti o n is n otice d, t h e s u bject will c o ntact 
t he site bef ore d osi n g.  
 
T he s u bject will n ot a p pl y st u d y gel u ntil recei vi n g c o nfir mati o n fr o m t he site 
t o pr ocee d. 
If t h e s u bject c o ntacts t he sit e a n d t he n t he a p pli cati o n site reacti o n is j u d ge d
t o 
meet t h e disc o nti n uati o n criteria (Secti o n 4. 3 ), t he s u bject will be 
disc o nti n ue d fr o m t he st u d y. At t hat ti me, t he s u bject will be as ke d t o gat her 
safet y refere nce i nf or mati o n as f oll o ws: 
o  
Rec or d t h e s c ore of d er mal res p o nse ( Secti o n 5. 2. 6 ) i n t he e- diar y. 
Refere n ce i m a ges of a p plicati o n site reacti o ns are s h o w n i n A p pe n di x 4 .
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 8 of 6 0 
5. 0
P R O C E D U R E S F O R E F FI C A C Y A N D S A F E T Y 
E V A L U A TI O N S 
5. 1  
E F FI C A C Y E V A L U A TI O N S
5. 1. 1
P ai n I nte nsit y  
Pri or t o e xercis e t o i n d uce D O M S, p ai n will be assesse d f or b ot h le gs at rest a n d w hile 
sta n di n g usi n g a 0- 1 0 0 p oi nt pa per V A S t o e xcl u d e s u bjects wit h ot her pai n. 
F oll o wi n g e xercise t o i n d uce D O M S, pai n at rest a n d w hile st a n di n g will be assesse d f or 
b ot h le gs usi n g a 0- 1 0 0 p oi nt e V A S a n d a cate g orical scale t o deter mi ne q ualificati o n f or 
ra n d o mizati o n a n d t o i de ntif y t he st u d y le g ( baseli ne assess me nt). All pai n assess me nts 
will b e rec or d e d i n t he e- diar y. 
After ra n d o mizati o n, pai n at rest a n d w hile sta n di n g will be assesse d f or t he st u d y le g a n d 
t he n o n-st u d y le g usi n g a 0- 1 0 0 p oi nt e V A S at all p ost-st u d y gel a p plicati o n ti me p oi nts i n 
Peri o d 1 ( T a ble 2 ). W he n st u d y gel a p plicati o n a n d p ai n assess me nt occ ur at t h e sa me ti me 
p oi nt, p ai n assess me nts will be perf or me d b ef ore st u d y gel a p pli cati o n. 
T he s u bject will rest q uietl y f or at least 5 mi n utes bef ore assessi n g pai n at rest f or t he st u d y 
le g a n d n o n-st u d y le g (t h e st u d y le g will be ass esse d first). T he s u bject will sit f or at least 
5 mi n utes, t he n sta n d u p a n d rate t h e w orst p ai n ca us e d b y sta n di n g (t he act of m o vi n g 
fr o m a sitti n g t o sta n di n g p ositi o n) f or t he st u d y le g a n d n o n-st u d y le g (t h e st u d y le g will 
be assesse d first). 
5. 1. 1. 1  
T he pai n V A S, a u ni di m e nsi o nal meas ure of p ai n i nte nsit y, is a c o nti n u o us scale fr o m 0 t o 
1 0 0 c o m prise d of a h oriz o ntal li ne a nc h ore d b y 2 descri pt ors, o ne f or eac h s y m pt o m 
e xtre me: “ n o pai n” (sc ore of 0) a n d “ w orst p ossi ble pai n” (sc ore of 1 0 0). A pa per versi o n
of t he pai n V A S will be use d f or pre-e x ercis e p ai n assess me nts ( A p pe n di x 1 ). 
T he pai n e V A S is el ectr o nicall y dis pla ye d a n d is c o m plete d b y t he s u bject f or baseli ne a n d 
eac h p ost-ra n d o mizati o n pai n i nte nsit y assess me nt b y t o uc hi n g t he p oi nt o n t h e e V A S t hat 
re pres e nts t heir pai n i nte nsit y. ( A ca pt ure pr o gra m will li nearl y c o n vert t he pi x el t o uc he d 
t o a n i nte ger b et wee n 0 a n d 1 0 0). T he i nte g ers of t h e e V A S will b e referre d t o as p oi nts. 
T he assess me nt d ate a n d ti me f or t h e st u d y le g a n d f or t he n o n-st u d y le g is rec or de d i n t he 
e- diar y ( A p pe n di x 1 ).  
5. 1. 1. 2
A 4- p oi nt cate g orical scale ( n o ne, mil d, m o derate, se vere) at rest will b e use d t o assess pai n 
i nte nsit y f oll o wi n g t he e xercise sessi o n. A cate g orical scal e is pr o vi de d i n A p pe n di x 2 . 
5. 1. 2  Use of Res c ue Me dic ati o n 
Use of a n y resc u e me dicati o n f or D O M S is str o n gl y dis c o ura ge d u ntil 1 6 8 h o urs after t he 
first st u d y gel a p plicati o n, at w hic h ti me O T C aceta mi n o p he n ( o ne 5 0 0 m g aceta mi n o p he n 
ta blet t wice d ail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue me dicati o n is per mitte d if 
re q uire d.
S u bjects e x perie nci n g s e vere p ai n, or i na bilit y t o m o ve or wal k d ue t o pai n,
ma y be 
per mitte d t o use res c ue me dicati o n ( o ne 5 0 0 m g O T C aceta mi n o p he n ta blet t wice dail y, 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 1 9 of 6 0 
n ot m ore t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs after t he first st u d y gel a p plicati o n. If 
s u bjects ta ke resc ue me dicati o n wit hi n t he first 1 6 8 h o urs after t h e first st u d y gel 
a p plicati o n, it 
will be rec or de d i n t he e- diar y as resc ue 
me dicati o n a n d 
will be 
pr o gra m maticall y c ate g orize d as a c o nc o mita nt me dicati o n. S u bjects will rec or d t heir p ai n 
i nte nsit y i n t h e e- diar y bef ore ta ki n g t he res c ue me dicati o n. T he n u m b er of ta blets ta ke n 
a n d t he d ate a n d ti me will be rec or de d i n t he e- diar y. 
5. 1. 3  Ti m e t o O ns et of First Perce pti bl e a n d Me a ni n gf ul P ai n Relief  
Pai n assess me nts of ti me t o first perce pti ble p ai n relief a n d ti m e t o mea ni n gf ul pai n relief 
f or b ot h le gs at rest a n d w hile st a n di n g will be rec or de d b y s u bjects usi n g t heir e- diar y. At 
t he ti me of first perce pti ble p ai n relief a n d at t he ti me of mea ni n gf ul pai n relief, s u bjects 
will use t h eir e- diar y t o rec or d t h e ti me t he e ve nts are e x perie nce d. Si nce t hese assess me nts 
will be ca pt ure d i n t he e- diar y, t he electr o nic d ata base will be t he direct p oi nt of data 
ca pt ure a n d will ser v e as s o urce f or t his varia ble.  
5. 1. 3. 1
O nset of p erce pti ble pai n relief will be ass esse d f or t he st u d y le g a n d n o n-st u d y le g b y 
res p o n di n g “n o ” or “yes” t o a q uesti o n s uc h as t h e f oll o wi n g e xa m ple: 
“ H ave y o u ex perie n ce d a n y p ai n relief i n t he st u dy le g ( n o n-st u dy le g) si n ce st arti n g t o 
use t he st u dy g el ? ”.  
5. 1. 3. 2  
O nset of mea ni n gf ul pai n relief is assesse d f or t h e st u d y le g a n d n o n-st u d y le g o nl y after 
o nset of perce pti ble pai n reli ef has bee n ac hie ve d. T he s u bject res p o n ds “ n o ” or “yes” t o a 
q uesti o n s uc h as t he f oll o wi n g e xa m ple:
“ H ave y o u ex peri e nce d me a ni n gf ul p ai n r elief i n t he st u dy l e g ( n o n-st u dy le g) si nce 
st arti n g t o use t he st u dy gel ?”.
T he s u bject will be t ol d t h at “ mea ni n gf ul p ai n r elief” is “ W he n t h e relief fr o m p ai n is 
me a ni n gf ul or si g nific a nt t o y o u. T his d oes n ot necess arily me a n t h at y o u f eel c o m plet ely 
better, alt h o u g h y o u mi g ht. ”
5. 2  
S A F E T Y E V A L U A TI O N S 
5. 2. 1  A d verse E ve nts  
A d vers e e ve nts will be rec or de d acc or di n g t o t he s c he d ule i n Ta bl e 2 . All A Es, w het her 
ascri b e d t o st u d y pr oce d ures or n ot, will be d oc u me nte d o n t he e C R F a n d will i ncl u de t he 
date a n d ti me of o nset, a descri pti o n of t he A E, se verit y, d urati o n, acti o ns ta ke n, o utc o me, 
a n d t he relati o ns hi p bet wee n t h e st u d y gel
a n d t he e ve nt. 
A n y s u bject 
w h o 
disc o nti n ues/ wit h dra ws fr o m t he st u d y d ue t o a n A E will be f oll o we d u p u ntil t h e o utc o me 
is d eter mi ne d a n d writt e n r e p orts are pr o vi de d b y t he i n v esti gat or. A d verse e ve nt 
defi niti o ns, a n d re p orti n g a n d f oll o w- u p re q uire me nts are descri b e d i n Secti o n 9. 1 , 9. 2, a n d 
9. 3 , res pecti vel y. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 0 of 6 0 
5. 2. 2
Cli ni c al L a b or at or y Tests
Cli nical la b orat or y tests will be perf or me d b y t he sit e’s l ocal la b orat or y. Bl o o d sa m ples 
will be c ollecte d acc or di n g t o t he sc he d ule i n Ta ble 2 a n d pr ocesse d as detaile d i n t he 
La b orat or y M a n ual.  
Uri nal ysis will be perf or me d b y t he site’s l ocal la b orat or y acc or di n g t o t he sc he d ule i n 
Ta ble 2 . Uri ne s a m ples will be c ollecte d a n d pr ocesse d as detaile d i n t he La b orat or y
Ma n ual. If micr os c o p y is re q uire d, a uri ne s a m ple will be se nt t o t he l ocal la b orat or y. 
T he para meters b ei n g meas ure d are s h o w n i n T a ble 3 . 
T a bl e 3. Cli nic al L a b o r at or y Test P a r a m eters
He m at ol o g y
Cli nic al C he mistr y
Uri n al ysis
Bas o p hils 
E osi n o p hils 
He mat o crit 
( Pac ke d cell 
v ol u me) 
He m o gl o bi n 
L y m p h oc ytes 
Mea n cell 
h e m o gl o bi n 
Mea n cell 
h e m o gl o bi n 
c o n ce ntrati o n 
Mea n cell v ol u me  
M o n oc ytes 
Ne utr o p hils 
Platelet c o u nt 
Re d bl o o d cell 
 
c o u nt 
W hite bl o o d cell 
c o u nt 
 
Ala ni n e a mi n otra nsferase  
Al b u mi n 
Al k ali ne p h os p hatase 
As partate a mi n otra nsferase 
Bicar b o n ate 
Bilir u bi n (t otal) 
Bilir u bi n ( direct; o nl y if t otal is ele v ate d) 
Calci u m 
C hl ori d e 
Creati n e ki n ase 1 
Creati ni n e 
F ollicle-sti m ulati n g h or m o n e ( p ost- m e n o pa usal fe male 
p atie nts o nl y) 
Ga m m a gl uta m yl tra nsferase 
Tri gl y ceri des 
Gl u c ose (fasti n g) 
H u ma n c h ori o nic g o n a d otr o pi n (all fe male p atie nts) 
L actate d e h y dr o g e n ase 
Ma g nesi u m 
P otassi u m 
P h os p h ate (i n or g a nic) 
Pr otei n (t otal) 
S o di u m 
Bl o o d urea nitr o g e n ( B U N) 
Uric aci d
Bilir u bi n
Bl o o d 
Gl u c ose 
Ket o n es 
L e u k o c ytes 
Nitrites 
p H 
Pr otei n 
S p ecific gra vit y 
Ur o bili n o g e n 
At t he discreti o n of 
t he i n v esti g at o r b ase d 
o n uri n al ysis res ults 
Micr o bi ol o g y 
Uri ne Micr osc o p y 
1 Ele vate d le vels of creati ne ki n ase are e x p ecte d as a res ult of t h e e x ercise p erf or me d o n Da y - 1 a n d will be h a n dle d as 
d escri b e d i n Secti o n  5. 2. 2. 1.
 
5. 2. 2. 1
Ele vati o ns of ser u m creati ne ki nase ( C K) are e x p ecte d t o o cc ur as a c o ns e q u e nce of t h e 
e xercis e perf or me d o n Da y - 1 a n d will n ot be re p orte d as A Es. A d diti o nal s afet y ste ps will 
be ta ke n t o m o nit or t he s u bjects f or si g ns of r ha b d o m y ol ysis. If a s u bject has a ser u m C K
a b o ve 1 0, 0 0 0 U/ L (a n d ass ociate d el e vati o ns of lactate de h y dr o ge nas e
L D H], as partate 
a mi n otra nsfer ase  
, or al a ni n e a mi n otr a nsferase  
]), b ut n o si g nifica nt si g ns or 
s y m pt o ms of r ha b d o m y ol ysis ot her t h a n m uscle pai n a n d s welli n g at t he e x ercise d m uscles, 
t he f oll o wi n g acti o ns will be ta ke n wit h t he s u bject u ntil t he E O S Visit ( Da y 8 f or s u bjects 
d osi n g d uri n g Peri o d 1 a n d Da y 2 2 f or s u bje cts d osi n g d uri n g Peri o d 2): 
 
S u bjects will be i nstr ucte d t o m o nit or t he uri ne f or c ha n ges i n c ol or caref ull y. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 1 of 6 0 
 
S u bjects will be i nstr ucte d t o re p ort a n y uri ne disc ol orati o n, s uc h as dar k yell o w,
br o w n, c ola or t ea c ol ore d uri ne, t o st u d y pers o n n el.
S u bjects will be i nstr ucte d t o mai ntai n a de q uate h y drati o n at h o me (a p pr o xi matel y 1 5. 5 
c u ps 3. 7 lit ers] of fl ui ds f or males a n d 1 1. 5 c u ps 2. 7 lit ers] of fl ui ds a d a y f or fe mal es) 
  
I n a d diti o n, t he f oll o wi n g acti o ns ma y be ta ke n wit h t he s u bject at t he discreti o n of t he 
i n vesti gat or: 
S u bjects will be as ke d t o sta y o ver ni g ht at t he st u d y site w here vi g or o us h y drati o n will 
be a d mi nistere d a n d m o nit ori n g f or a n y cli nical si g ns or s y m pt o ms of r ha b d o m y ol ysis 
will b e u n derta ke n. T he s u bject will be releas e d w h e n, per t he i n vesti gat or’s discreti o n, 
it is a p pr o priate t o d o s o. Pri or t o releas e, t h e s p o ns or’s Me dical M o nit or will be 
n otifie d.
S u bjects will ha ve a ser u m C K cli nical la b orat or y re peate d as cli nic all y i n dicate d.
 
S u bjects will ha ve a uri n al ysis re peat e d as cli nicall y i n dicate d. 
 
If t here is a n ele vati o n i n C K a n d r h a b d o m y ol ysis is s us pecte d, t he w or k- u p s h o ul d als o 
i ncl u de e val uati o n of C K, C K- m y ocar dial b a n d ( C K- M B), C K i n s keletal 
m uscle 
( C K- M M), tr o p o ni n, creati ni ne, 
m y o gl o bi n (ser u m a n d uri ne), tra nsa mi nases, t otal 
bilir u bi n le vels, a n d uri nal ysis i ncl u di n g uri ne se di me nt. A p h ysical e xa mi n ati o n s h o ul d be 
perf or me d t o d oc u me nt fi n di n gs s uc h as m uscle te n der ness, wea k n ess, or ras h. A n E C G 
s h o ul d als o be perf or me d. A b n or malities s h o ul d be f oll o we d u ntil t h e y ha ve ret ur n e d t o 
baseli n e, or u ntil t he i n vesti gat or c o nsi ders t he m cli nicall y sta ble. 
5. 2. 3  Vit al Si g ns 
Vital si g n meas ure me nts will i n cl u de s yst oli c bl o o d press ure, diast olic bl o o d press ure, 
p ulse rate, res pirat or y rat e a n d oral b o d y te m perat ure. Bl o o d press ure a n d p ulse rate will 
be meas ure d after t he s u bject has bee n resti n g i n t he s u pi ne p ositi o n f or at least 5 mi n utes.
Meas ure me nts will be p erf or me d acc or di n g t o t h e sc he d ule i n Ta ble 2 .
5. 2. 4
Electr oc a r di o gr a m
T he E C Gs will be perf or m e d acc or di n g t o t h e sc h e d ule i n Ta ble 2 . 
5. 2. 5
P h ysic al E x a mi n ati o n
Ge neral p h ysical e xa mi n ati o ns will be perf or me d acc or di n g t o t h e sc he d ul e i n Ta ble 2 . T he 
e xa mi n ati o n will i n cl u de t he f oll o wi n g: ge neral c o n diti o n, der mat ol o gic, e yes, ears, n os e, 
t hr oat, nec k, t h yr oi d, heart, res pirat or y s yste m, a b d o me n, ki d ne ys, s k eletal s yste m, 
e xtre mities, l y m p hatic s yste m, ner v o us s yste m.  
5. 2. 6   S ki n E x a mi n ati o n ( A p plic ati o n Site Re acti o n)
S ki n e xa mi nati o n will be perf or me d acc or di n g t o t he sc he d ul e i n T a ble 2 . T he i n vesti gat or
or desi g nee will assess t he tar g et a p plicati o n site t o e ns ure t hat t he s ki n is n ot br o ke n or 
irritate d bef ore eac h st u d y gel a p pli cati o n a n d d oc u m e nt t he s ki n c o n diti o n i n t he e C R F 
usi n g f oll o wi n g rati n g scales.  
Der m al Res p o nses
0 = n o e vi de nce of irritati o n 
1 = mi ni mal er yt h e ma, b arel y perce pti ble


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 2 of 6 0 
2 = defi nite er yt he ma, rea dil y visi ble; mi ni m al e de ma or mi ni mal pa p ular res p o nse 
3 = er yt h e ma a n d pa p ules 
4 = defi nite e de ma
5 = er yt h e ma, e de ma a n d pa p ules
6 = vesic ular er u pti o n 
7 = str o n g reacti o n s prea di n g be y o n d a p pli cati o n site
N otes: Pa p ules are d efi n e d as s oli d, circ u mscri b e d s ki n ele vati o ns u p t o t h e size of a s plit p ea ( 5 m m). 
Vesicles are d efi n e d as s mall blisters. 
 
Ot her Effects ( Wit h C o rres p o n di n g N u meric Sc ore) 
N o ne ( 0) = n o c ha n g e i n a p peara nce 
A ( 0) = sli g htl y glaze d a p peara n ce
B ( 1) = mar ke d glaze d a p peara n ce
C ( 2) = glazi n g wit h peeli n g a n d crac ki n g 
F ( 3) = glazi n g wit h fiss ures
G ( 4) = fil m of drie d ser o us e x u dates c o v eri n g all or part of t h e a p plicati o n site
H ( 5) = s m all p etec hial er osi o ns a n d/ or sca bs 
 
S u bjects will be i nstr ucte d t o n otif y st u d y staff if t he y e x perie nce a n y dr y ness, it c hi n g, 
b ur ni n g, pai n, s ore ness, or ot her s y m pt o m at t he a p plicati o n site e ve n d uri n g t h e o ut- patie nt 
peri o d. If t here are u nsc he d ule d visits d ue t o A Es, t he i n vesti gat or will assess t he tar get 
a p plicati o n site a n d all a p plicati o n site reacti o ns will be rec or d e d i n t he e C R F. 
T hese si g ns of s ki n irritati o n will be i ncl u de d i n t he A E s ecti o n of t he e C R Fs. If a s u bject 
is dis c o nti n ue d fr o m t h e st u d y d ue t o a n a p pli cati o n site reacti o n, t he A E will be f oll o we d 
t o res ol uti o n or u p t o 3 0 da ys after t h e last d ose, w hic he ver c o mes first. 
S u bjects w h o disc o nti n ue d d ue t o a p pli cati o n site reacti o n ma y u n der g o a patc h test, at t he 
discreti o n of t h e i n vesti g at or. 
5. 2. 7  C o nc o mit a nt Me dic ati o ns 
C o nc o mita nt me dicati o ns will be rec or d e d acc or di n g t o t he sc he d ule i n Ta ble 2 .  
5. 3  
O T H E R E V A L U A TI O N S 
5. 3. 1  De m o gr a p hics, Me dic al Hist or y a n d Ot her B aseli n e C h a r acteristics 
De m o gra p hics a n d ot her baseli ne c haracteristics (a g e, se x, race, et h nicit y, hei g ht, a n d 
wei g ht) as well as me dical hist or y i nf or mati o n i ncl u di n g i de ntificati o n of d o mi na nt le g, 
s ki n c o n diti o n ( hist or y of ras h, aller g y, ecze ma, etc.) a n d a n y aller g y hist or y (i ncl u di n g 
fra gra nce, j e welr y, d ust, cl ot hi n g, h o use d ust, a ni mal, metal, r u b ber, n yl o n, f o o d, p olle n 
aller g y, etc.) will be c ollecte d o n all s u bjects at t h e Scree ni n g Visit. 
5. 3. 2  Dr u g a n d Alc o h ol Scree ni n g 
A uri ne dr u g scree n a n d alc o h ol breat h test will b e c o n d ucte d acc or di n g t o t he sc he d ule i n 
Ta ble 2 . Uri ne dr u g s cree n will i ncl u de uri ne s cree n f or c ocai ne, m arij ua na, o piates, 
a m p heta mi nes, met ha m p heta mi nes, p he nc ycli di ne ( P C P), be nz o di aze pi n es, bar bit urat es, 
met ha d o ne, o x yc o d o n e, 3, 4- met h yle ne di o x y- met h a m p heta mi ne ( M D M A or ecstas y), a n d 
tric yclic a nti de pressa nts. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 3 of 6 0 
5. 3. 3
Pre g n a nc y
All fe male s u bjects will ha ve a ser u m pre g n a nc y test at t he Scree ni n g Visit. S u bjects wit h 
a p ositi v e pre g na nc y test res ult will n ot be ra n d o mize d. A uri ne pre g na nc y test will be 
perf or me d at t he E xercis e visit a n d at t h e E O S/ E T Visits ( Da y 8 or Da y 2 2). 
5. 3. 4  St a n d ar dize d E x ercise Re gi m e n 
All e nr olle d s u bjects will p erf or m a sta n d ar diz e d re petiti ve q u a drice ps m uscle e x ercise 
c o nsisti n g of war m- u p, deter mi nati o n of ma xi m u m t olerate d wei g ht ( M T W), a n d ti me d 
a n d u nti me d w or k- o ut p hases, des cri b e d b el o w. S u bjects will be i nstr ucte d t o sta y well 
h y drate d b y i ncreasi n g t h eir water i nta ke, mi ni mizi n g caffei nate d be v era g es, a n d a v oi di n g 
alc o h ol d uri n g t h e e xercis e re gi me n. 
1. War m- u p a n d deter mi nati o n of M T W 
S u bjects will c o m plete a war m- u p of 4 sets of 1 0 re g ular b o d y wei g ht s q uat e xercis es fr o m 
sta n di n g p ositi o n ( 2 sets wit h o ut wei g hts a n d 2 sets wit h a p pr o xi matel y 1 0- 2 0 p o u n ds of 
wei g ht). T he M T W o n t h e le g c url m ac hi n e is t he n deter mi ne d f or eac h le g b y ha vi n g t he 
s u bject d o a f ull e xte nsi o n a n d fle xi o n wit h resista nce starti n g wit h a l o w b ut reas o na bl e 
wei g ht selecte d b y t he st u d y staff a n d i ncreasi n g it wit h e ver y re petiti o n u ntil s u bjects reac h 
t heir M T W. T h e M T W is defi n e d as t he hi g h est wei g ht u n der w hic h a s u bject c o ul d 
perf or m a f ull e xte nsi o n a n d fle xi o n. 
2. W or k o ut: ti me d p hase 
Starti n g wit h t he d o mi na nt le g, s u bjects will perf or m 6 sets of 1 0 le g e xte nsi o n a n d fle xi o n 
e xercis es wit h eac h l e g o n t he c url m ac hi n e u n d er 8 0 % of t h e M T W f or t hat le g. Eac h 
re petiti o n is perf or me d t hr o u g h t he f ull pai n-free ra n ge of m oti o n i n a sl o w, c o ntr olle d 
ma n ner. S u bjects perf or m t he c o nce ntric p orti o n of t he re p etiti o n f or 2 sec o n ds, pa use at 
f ull c o ntracti o n f or 1 sec o n d, a n d t h e n c o m plete t he e cce ntric p orti o n o ver a 4 sec o n d 
peri o d (f or a t otal of 7 sec o n ds per re petiti o n). S u bjects perf or m eac h set as t olerate d a n d 
are gi v e n a 1- 2 mi n ute rest peri o d i n bet wee n s ets. Re petiti o ns are p erf or me d u ntil s u bjects 
are u na bl e t o m o ve t h e wei g ht l oa d t hr o u g h t he f ull ra n ge of m oti o n. If s u bjects are u n a ble 
t o c o m plete t he f ull 6 s ets u n der 8 0 % M T W, t he wei g ht is decreas e d i n 5 p o u n d i ncre me nts 
u ntil s u bjects ca n n o l o n ger c o m plete 6 0 % M T W, or 6 sets are c o m plete d. 
3. W or k o ut: u nti me d p hase 
S u bjects c o m plete u nti me d fle xi o n-a n d-e xte nsi o n e xercises ( 1 5- 2 0 re petiti o ns) be gi n ni n g 
wit h t h e last wei g ht use d i n t he ti me d p hase. T he wei g hts are gra d u all y decrease d i n 
i ncre me nts of 5 p o u n ds u ntil n o wei g ht is use d.  
T he sa me pr ot oc ol is perf or me d o n t he s u bject’s o p p osite le g. 
5. 3. 5  P h ot o gr a p h a n d Resi d ue E v al u ati o n 
5. 3. 5. 1  
T o vis ualize t he s ki n c o n diti o n at t he site of st u d y gel a p plicati o n, p h ot o gra p hs of t h e 
a p plicati o n site will be ta ke n bef ore t h e 
 st u d y gel a p plicati o ns o n   
  
Als o, w he n a n a p plicati o n sit e reacti o n is o bser ve d at t h e cli nical sit e, p h ot o gra p hs of t he 
a p plicati o n site will be t a ke n b y site staff t o vis uall y d oc u me nt t he s ki n c o n diti o n at t he site 
of gel a p plicati o n. P h ot o gra p hs ma y be t a ke n peri o dicall y as nee d e d t o f oll o w- u p o n t he 
c o n diti o n of t he a p plicati o n sit e reacti o n. If a n a p plicati o n site reacti o n is o bser ve d at h o me, 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 4 of 6 0 
p h ot o gra p hs of t he a p pli cati o n site will be ta ke n b y site staff w he n s u bject ret ur ns t o t he 
cli nical site. 
P h ot o gra p hs s h o ul d be ta ke n at a n a n gle of less t h a n 4 5 de grees relati ve t o t h e s ki n pla ne 
wit h t h e area of g el a p plicati o n cl osest t o t he di git al ca mera. Eac h p h ot o gra p h will i n cl u de 
a pa per la b el i n t he p h ot o gra p h i de ntif yi n g t he s u bj ect n u m ber, date, assess m e nt ti me p oi nt, 
a n d i nitials of t he p h ot o gra p her. T he la b el will b e place d o n t he s ki n a djace nt t o t he gel 
a p plicati o n. 
5. 3. 5. 2  
T o e val uate t he s u bject’s i m pressi o n of t he drie d w hite gel resi d ue, t h e f oll o wi n g rati n g 
scale will be assesse d b ef ore t h e fift h a n d si xt h st u d y gel a p plicati o ns o n Da y 2 a n d will be 
rec or d e d o n t he a p pr o priate f or m. S u bjects m ust n ot s h o wer, bat he, or was h t he treate d area
u ntil after disc har g e o n Da y 2. 
T he f oll o wi n g rati n g scal e will be use d:
0 = N o drie d w hite resi d ue was o bser ve d
1 = Drie d w hite resi d ue was o bser v e d b ut n o disc o mf ort. 
2 = Drie d w hite resi d ue was o bser v e d a n d sli g ht dis c o mf ort ( bet wee n 1 a n d 3) 
3 = Drie d w hite resi d ue was o bser v e d a n d u nc o mf orta ble 
 
5. 4  
T O T A L B L O O D V O L U M E
T he t otal bl o o d v ol u me pla n n e d f or c ollecti o n d uri n g t he st u d y will be d escri be d i n t h e 
i nf or me d c o nse nt f or m (I C F).
 
6. 0  
C O N D U C T O F S T U D Y 
6. 1  
S T U D Y B LI N DI N G A N D R A N D O MI Z A TI O N  
T he st u d y will be d o u ble- bli n d. T he i n vesti g at or, s u bjects, a n d s p o ns or pers o n nel i n v ol v e d 
i n t h e m o nit ori n g or c o n d uct of t he st u d y will be bli n de d t o t he i de ntit y of t he treat m e nt 
fr o m t he ti me of ra n d o mizati o n u ntil t he ti m e of u n bli n di n g. U n bli n di n g will o nl y occ ur i n 
t he case of s u bject e mer g e ncies (Secti o n 7. 8 ) a n d at t he c o ncl usi o n of t he st u d y. St u d y staff 
will i nstr uct s u bjects n ot t o tal k a b o ut t h eir st u d y me dicati o n, t h eir pai n i nte nsit y, st u d y 
desi g n etc., a m o n g s u bje cts. 
 will pre pare t he ra n d o mi zati o n s c he d ule bef ore 
t he st u d y. E nr olle d, eli gi ble s u bjects will recei ve a kit c o ntai ni n g st u d y gels acc or di n g t o 
a n all o cati o n ta ble t h at ra n d o ml y assi g ns s u bjects b y or der of e nr oll me nt t o recei v e st u d y 
gel f or 
 i n 1 of 2 treat m e nt ar ms ( A or B) 
(Secti o n 7. 2 ). Se parate all o cati o n ta bles will be pre pare d f or 1 2 0 mal e a n d 1 2 0 fe mal e 
s u bjects. Male or fe mal e e nr oll me nt ma y e xcee d t he tar g et sa m ple size ( n = 1 2 0 eac h 
ge n der) b y ± 1 0 %. If t he t ar get s a m ple size is e x cee de d i n o ne ge n der, t he ne xt a vaila ble kit 
n u m ber i n t he ot her ge n d er will be assi g ne d. 
T he i de ntit y of t he st u d y gels i n t h e treat m e nt ar ms will be m as ke d b y h a vi n g i de ntical 
a p peara nce, pac k a gi n g, la beli n g a n d sc he d ul e of a d mi nistrati o n. Ra n d o mizati o n data are 
ke pt strictl y c o nfi de nti al, accessi ble o nl y t o a ut h orize d pers o ns, u ntil t h e ti me of u n bli n di n g.  


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 5 of 6 0 
6. 2  
S U B J E C T I N F O R M E D C O N S E N T 
Writte n c o nse nt will be o btai ne d fr o m t he s u bject pri or t o a n y st u d y s p ecifi c pr oc e d ure or 
i n vesti gati o n. 
I nf or mati o n a b o ut t h e st u d y will b e gi v e n t o t h e s u bject b ot h ver b all y a n d i n writi n g. T he 
writte n s u bject i nf or mati o n will e x plai n t he o bjecti v es of t h e st u d y, its p ote ntial ris ks a n d 
be nefits. T he s u bject m ust ha ve a de q uate ti me t o rea d t h e i nf or mati o n a n d t o as k t he 
i n vesti gat or a n y q u esti o ns. T he i n vesti g at or
m ust be satisfie d t hat t h e s u bject h as 
u n derst o o d t he i nf or mati o n pr o vi de d b ef ore writt e n c o nse nt is o btai ne d. If t h ere is a n y 
d o u bt as t o w het her t he s u bject has u n derst o o d t he writte n a n d v er b al i nf or mati o n, t h e 
s u bject s h o ul d n ot e nter t he st u d y. 
Partici pati n g s u bjects will be as ke d t o si g n a n d date a n I C F, t he ori gi n al c o p y of w hic h will 
be ke pt b y t he i n vesti gat or. A c o p y of t he si g ne d I C F will be gi ve n t o t he s u bject. A rec or d 
will b e ma de i n t he n otes t hat t h e s u bject v ol u ntaril y a gree d t o parti ci p ate i n t he st u d y. T he 
ori gi nal si g ne d I C F m ust be ma de a vaila ble t o t he st u d y m o nit or f or i ns pecti o n.  


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 6 of 6 0 
6. 3  
S T U D Y VI SI T S 
N ote: Ti mi n g of pr oce d ures a n d assess me nts are pr o vi d e d as e xa m ples. Act ual ti mi n g ma y 
var y f or eac h s u bject. Ti me p oi nts a n d ti me wi n d o ws f or st u d y gel a p pli cati o n a n d p ai n 
assess me nts are d escri b e d i n Ta ble 2 . 
 Da y - 3 0 t o Da y - 2:  
o  Scree ni n g Visit: T he Scree ni n g Visit at t he cli nic t o deter mi ne s u bject 
eli gi bilit y ca n t a ke place a n yti me wit hi n t his ti me peri o d.
Assess me nts 
i ncl u de t he f oll o wi n g: 
I nf or me d c o ns e nt
 De m o gra p hics
 Me dical/ m e dicati o n hist or y 
 Pre-e x ercis e i n cl usi o n criteria, e xcl usi o n criteria 
 Hei g ht a n d wei g ht 
 Vital si g ns 
 E C G 
 P h ysi cal e xa mi n ati o n
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site
 Pre g na nc y test (ser u m) (fe males o nl y) 
Uri ne dr u g scree n a n d al c o h ol test 
Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis)
 Rec or d A Es
Rec or d c o n c o mita nt me dicati o ns 
 Da y - 1:  
o  E xercis e Visit: O n Da y - 1 pr oce d ures a n d assess me nts are as f oll o ws:
U p date Me dic al/ m e dicati o n hist or y
Pre-e x ercis e i n cl usi o n a n d e xcl usi o n criteria
 Pai n assess me nt ( pre-e x ercise t o e xcl u de s u bjects wit h ot her pai n 
usi n g a pa per V A S) 
 D O M S i n d ucti o n e xercis e  
 Vital si g ns 
 E C G 
 P h ysi cal e xa mi n ati o n
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site
 e- diar y, st u d y trai ni n g 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 7 of 6 0 
Uri ne dr u g scree n a n d al c o h ol test 
Pre g na nc y test ( uri ne) (fe males o nl y) 
 Rec or d A Es
Rec or d c o n c o mita nt me dicati o ns 
 S u bjects ret ur n h o me after c o m pleti n g pr oce d ures a n d assess me nts
 Da y 1 t o Da y 2
o  A d missi o n Visit: O n Da y 1, s u bjects will b e a d mitte d t o t he cli nic. Da y 1 
pr oce d ures a n d ass ess me nts are as f oll o ws: 
V A S Q ualif yi n g Pai n assess me nts. N ote: Ti me 0 h o urs is t h e 
baseli n e ti me p oi nt f or t he first st u d y gel a p plicati o n a n d occ urs 
wit hi n 3 0 mi n utes of q ualif yi n g pai n assess me nts ( p ost-e xercise 
i ncl usi o n criteria). 
Cate g orical Q u alif yi n g Pai n ass ess me nts. N ote: Ti me 0 h o urs is t he 
baseli n e ti me p oi nt f or t he first st u d y gel a p plicati o n a n d occ urs 
wit hi n 3 0 mi n utes of q ualif yi n g pai n assess me nts ( p ost-e xercise 
i ncl usi o n criteria). 
 P ost-e xercise i ncl usi o n criteria 
 Ra n d o mizati o n (f or s u bjects w h o meet p ost-e xercise eli gi bilit y 
criteria) 
 Iss u e e- diar y 
 Vital si g ns 
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 A p pl y st u d y gel acc or di n g t o treat me nt sc he d ule  
 V A S pai n i nte nsit y assess me nt ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess m e nt occ ur at t he sa me ti me 
p oi nt). 
 Perce pti ble a n d mea ni n gf ul pai n relief assess me nts ( bef ore st u d y gel 
a p plicati o n w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt).  
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p plicati o n, be gi n ni n g wit h t he s ec o n d st u d y gel 
a p plicati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 8 of 6 0 
o  Da y 2 pr oce d ures a n d ass ess me nts are as f oll o ws: 
 Vital si g ns 
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 V A S pai n i nte nsit y assess me nt ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess m e nt occ ur at t he sa me ti me 
p oi nt) 
 Perce pti ble a n d mea ni n gf ul pai n relief assess me nts ( bef ore st u d y gel 
a p plicati o n w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt) 
 P h ot o gra p hic a n d resi d ue e val uati o n ( bef ore t he fift h a n d si xt h st u d y 
gel a p pli cati o ns) 
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 A p pl y st u d y gel acc or di n g t o treat me nt sc he d ule 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n 
 Dis pe nse st u d y gel (f or o ut- patie nt p orti o n) 
 Disc har ge fr o m t he cli nic (aft er st u d y assess me nts at 2 4 h o urs a n d 
t he si xt h st u d y gel a p plicati o n are c o m plet e d) 
 Da y 3 t o Da y 8 
o
O ut- patie nt p orti o n Peri o d 1: S u bjects a p pl y st u d y gel acc or di n g t o t heir 
assi g ne d treat m e nt a n d rec or d assess m e nts as f oll o ws: 
 V A S pai n i nte nsit y assess me nt ( bef ore st u d y g el a p plicati o n w he n 
st u d y gel a p plicati o n a n d pai n assess m e nt occ ur at t he sa me ti me 
p oi nt)  
 Perce pti ble a n d mea ni n gf ul pai n relief assess me nts ( bef ore st u d y gel 
a p plicati o n w he n st u d y g el a p plicati o n a n d pai n assess me nt occ ur at 
t he sa me ti me p oi nt)  
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 A p pl y st u d y gel acc or di n g t o treat me nt sc he d ule  
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 5 ( ± 1 da y): 
o  Tele p h o ne Call Peri o d 1 t o assess safet y a n d s ki n c o n diti o n. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 2 9 of 6 0 
Rec or d A Es
Rec or d s ki n c o n diti o n if a p plica bl e.
Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 8:  
o  E O S Visit Peri o d 1 ( + 1 da y). Pr oce d ures a n d assess me nts are as f oll o ws: 
 Vital si g ns 
 E C G 
 Pre g na nc y test ( uri ne) (fe males o nl y) 
 Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis) 
 P h ysi cal e xa mi n ati o n 
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 
  
 
 
 
 A p pl y st u d y gel at 6 a m o n Da y 8 
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 C oll ect st u d y gel 
 C oll ect e- diar y 
o  Safet y Visit Peri o d 2 ( ± 1 da y). Pr oce d ures a n d ass ess me nts are as f oll o ws: 
 Vital si g ns 
 P h ysi cal e xa mi n ati o n 
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 
  
 
 
 
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 0 of 6 0 
Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 A p pl y st u d y g el (
 acc or di n g t o treat m e nt assi g n me nt. 
N ote: s o me st u d y gel a p plicati o ns ma y occ ur o utsi de t he cli nic visit.
Dis pe nse st u d y gel (f or o ut- patie nt p orti o n) 
 Da y 9 t o Da y 2 2: 
o  O ut- patie nt p orti o n Peri o d 2: S u bjects a p pl y st u d y gel acc or di n g t o t heir 
assi g ne d treat m e nt a n d rec or d assess m e nts as f oll o ws: 
 A p pl y st u d y gel (
 acc or di n g t o treat m e nt assi g n me nt. 
P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 1 1 ( ± 1 da y): 
o  Tele p h o ne Call Peri o d 2 t o assess safet y a n d s ki n c o n diti o n. 
 Rec or d A Es 
 Rec or d s ki n c o n diti o n if a p plica bl e 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 1 5 ( ± 1 da y): 
o  F oll o w- u p Tele p h o n e Call Peri o d 1 t o assess safet y a n d s ki n c o n diti o n. 
 Rec or d A Es 
 Rec or d s ki n c o n diti o n if a p plica bl e 
 Rec or d c o n c o mita nt me dicati o ns 
o  Safet y Visit Peri o d 2 
 Vital si g ns 
 P h ysi cal e xa mi n ati o n
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 1 of 6 0 
A p pl y st u d y g el (
 acc or di n g t o treat m e nt assi g n me nt.
N ote: s o me st u d y gel a p plicati o ns ma y occ ur o utsi de t he cli nic visit.
Dis pe nse st u d y gel (f or o ut- patie nt p orti o n) 
 Da y 1 8 ( ± 1 da y): 
o  Tele p h o ne Call Peri o d 2 t o assess safet y a n d s ki n c o n diti o n. 
Rec or d A Es
Rec or d s ki n c o n diti o n if a p plica bl e.
Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 Da y 2 2 ( + 1 d a y): 
o  E O S Visit Peri o d 2: T he visit pr oce d ures i ncl u de safet y assess me nts, a n d 
c ollecti o n of st u d y gel a n d e- diaries.
Vital si g ns
E C G 
Pre g na nc y test ( uri ne) (fe males o nl y) 
Cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, a n d 
uri nal ysis)
 P h ysi cal e xa mi n ati o n
 S ki n e xa mi n ati o n / ass ess me nt at st u d y gel site 
 A p pl y st u d y gel at 6 a m o n Da y 2 2 
 P h ot o gra p hic e val u ati o n of a p plicati o n site reacti o ns, as nee de d 
( bef ore st u d y gel a p pli cati o n) 
 Rec or d A Es 
 Rec or d c o n c o mita nt me dicati o ns 
 Rec or d res c ue me di cati o n use 
 C oll ect st u d y gel 
 C oll ect e- diar y 
 Da y 2 9 ( ± 1 da y): 
o  F oll o w- u p Tele p h o n e Call Peri o d 2 t o assess safet y a n d s ki n c o n diti o n. 
 Rec or d A Es 
 Rec or d s ki n c o n diti o n if a p plica bl e. 
 Rec or d c o n c o mita nt me dicati o ns 
T he pr oce d ures a n d assess me nts t o be perf or me d at eac h visit are i n dicate d i n Ta ble  2 .  


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 2 of 6 0 
6. 4   
C O M P LI A N C E WI T H T H E P R O T O C O L
T he i n vesti gat or m ust a gree t o i m ple me nt t he st u d y pr ot oc ol as writte n a n d a d here t o t he 
g ui deli nes gi ve n i n t he “I n v esti gat or’s State me nt ”, w hic h will be si g ne d pri or t o t he start 
of t he st u d y. T he st u d y will be perf or me d i n acc or da nce wit h Healt h I ns ura nce P orta bilit y 
a n d 
Acc o u nta bilit y 
Act, 
Declarati o n 
of 
Helsi n ki, I nter nati o nal 
C o nfere nce 
o n 
Har m o nisati o n (I C H) G o o d Cli nical Practice ( G C P) g ui deli nes, l o cal la ws, F o o d a n d Dr u g 
A d mi nistrati o n ( F D A) G C P re g ulati o ns 
5 0, 5 4, 5 6, a n d 3 1 2), a n d ot her a p pli ca ble g ui d a nce d oc u me nts.
If t h e i n v esti gat or c o nsi d ers e nr olli n g a s u bject t hat d oes n ot meet all i ncl usi o n or e x cl usi o n 
criteria, a n e xe m pti o n m ust be re q u este d fr o m t h e K o wa R esearc h I nstit ute, I nc. ( K RI) 
Me dical M o nit or pri or t o s u bject e nr oll m e nt. T he j ustificati o n f or t he e xe m pti o n m ust be 
d oc u me nt b y t he i n vesti gat or. T he a p pr o val or rejecti o n of t he e xe m pti o n m ust be 
d oc u me nte d b y t he K RI Me dical M o nit or pri or t o t he s u bject’s e nr oll me nt or scree n fail ure.  
Pr ot oc ol n o nc o m plia nce m ust be re p orte d t o t h e 
C R O] 
Me dical M o nit or a n d K RI. Eac h de viati o n a n d t he reas o n f or its o cc urre nce m ust b e 
d oc u me nte d a n d e ntere d o n t h e C R F/e C R F. K RI retai ns t h e ri g ht t o re q uire t he wit h dra wal 
of a n y s u bject w h o vi olat es t he pr ot o c ol. 
6. 5  
T E R MI N A TI O N O F T H E S T U D Y 
If, i n t he o pi ni o n of t he i n vesti gat or, t h e cli nical o bser vati o ns i n t he st u d y s u g gest t hat it 
ma y be u n wise t o c o nti n ue, or if t here is a n u n e x p ecte d, u nacce pta ble or si g nifica nt safet y 
ris k p ose d t o war d st u d y s u bjects, t he st u d y ma y b e ter mi nate d after c o ns ultati o n wit h t h e 
a n d K RI. A writte n state m e nt f ull y d oc u m e nti n g t he reas o n(s) f or 
t he ter mi nati o n will b e pr o vi de d t o K RI. I n a d diti o n, K RI ma y ter mi nate t he st u d y at a n y 
ti m e.  
If it bec o mes a p p are nt t hat s u bject e nr oll me nt is u nsatisfact or y wit h res p ect t o q ualit y or 
q ua ntit y, or data rec or di n g is i nacc urate or i nc o m plete o n a c hr o nic b asis, or pr ot o c ol 
re q uire me nts are n ot bei n g met, K RI has t he ri g ht t o ter mi n ate t he st u d y a n d re m o ve all 
st u d y m aterials fr o m t he i n vesti gati o nal sit e. A writte n state me nt will be pr o vi de d t o t he 
i n vesti gat or, t he I nstit uti o nal Re vie w B oar d/I n d e p e n de nt Et hics C o m mittee (I R B/I E C), 
a n d re g ul at or y a ut h orities, if re q uire d. I n t h e e ve nt of a n y seri o us or n o n-seri o us A Es 
ha vi n g occ urre d at a site, all d oc u me ntati o n rel ati n g t o t he e ve nt(s) m ust b e o btai ne d. 
 
7. 0  
S T U D Y M E DI C A TI O N 
7. 1   
D E S C RI P TI O N O F S T U D Y M E DI C A TI O N
T he st u d y gels i ncl u de K- 2 8 5 a n d me nt h ol gel. 
 
K- 2 8 5 is a t o pical g el w hic h c o ntai ns 
 
 
Me nt h ol gel c o ntai ns 
. 
 
Eac h of t h e st u d y gels c o ntai ns t he f oll o wi n g e xci pie nts: 
 
, 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 3 of 6 0 
 
7. 2 
D R U G P A C K A GI N G  
T he st u d y gels are fille d i n al u mi n u m-la mi nate d t u bes at a wei g ht of   
of st u d y gel 
per t u be. 
F or eac h tr eat m e nt ar m, 2 t y pes of kits c o ntai ni n g st u d y gel, d osi n g s p o o ns, a n d a p plicati o n 
te m plate materi als will be pre pare d (
) (Fi g ure 2 ). 
 
   
 
 
 
 
T he bl ue c ol or b o x i n Fi g ure 2 re prese nts kits f or s u bjects assi g ne d t o 
 
( Peri o d 1) (act ual cart o n will be w hite). Eac h s u bject will a p pl y   
of assi g ne d st u d y 
 T h e a m o u nt of st u d y gel nee de d per s u bject is 
). Eac h s u bject will be assi g ne d a kit c o ntai ni n g 
 of assi g ne d 
st u d y gel (f or a t otal of   
 eac h st u d y gel). 
T he pi n k c ol or b o x i n Fi g ure 2 re pres e nts kits f or s u bjects assi g ne d t o 
 
( Peri o d 1 a n d Peri o d 2) (act u al cart o n will be w hit e). Eac h s u bject will a p pl y 
 
 
 a n d eit her 
 f or a n ot her 2 wee ks. T he 
ma xi m u m a m o u nt of st u d y gel nee de d per s u bject is 
 
 
 
 Eac h s u bject will be assi g ne d a kit c o ntai ni n g 
 t u bes of 
st u d y gel (f or a t otal of 
st u d y gel).  
Dis pe nsi n g of st u d y gel is descri be d i n Secti o n  7. 5. 1 . 
Re place m e nt kits will be pr o vi de d o nl y if p ac ka gi n g is da ma ge d pri or t o recei pt of deli ver y. 
7. 3  
D R U G L A B E LI N G 
St u d y gel will be la bele d wit h t he f oll o wi n g i nf or mati o n: 
1)  St u d y n u m ber 
2)  C o nte nts a n d a m o u nt 
3)  L ot n u m ber 
4)  Kit N u m ber 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 4 of 6 0 
5)
T he st ora ge c o n diti o ns 
6)
Na me a n d a d dress of S p o ns or (e. g., K RI)  
7)  Ca uti o n - Ne w Dr u g Li mite d b y Fe deral La w t o I n vesti g ati o nal Use 
8)  Ca uti o n - Kee p o ut of reac h of c hil dre n 
9)  Ca uti o n – A v oi d o pe n fire or s m o ki n g u ntil t h e gel has drie d 
1 0)  I nstr u cti o n – A p pl y t h e g el usi n g t he pr o vi de d d osi n g s p o o ns acc or di n g t o t he 
detail e d i nstr ucti o ns o n t he kit pac ka g e la bel 
7. 4  
D R U G S T O R A G E 
St u d y gels m ust be st ore d at c o ntr olle d r o o m t e m p erat ure of 
 wit h 
e xc ursi o ns p er mitte d bet wee n 
 as i n dicate d o n t h e dr u g la bel. 
7. 5  
DI S P E N SI N G A N D A D MI NI S T R A TI O N O F T R E A T M E N T 
7. 5. 1  Dis pe nsi n g of St u d y Gel 
St u d y gel will be dis pe nse d o n Da y 2, Da y 8 a n d Da y 1 5. A s ufficie nt n u m ber of t u bes t o 
s u p pl y e n o u g h st u d y gel f or 1 wee k at a ti me will be pr o vi d e d. 
7. 5. 2  A p plic ati o n Tr ai ni n g 
O n Da y - 1, s u bjects will rec ei ve trai ni n g o n t h e a p plicati o n of st u d y gel i ncl u di n g vi de o 
trai ni n g. F urt her a p plicati o n i nstr ucti o ns are pr o vi de d i n A p pe n di x 3 . 
7. 5. 3  Dr u g A d mi nistr ati o n  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 5 of 6 0 
3.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 6 of 6 0 
 
 
7. 5. 4  e- Di ar y 
A n e- diar y will be iss ue d t o eac h s u bject b y st u d y staff o n Da y 1. S u bjects will rec or d
i nf or mati o n as d etaile d i n t he e- diar y trai ni n g a n d d oc u me ntati o n f or t he st u d y l e g a n d 
n o n-st u d y le g (if re q uir e d) at t h e ti m e p oi nts s pecifie d i n Ta ble 2 .  
T he act u al ti me a n d date t hat eac h set of pai n assess m e nts is starte d at eac h ti m e p oi nt m ust 
be rec or de d i n t he e- diar y. 
T he e- diar y will be c ollecte d fr o m t he s u bj ect o n Da y 8 (s u bjects d osi n g d uri n g Peri o d 1) 
or Da y 2 2 (s u bjects d osi n g d uri n g Peri o d 2) after t he E O S/ E T assess me nt a n d data will be 
tra nscri b e d i nt o t he e C R F b y a me m ber of t h e st u d y staff. 
7. 5. 5  P h ysic al E xercise 
T he sta n dar dize d re petiti v e q ua drice ps m uscle e xercise is descri be d i n Secti o n 5. 3. 4 . 
S u bjects will n ot e n ga ge i n a n y stre n u o us p h ysical acti vit y d uri n g st u d y peri o d. 
7. 6  
C O M P LI A N C E WI T H P R E S C RI B E D S T U D Y G E L D O SI N G R E GI M E N 
T he st u d y gel will be a p plie d at t he cli nic o n Da ys 1 a n d 2. St u d y gel f or a p pli cati o n b y 
s u bjects fr o m t he ni g ht d ose o n Da y 2 t hr o u g h t he m or ni n g d ose o n Da y 8 will b e dis pe nse d 
t o s u bjects o n Da y 2. F or s u bjects assi g ne d t o Peri o d 2, st u d y gel f or a p plicati o n b y s u bjects 
will b e dis pe nse d at t he Da y 8 a n d Da y 1 5 Safet y visits. St u d y gel t u bes will be wei g he d, 
i n gra ms, a n d t he t otal wei g ht f or all t u bes rec or d e d pri or t o dis pe nsi n g t o s u bjects. St u d y 
gel will be c ollecte d o n Da y 8 (f or Peri o d 1 s u bjects) a n d Da y 2 2 (f or Peri o d 2 s u bjects), 
wei g he d a n d t h e fi nal wei g ht rec or de d. C o m plia nce will be d eter mi ne d fr o m t he fi nal 
wei g ht of t he t u bes c o m pare d t o t he e x p ecte d decreas e fr o m t h e starti n g wei g ht, base d o n 
t he assi g ne d d osi n g sc he d ule (  
per d ose × t he n u m ber of d os es). 
7. 7  
D R U G A C C O U N T A BI LI T Y 
T he i n vesti gat or or desi g nee will si g n a recei pt f or t he st u d y gel w he n recei v e d. T he st u d y 
gel m ust b e st ore d as d es cri be d ( Secti o n 7. 4 ), ke pt i n a s ec ure d l ocati o n t o w hic h o nl y t he 
i n vesti gat or a n d desi g nate d staff ha ve access, a n d dis pe nse d o nl y t o t h ose s u bjects f or mall y 
e nr oll e d i n t he st u d y.  
T he i n vesti gat or or desi g nee m ust mai ntai n a n acc urate rec or d of t h e s hi p me nt a n d 
dis pe nsi n g of st u d y g el i n a dr u g acc o u nt a bilit y le d ger. Dr u g acc o u nt a bilit y will be 
m o nit ore d b y t h e st u d y m o nit or d uri n g m o nit ori n g visits a n d at t h e c o m pleti o n of t he st u d y.
All dr u g will b e i n ve nt orie d b y   
 at t he c o ncl usi o n of t he st u d y. Sec ure dis p osal at t he 
e n d of t h e st u d y will be arra n ge d after t he cli nical st u d y re p ort has bee n fi n alize d.  
7. 8  
P R O C E D U R E F O R U N B LI N DI N G 
As nee de d, t he ra n d o miz ati o n c o d e ma y be br o ke n b y t he i n vesti gat or t o m a na ge a n ur ge nt 
me dical e ve nt. W h e n p ossi ble, u n bli n di n g will be reser v e d f or sit uati o ns w here treat me nt 
all ocati o n is re q uire d t o be k n o w n f or safet y reas o ns. If p ossi ble, t he Me dical M o nit or is 
c o ntacte d t o disc uss t he case bef ore t he c o de is br o ke n. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 7 of 6 0 
If it bec o mes n ecess ar y t o u n bli n d treat me nt i nf or mati o n d uri n g t h e st u d y, t he reas o n f or 
u n bli n di n g is d oc u me nte d i n t he C R F/e C R F. T he i n vesti gat or m ust c o ntact t he Me di cal 
M o nit or pr o m ptl y a n d e x plai n t he reas o n f or t he pre m at ure u n bli n di n g. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 8 of 6 0 
8. 0
C O N C O MI T A N T M E DI C A TI O N
T he i n vesti gat or m ust rec or d t he use of all c o nc o mita nt me dicati o ns, b ot h prescri be d a n d 
o ver-t h e-c o u nter, i n t he C R F/e C R F. T his i ncl u des dr u gs use d o n a c hr o nic a n d as- n ee de d 
basis. S u bjects m ust be disc o ura ge d fr o m starti n g a n y ne w m e dicati o n, b ot h prescri be d a n d 
o ver-t h e-c o u nter, wit h o ut c o ns ulti n g t he i n vesti gat or, u nless t he ne w me dicati o n is 
re q uire d f or e mer ge nc y use.
8. 1   
G E N E R A L C O N SI D E R A TI O N S 
All me dicati o ns a n d ot her treat m e nts ta ke n b y s u bjects wit hi n 3 0 da ys bef ore d osi n g a n d 
d uri n g t he st u d y will be rec or de d i n t h e C R F. A n y c ha n ges i n t he c o nc o mit a nt me dicati o ns 
after disc h ar g e fr o m t he cli nic o n Da y 2, eit her prescri be d or self-a d mi nistere d, will be 
d oc u me nte d a n d re vie we d acc or di n g t o t he s c he d ule i n Ta ble  2.   
8. 2  
P R O HI BI T E D M E DI C A TI O N A N D T H E R A PI E S 
T he f oll o wi n g me di cati o ns a n d t hera pies are pr o hi bite d d uri n g t he st u d y: 
 
Oral or t o pical a nal gesi c me dicati o ns wit hi n 1 4 da ys bef ore t h e S cree ni n g Visit.
 
S yst e mic c ortic oster oi d wit hi n 3 0 d a ys bef ore t h e Scree ni n g Visit.
 
Prescri pti o n or o ver-t he-c o u nter pr o d u cts c o ntai ni n g me nt h ol or N S AI Ds. 
 
Slee p 
me dicati o n, 
m us cle rela xa nt, a ntic o n v ulsa nt, or a nti de press a nt i n t he last 
6 m o nt hs t o treat a c hr o nic pai n c o n diti o n. 
 
A ntic o n v ulsa nt or a nti de pressa nt f or a n o n- p ai nf ul c o n diti o n at a d ose t hat h as n ot bee n 
sta ble f or at least 3 m o nt hs bef ore t h e Scree ni n g Visit.
 
T he a p pli cati o n or us e of ice, heat, mass a ge, a n d wra p pi n g o n t he l e gs 
 
Me dicati o ns or treat m e nts t hat w o ul d si g nifica ntl y i nfl ue nce or e xa g gerat e res p o nses 
t o t h e gel, or t h at w o ul d alter i nfla m mat or y or i m m u ne res p o nses t o t h e g el, wit hi n 3 0 
da ys bef ore t he first d ose of st u d y g el (e. g., c ycl os p ori ne, tacr oli m us, c yt ot o xic dr u gs, 
i m m u ne gl o b uli n, Bacill us Cal mette- G ueri n vacci n e, m o n ocl o nal a nti b o dies, ra di ati o n 
t hera p y). 
 
S u bjects will n ot e n ga ge i n a n y stre n u o us p h ysical acti vit y d uri n g st u d y peri o d. 
8. 3  
P E R MI T T E D M E DI C A TI O N 
Use of a n y resc u e me dicati o n f or D O M S is str o n gl y dis c o ura ge d u ntil 1 6 8 h o urs after t he 
first st u d y gel a p plicati o n, at w hic h ti me o ver-t h e-c o u nter ( O T C) acet a mi n o p he n ( o ne 
5 0 0 m g aceta mi n o p he n ta blet t wice dail y, n ot m ore t ha n e ver y 6 h o urs) as resc ue 
me dicati o n is per mitte d, if re q uire d. S u bjects e x p erie nci n g se vere pai n or i na bilit y t o m o ve 
or wal k d ue t o pai n m a y be per mitte d t o use resc ue me dicati o n ( o ne 5 0 0 m g O T C 
aceta mi n o p he n ta blet t wi ce dail y, n ot m ore t ha n e ver y 6 h o urs) pri or t o 1 6 8 h o urs aft er t h e 
first st u d y gel a p plicati o n. If s u bjects ta k e resc u e me dicati o n bef ore t he first 1 6 8 h o urs, it 
will b e ca pt ure d as a c o n c o mit a nt me dicati o n. 
N o ot her m e dicati o ns (i n cl u di n g s u p ple me nts) are per mitte d d uri n g t h e st u d y, e xce pt as 
necessar y t o treat a n A E, at t he i n vesti gat or’s dis creti o n. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 3 9 of 6 0 
9. 0
A D V E R S E E V E N T S
9. 1   
A D V E R S E E V E N T D E FI NI TI O N 
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject a d mi nistere d a p har m ace uti cal 
pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t h e p har mace utical 
pr o d uct. A n A E ca n, t h eref ore, be a n y u nfa v ora ble a n d u ni nte n de d si g n, s y m pt o m, or 
disease te m p orall y ass o ciate d wit h t he use of a m e dici nal pr o d uct, w h et her or n ot relate d 
t o t h e me dici n al pr o d uct. A n y w orse ni n g of t he s u bject’s disease u n der st u d y or ot h er 
me dical c o n diti o ns will als o be c o nsi dere d t o be a n A E, u nless it is wit hi n t he n or mal ra n g e 
of disease fl u ct uati o n f or t hat s u bject. 
Cli nicall y mea ni n gf ul (f or a gi ve n s u bject) c h a n g es i n p h ysical e xa mi nati o n fi n di n gs a n d 
a b n or mal o bjecti v e test fi n di n gs (e. g. cli nical la b orat or y tests e xce pt f or ele vate d test
res ults f or ser u m C K, Secti o n 5. 2. 2. 1 ], E C Gs) are als o rec or d e d as A Es. T he criteria f or 
deter mi ni n g w het her a n a b n or mal o bjecti v e test fi n di n g s h o ul d be re p orte d as a n A E are as 
f oll o ws:
1. test res ult is ass ociate d wit h acc o m pa n yi n g s y m pt o ms, a n d/ or; 
2.  test res ult re q uires a d diti o nal dia g n ostic testi n g or me dical/s ur gical i nter ve nti o n, 
a n d/ or; 
3.  test res ult lea ds t o a c ha n ge i n st u d y d osi n g or dis c o nti n uati o n fr o m t he st u d y, 
si g nifica nt a d diti o nal c o nc o mita nt dr u g treat m e nt or ot h er t h era p y, a n d/ or;
4. test res ult lea ds t o a n y of t he o utc o mes i ncl u de d i n t he defi niti o n of a seri o us A E
( S A E). 
Merel y re p eati n g a test, i n t h e a bse nce of a n y of t he a b o ve c o n diti o ns, d oes n ot m eet 
c o n diti o n n u m b er 2 a b o v e f or re p orti n g as a n A E.
A n y a b n or mal test res ult t hat is deter mi ne d t o b e a n err or d o es n ot re q uire re p orti n g as a n 
A E. 
A T E A E is defi n e d as a n A E t h at be gi ns after t h e start of st u d y gel or a n e ve nt t hat be gi ns 
bef ore t h e start of t he st u d y gel a n d w orse ns i n i nt e nsit y after starti n g treat m e nt.
9. 2   
R E P O R TI N G A D V E R S E E V E N T S 
At eac h e val uati o n, t h e i n vesti gat or will d eter mi ne w het her a n y A Es h a ve occ urre d. T h e 
s u bject will be q uesti o ne d i n a ge n eral wa y a n d n o s pecific s y m pt o ms will b e s u g geste d. If 
a n y A Es h a ve o cc urre d, t he y will be rec or de d o n t he A E pa ges of t he C R F or e C R F a n d i n 
t he s u bject’s me dical rec or d. If k n o w n, t h e dia g n osis will b e rec or d e d, i n prefere nce t o t he 
listi n g of i n di vi d ual si g ns a n d s y m pt o ms. 
A d vers e e ve nt re p orti n g be gi ns w he n i nf or m e d c o nse nt is o btai ne d a n d e n ds at t he 
c o ncl usi o n of t h e st u d y, u nless a n u nres ol ve d A E is still bei n g f oll o we d.
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 0 of 6 0 
T he se verit y of t h e A E will b e gra de d as f oll o ws: 
 
Mil d 
T he A E is easil y t olerat e d a n d d oes n ot i nterfere wit h n or mal dail y 
acti vities. 
 
M o derat e   
T he A E ca uses s o me i nterfere nce wit h dail y acti vities. 
 
Se vere 
T he A E ca uses all n or mal dail y acti vities t o be c o m pletel y halte d.
 
T he i n vesti gat or will ma ke a j u d g me nt re gar di n g w het her or n ot t he A E was relat e d t o t he 
st u d y gel. ( Please refer t o t he defi niti o ns bel o w.) T he i n vesti gat or will e val uate a n y c ha n g es 
i n la b orat or y val ues, ma ke a deter mi n ati o n as t o w het her or n ot t he c ha n ge is cli nicall y 
i m p orta nt, a n d w het her or n ot t h e c h a n ges were relate d t o t he st u d y gel. H o we ver, e ve n if 
t he i n vesti gat or feels t here is n o relati o ns hi p t o t he st u d y g el, t he A E or l a b orat or y 
a b n or malit y M U S T  be rec or de d i n t he C R F/e C R F. T he f oll o wi n g g ui da n ce will be use d 
b y i n vesti gat ors w he n assessi n g relati o ns hi p: 
Rel ate d 
 
Occ urs wit hi n a reas o n a ble te m p oral se q ue n ce t o a d mi nistrati o n of st u d y gel or,
 
Ca n n ot be e x plai n e d b y c o nc urre nt disease or ot h er dr u gs or c h e micals or,  
 
I m pr o v es or disa p p ears o n st o p pi n g or re d uci n g st u d y gel ( de-c halle n ge) 
 
Rea p pears o n re p eate d e x p os ure t o st u d y gel (re-c halle n ge) 
 
Is a n u n us u al e v e nt t hat is k n o w n t o b e ass ociate d wit h t he dr u g or t his class of 
c o m p o u n d, a n d ca n n ot be e x plai ne d b y ot her t hera p y or t he p artici pa nt’s p h ysical 
c o n diti o n 
 
U nli kel y t o be attri b ute d t o c o nc urre nt disease or ot her dr u gs or a cli nicall y reas o na bl e 
res p o nse o n wit h dra wal ( de-c h alle n ge) 
U nrel ate d 
 
Occ urs wit h a te m p oral relati o ns hi p t o a d mi nistrati o n of st u d y gel w hic h m a kes a ca us al 
relati o ns hi p i m pr o ba ble or,  
Ot her dr u gs, c he micals or u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns of 
ca usalit y or, 
 
Is k n o w n t o b e ass ociate d wit h t he partici pa nt’s cli nical c o n diti o n, or wit h ot her 
me dicati o n ta ke n b y t he partici pa nt
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 1 of 6 0 
T he i n vesti gat or will rec or d t h e acti o n ta ke n a n d o utc o me f or eac h A E acc or di n g t o t he 
f oll o wi n g:
Acti o n t a ke n
 
N o ne
 
Treat m e nt re q uire d 
 
H os pitalizati o n
S u bject wit h dra w n
Ot her (s pecif y)
Acti o n T a ke n Wit h St u d y Tre at me nt 
 
D ose n ot c ha n g e d
 
Dr u g i nterr u pte d 
Dr u g wit h dra w n
N ot a p plica ble
O utc o m e 
 
Res ol ve d: T he e ve nt h as rec o v ere d
 
N ote: A n S A E/ A E st o p date s h o ul d be pr o vi d e d.
 
Rec o vere d/ Res ol ve d wit h se q uelae: T he st u d y s u bject h as rec o vere d as m uc h as ma y 
be e x pecte d b ut is left wit h se q uela e of t he e ve nt t h at are n ot e x p ecte d t o rec o ver f urt her
 
N ote: If t h e se q uelae are se vere e n o u g h t o re prese nt a si g nifica nt disa bilit y or 
i nca pacit y t he n t he e ve nt s h o ul d be re p orte d as a n S A E. 
 
Rec o veri n g/ Res ol vi n g: C a n be use d i n cases w here st u d y s u bject is k n o w n t o be clearl y 
rec o v eri n g fr o m t he e ve nt at t he e n d of a st u d y, alt h o u g h t he e ve nt is n ot yet res ol ve d, 
a n d t he i n vesti gat or a n d Me dical M o nit or a gree t hat f urt her f oll o w- u p is n ot necess ar y.
 
Fatal: T he st u d y s u bject die d as a res ult of t h e A E 
 
N ote: Deat h is c o nsi dere d a n o utc o me of a n A E rat her t ha n a n A E i n its o w n 
ri g ht, a n d t he ca us e of deat h s h o ul d be rec or de d as t he A E. T here ma y be rare 
circ u msta nc es w here t h e ca use of d eat h is u n k n o w n a n d t he deat h ma y h a ve t o 
be rec or de d as t he e ve nt (e. g., “s u d de n car diac deat h ”). A d vers e e ve nts 
res ulti n g i n deat h are S A Es.
 
N ot rec o v ere d/ N ot res ol ve d: T he s u bject has a n A E t hat has n ot i m pr o ve d or 
rec u p erate d at t h e ti me of t he re p ort 
9. 3  
F O L L O W- U P O F A D V E R S E E V E N T S
If a n y A Es are prese nt w he n a s u bj ect c o m pletes t he st u d y, or w he n a s u bje ct dis c o nti n ues 
or is wit h dra w n fr o m t h e st u d y, t he s u bject will be re-e v al uate d. At t h e i n vesti gat or’s 
discreti o n, mi n or A Es ca n be re-e val uate d via tele p h o ne a n d d oc u me nte d. If t he A E is still
n ot res ol ve d, a d diti o nal f oll o w- u p will be perf or m e d as a p pr o priate. E v er y eff ort will be 
ma de b y t he i n v esti gat or or dele gate t o c o ntact t he s u bject u ntil t h e A E is res ol ve d or 
sta bilize d, or t h e M e dical M o nit or a n d i n vesti gat or a gree t hat f urt her f oll o w- u p is n ot 
necessar y. T he f oll o w- u p of A Es will be d oc u me nte d i n t he s u bject’s me dical rec or ds.


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 2 of 6 0 
1 0. 0
S E RI O U S A D V E R S E E V E N T S
A n S A E is a n y u nt o war d me di cal o cc urre nce t hat at a n y d ose:
 
Res ults i n deat h 
Is lif e-t hreate ni n g
Re q uires s u bject h os pit alizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
 
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 
Is a c o n ge nital a n o mal y/ birt h defect
 
I m p ort a nt me dical e v e nt 
Me dical a n d scie ntific j u d g me nt will be e x ercis e d i n deci di n g w het h er e x pe dite d re p orti n g 
is a p pr o priate i n ot h er sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot b e 
i m m e diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par diz e t he 
s u bject or ma y re q uire i nter ve nti o n t o pre ve nt o n e of t he ot h er o utc o mes liste d i n t he 
defi niti o n a b o ve. E v e nts t h at re q uire e x p e dite d re p orti n g will als o be c o nsi dere d t o be 
S A Es. 
1 0. 1  
LI F E- T H R E A T E NI N G A D V E R S E E V E N T 
T he ter m “life-t hreate ni n g” i n t he defi niti o n of “s eri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of deat h at t he ti me of t h e e v e nt. It d o es n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h, if it were m ore se vere.
1 0. 2  
H O S PI T A LI Z A TI O N 
H os pitalizati o n is d efi n e d as t he s u bject bei n g h os pitalize d o ver ni g ht, or t he s u bject’s 
h os pital sta y bei n g pr ol o n ge d f or at least a n a d diti o nal o ver ni g ht sta y. Pre- pla n ne d h os pit al 
sta ys or h os pital sta ys f or n o n- me dical s oci al reas o ns are n ot a p plica ble. T we nt y-t hree h o ur 
h os pitalizati o ns f or o bser v ati o n will be disc usse d wit h t he Me dic al M o nit or t o deter mi ne 
w het h er t h e y are a p pr o priate f or S A E re p orti n g. 
1 0. 3  
I M P O R T A N T M E DI C A L E V E N T 
Me dical a n d sci e ntific j u d g me nt will be e xercis e d i n deci di n g w het her e x p e dite d 
re p orti n g is a p pr o priat e i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot 
be i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pit alizati o n b ut ma y je o par dize 
t he s u bject or ma y re q uir e i nter v e nti o n t o pre ve nt o ne of t h e ot h er o ut c o mes liste d i n t he 
defi niti o n a b o ve. 
1 0. 4  
P R E G N A N C Y 
A n y s u bject 
w h o 
bec o mes 
pre g na nt 
d uri n g t he st u d y 
m ust i m me diatel y 
be
disc o nti n ue d/ wit h dra w n. T he i n vesti g at or is re q uire d t o n otif y t he K RI M e dical M o nit or 
i m m e diatel y if a n y s u bj ect bec o mes pre g na nt d uri n g t h e st u d y. Pre g n a nt s u bjects will 
re q uire peri o dic f oll o w- u p wit h d oc u me ntati o n of t he o utc o me of t he pre g na nc y i n t he 
st u d y rec or ds.


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 3 of 6 0 
1 0. 5
S U B J E C T DI S C O N TI N U A TI O N A N D WI T H D R A W A L
If a s u bject e x perie n ces a n A E t hat lea ds t o disc o nti n uati o n of st u d y gel treat m e nt a n d 
wit h dra wal fr o m t he st u d y, t he C R F/e C R F
will i de ntif y t he A E as t he reas o n f or 
wit h dra wal. S u bjects t hat disc o nti n ue st u d y gel treat me nt will be as ke d t o c o nti n ue 
sc he d ule d st u d y visits t hr o u g h t he F oll o w- u p p h o n e call. 
1 0. 6  
S E RI O U S U N E X P E C T E D S U S P E C T E D A D V E R S E R E A C TI O N S
Acc or di n g t o F D A C F R 3 1 2. 3 2(a) a n d F D A G ui da nce “ Safet y Re p orti n g Re q uire me nts f or 
I N Ds a n d B A/ B E St u dies” fi nalize d Dece m ber 2 0 1 2, s us pecte d a d vers e r e acti o n mea ns 
a n y A E f or w hic h t h ere is a reas o na bl e p ossi bilit y t hat t h e m e dici nal pr o d uct ca us e d t he 
A E. T he p hrase “reas o n a ble p ossi bilit y” mea ns t here is e vi d e nce t o s u g gest a ca usal 
relati o ns hi p bet wee n t h e A E a n d t he m e dici nal pr o d uct. 
 
T he f oll o wi n g are e x a m ples of t y pes of e vi d e nce t hat w o ul d s u g gest a ca us al relati o ns hi p 
bet wee n t h e dr u g a n d t he A E (i.e., re as o n a ble p ossi bilit y): 
 
A si n gle occ urre nce of a n e ve nt t hat is u n c o m m o n a n d k n o w n t o b e str o n gl y ass ociate d 
wit h dr u g e x p os ure (e. g., a n gi o e de ma, h e patic i nj ur y, Ste ve ns-J o h ns o n S y n dr o me)  
 
O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociat e d wit h dr u g 
e x p os ure, b ut is ot her wise u nc o m m o n i n t h e p o p ulati o n e x p ose d t o t he dr u g 
(e. g., te n d o n r u pt ure)  
 
S us pecte d a dverse re acti o ns are t he s u bset of all A Es f or w hic h t here is a reas o na ble 
p ossi bilit y t hat t he dr u g ca use d t he e v e nt. 
 
A s us pecte d a d v ers e reacti o n is c o nsi d ere d “ u ne x pecte d ” if it is n ot liste d i n t he 
I n v esti gat or’s Br oc h ure or ot h er a p plica ble pr o d uct i nf or mati o n or is n ot liste d at t h e 
s pecificit y or se v erit y t hat has bee n o bser ve d.
 
A n A E or s us pecte d a d v erse reacti o n is c o nsi dere d “seri o us” if, i n t he vie w of eit her t he 
i n vesti gat or or s p o ns or, it res ults i n a n y of t h e f oll o wi n g o utc o m es: 
Deat h, a 
life-t hreat e ni n g A E, i n- p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, a 
persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t h e a bilit y t o c o n d uct n or m al 
life f u ncti o ns, or a c o n ge nital a n o mal y/ birt h defe ct. I m p ort a nt me dical e ve nts t hat ma y n ot 
res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d seri o us 
w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y j e o par dize t he patie nt or s u bject 
a n d ma y re q uire me dical or s ur gic al i nter ve nti o n t o pre ve nt o n e of t h e o ut c o mes liste d i n 
t his defi niti o n. 
 
A n y A E meeti n g t he defi niti o ns of s us pecte d a d verse reacti o n, u ne x pecte d, a n d seri o us is 
c o nsi dere d a seri o us u ne x pecte d s us p ecte d a d v ers e reacti o n ( S U S A R). I n acc or da n ce wit h 
t he F D A G ui da n ce “ Safet y Re p orti n g Re q uire me nts f or I N Ds a n d B A/ B E St u dies”, 
fi nalize d D ece m ber 2 0 1 2, K RI will u n bli n d t he st u d y data f or s u bjects e x peri e nci n g 
S U S A Rs a n d o nl y re p ort t h ose f or s u bjects w h o are o n st u d y gel. All s uc h re p orts will be 
s u b mitte d t o t he i n vesti gat or(s), F D A, a n d I R B/I E C i n a n e x pe dite d ma n ner. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 4 of 6 0 
1 0. 7
S E RI O U S A D V E R S E E V E N T R E P O R TI N G
 
S E RI O U S A D V E R S E E V E N T S A N D S A E S, W H E T H E R O R N O T R E L A T E D T O 
T H E S T U D Y G E L, M U S T B E R E P O R T E D I M M E DI A T E L Y T O T H E S T U D Y 
M E DI C A L M O NI T O R: 
 
 
 
Sit es nee di n g t o c o ntact t he Me dical M o nit or s h o ul d use t he a b o ve 2 4/ 7 S A E h otli ne 
n u m ber a n d 
e mail bef ore c o ntacti n g a n
i n di vi d ual M e dical M o nit or. T he h otli ne n u m b er will e m pl o y a call tree t o c o ntact 
i n di vi d uals i n or der of a call list. 
 
 
 
 
 
 
K o wa Researc h I nstit ute, I n c. will c o n d uct a me di cal re vie w of S A E re p orts. 
 
K o w a Rese arc h I nstit ute, I nc. 
 
 
 
 
 
 
K o wa Researc h I nstit ute, I nc. will o btai n details fr o m t he i n vesti g at or of all seri o us, 
u ne x pecte d a n d rel ate d A Es ( or ot her e ve nts de p e n di n g o n t he s pecific re q uire me nts) t h at 
s h o ul d be re p orte d t o I R Bs/I E Cs, as a p pr o priate. Writte n c o nfir m ati o n t h at t h ese seri o us, 
u ne x pecte d a n d r elate d A Es ha ve bee n s u b mitte d t o t h e I R B/I E C m ust be f or war de d t o 
K RI a n d ke pt i n t he i n vesti gat or files. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 5 of 6 0 
1 1. 0
S T A TI S TI C A L M E T H O D S A N D D A T A A N A L Y SI S
I n ge n eral, ass ess me nts 
wit h c o nti n u o us o utc o mes 
will b e s u m m arize d usi n g t he 
descri pti ve statistics n, mea n, sta n d ar d de vi ati o n ( S D), me dia n, mi ni m u m a n d ma xi m u m. 
F or assess m e nts wit h cate g orical o utc o mes, fre q ue nc y c o u nts a n d perce nta ge will be 
calc ulate d. Detaile d statistical met h o d ol o g y will be prese nte d i n a se parate statisti cal 
a nal ysis pla n.  
1 1. 1  
S A M P L E SI Z E J U S TI FI C A TI O N 
T he para meters are c o ns er vati v el y esti mate d base d o n t he D O M S st u d y wit h   
 g el.
T he bet wee n- gr o u p differe nce i n t h e me a n   
 is 1 1. 0 7 wit h a S D of 2 5. 6 2. T o ha ve 
statisti cal p o wer of 9 0 %, 
. T a ki n g i nt o acc o u nt 
i nf or mati o n l oss ca us e d b y missi n g data, it is esti mate d t hat   
 nee d t o be treat e d 
wit h eac h st u d y gel. 
1 1. 2  
S T U D Y P O P U L A TI O N S
T hree a nal ysis p o p ulati o ns will be e val uate d: 
 
T he f ull a nal ysis set ( F A S) will i ncl u de all ra n d o mize d s u bjects w h o h a ve a b aseli ne 
pai n sc ore a n d at least 1 st u d y gel a p plie d. 
 
T he per- pr ot o c ol set ( P P S) will i ncl u de all ra n d o mi ze d s u bjects w h o h a ve a baseli ne 
pai n sc ore, at least 1 st u d y gel a p plie d, a n d n o maj or pr ot oc ol vi olati o ns. 
 
T he safet y set will i ncl u de all s u bjects w h o ha ve at least 1 st u d y gel a p plie d. 
1 1. 3 
DI S P O SI TI O N
T he n u m ber of s u bjects scree n e d, ra n d o mize d, a n d treate d will be s u m marize d. T he 
n u m ber of s u bjects disc o nti n ui n g treat me nt/ wit h dra wi n g fr o m t he st u d y 
will be 
s u m marize d al o n g wit h t he reas o ns f or dis c o nti n uati o n/ wit h dra wal. S u bjects w h o are 
scree n fail ures al o n g wit h t he m ai n reas o ns f or fail ure will als o be s u m mari ze d. 
1 1. 4 
D E M O G R A P HI C/ B A S E LI N E I N F O R M A TI O N 
De m o gra p hics a n d ot her baseli ne c haract eristics will be s u m marize d wit h descri pti ve 
statisti cs. F or q u a ntitati v e data, mea ns, me dia ns, sta n d ar d d e viati o ns, mi ni m u m a n d 
ma xi m u m val ues will be deter mi ne d. F or q ualit ati ve data, perce nt a ges will be calc ul ate d.  
1 1. 5 
A N A L Y SI S O F E F FI C A C Y P A R A M E T E R S
1 1. 5. 1 Pri m ar y Effic ac y P ar a meters 
 
T he pri mar y a n al ysis p o p ulati o n is t he F A S. T he pri mar y a nal ysis will be re peate d usi n g 
t he P P S. 
 
 
 
. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 6 of 6 0 
If t here e xist missi n g V A S val ues t o be i m p ute d, a n y s uc h v al u es will be i m p ute d bef ore 
calc ulati n g t h e   
. I nt er m e diate missi n g V A S val ues d ue t o a n o missi o n of rec or di n g 
pai n i nte nsit y or s u bject’s slee p will n ot be i m p ute d, t heref ore, t he o bs er ve d val ues bef ore 
a n d after t h e missi n g meas ure me nt will be directl y c o n necte d i n or der t o calc ulate t h e 
. If s u bj ects nee d t o t a ke t he resc ue me di cati o n, t he y will rec or d t h eir pai n i nte nsit y 
i n t h e e diar y b ef ore ta ki n g t he resc ue m e dicati o n. If t he resc ue me dicati o n is ta ke n wit hi n 
6 h o urs of a n o mi nal pai n i nte nsit y assess me nt ti me p oi nt, t h e pai n i nte nsit y sc ore t h at was 
rec or d e d bef ore t a ki n g t he res c ue me dicati o n will be carrie d f or war d t o t he ne xt pai n 
i nte nsit y assess me nt ti me p oi nt. Missi n g val ues ca use d b y wit h dra wal fr o m t he st u d y d ue 
t o e ve nts w hic h are n ot prefera ble t o s u bjects s uc h as a n a d verse e ve nt a n d/ or lac k of 
effic ac y will be i m p ute d b y last o bs er vati o n carri e d f or war d ( L O C F) w hil e t h ose v al ues 
d ue t o l ost t o f oll o w- u p will be i m p ute d u n der t h e missi n g at ra n d o m ( M A R) ass u m pti o n 
wit h t h e m ulti ple i m p utati o n ( MI) t ec h ni q ue. B y usi n g t h e MI t ec h ni q ue, 1 0 0 datasets will 
be ge nerate d. After calc ul ati n g t he   
, a n a nal ysis of c o varia n ce ( A N C O V A) m o del will 
be a p pli e d f or t h e pri mar y e n d p oi nt wit h ge n d er a n d treat m e nt as m ai n effects a n d b aseli ne 
pai n as a c o v ariate i n eac h dataset. M ulti ple res ults will be c o m bi ne d usi n g R u bi n’s r ule. 
As f or a se nsiti vit y a nal ysis, t he L O C F val ues will be re place d b y t h e w orst val ue o bser ve d 
i n t his st u d y, a n d t he n t he sa me pr o ce d ure will be a p pli e d. 
1 1. 5. 2  Sec o n d ar y Effic ac y P ar a meters  
A mi xe d effect m o del re peate d- meas ures ( M M R M) will be a p plie d t o t h e PI D w hile 
sta n di n g a n d PI D at rest t o i n vesti gate treat m e nt differe nces. 
 
. T he ti me t o first 
d ose of resc ue me di cati o n, will be a nal yze d usi n g t he Ka pla n- Meier met h o d t o esti mate 
t he s ur vi val distri b uti o n f u ncti o n.  
1 1. 6 
A N A L Y SI S O F S A F E T Y D A T A
T he safet y e n d p oi nt data will be s u m marize d f or t he safet y set. 
T he A Es
will be c o de d usi n g t he latest versi o n of Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A). A ge neral s u m mar y of t h e A Es a n d S A Es will be s u m marize d b y 
o verall n u m ber of A Es, se verit y a n d relati o ns hi p t o st u d y gel, per treat m e nt gr o u p. T he 
n u m ber of A Es lea di n g t o disc o nti n uati o n/ wit h dra wal a n d S A Es lea di n g t o deat h will als o 
be s u m marize d. T he i nci de nce of A Es will b e s u m m arize d b y b o d y s yste m a n d treat m e nt 
gr o u p. T he i n ci de nce of T E A Es will als o be s u m marize d b y s yste m or ga n class a n d 
preferre d t er m. 
T he cli nical l a b orat or y d ata will be s u m marize d b y treat m e nt gr o u p, al o n g wit h c ha n g es 
fr o m t he b aseli ne. T he v al ues t hat are b el o w t he l o wer li mit or a b o ve t he u p per li mit of t h e 
refere nce ra n g e will be fl a g ge d. T h ose val u es or c ha n ges i n val ues, w hic h are i de ntifie d as 
bei n g cli nicall y si g nifica nt, will be fla g ge d. 
Vital si g ns will als o be s u m marize d b y treat m e nt gr o u p a n d ti m e p oi nt, al o n g wit h t h e 
c ha n ges fr o m baseli n e.  
All A E, cli nical la b orat or y, vit al si g n, p h ysical e xa mi nati o n, st u d y g el a p pli cati o n site 
reacti o n, st u d y gel use a n d c o nc o mita nt me dicati o n use will be prese nte d i n data listi n gs. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 7 of 6 0 
 
 
 
 
  
 
 
 
 
 
 
 
. 


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 8 of 6 0 
1 2. 0
S T U D Y M A N A G E M E N T A N D D A T A C O L L E C TI O N
1 2. 1 
E T HI C A L C O N D U C T O F T H E T RI A L
T his st u d y will be c o n d ucte d acc or di n g t o t he pr ot oc ol, F D A G C P, as descri be d i n 2 1 C F R
Parts 1 1, 5 0, 5 4, 5 6, a n d 3 1 2; t he W orl d Me dical Ass ociati o n Decl arati o n of Helsi n ki; t he
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A); a n d I C H G C P ( E 6/ R 1). 
Eac h i n vesti gat or will c o n d uct t he trial als o acc or di n g t o a p plica ble l ocal or re gi o nal 
re g ulat or y re q uire me nts. 
1 2. 2  
I N S TI T U TI O N A L R E VI E W B O A R D/I N D E P E N D E N T E T HI C S 
C O M MI T T E E 
T he I R B/I E C m ust b e c o nstit ute d acc or di n g t o t he a p plica ble state, fe deral a n d l ocal 
re q uire me nts of eac h partici pati n g l ocati o n, a n d t h ose of t he I C H G C P g ui da nce a n d F D A 
G C P re g ulati o ns. 
It is t he res p o nsi bilit y of eac h i n vesti gati o nal site t o s u b mit t he pr ot o c ol, I n v esti gat or’s 
Br oc h ure, s u bject i nf or me d c o nse nt, s u bject recr uit me nt materials (if a p plica ble), a n d ot her 
re q uire d d oc u m e ntati o n t o t he I R B/I E C f or re vi e w a n d a p pr o v al. C o pies of t he writte n 
a p pr o v als m ust be pr o vi d e d t o 
. T h e d oc u me ntati o n s h o ul d clearl y 
me nti o n t h e a p pr o val/fa v ora ble o pi ni o n of t he pr ot oc ol, t he s u bject I C F, a n d s u bject 
recr uit m e nt m aterials (if a p plica ble). T he res p ecti ve versi o n dates are t o b e i ncl u de d. T he 
writte n a p pr o vals a n d a list of t h e v oti n g me m bers, t heir titles or o cc u pati o ns, a n d t heir 
i nstit uti o nal affiliati o ns m ust be o btai ne d fr o m t he I R B/I E C a n d pr o vi de d t o 
 
pri or t o t he release of cli nical st u d y s u p plies t o t h e i n vesti gati o nal sit e a n d 
c o m me nce m e nt of t h e st u d y. If a n y me m ber of t h e I R B/I E C has direct partici pati o n i n t he 
st u d y, writt e n n otificati o n re gar di n g his or her a bsti ne nce fr o m v oti n g m ust als o be 
o btai ne d. 
Sit es m ust a d here t o all re q uire me nts sti p ulate d b y t he I R B/I E C. T his i n cl u des n otificati o n 
t o t h e I R B/I E C re g ar di n g pr ot o c ol a me n d me nts; u p dates t o t he s u bject i nf or me d c o ns e nt 
a n d recr uit me nt materi als i nte n de d f or vie wi n g b y s u bjects; I n vesti gati o nal Ne w Dr u g 
safet y re p orts; seri o us a n d u ne x pecte d A Es; u p dat es re gar di n g t he o n g oi n g re vie w of t h e 
st u d y at i nter vals s pecifie d b y t h e I R B/I E C; a n d fi nal st u d y re p orts or s u m maries. 
It is t he res p o nsi bilit y of eac h i n vesti gati o nal sit e t o s u b mit i nf or mati o n t o t he a p pr o priate 
I R B/I E C f or a n n ual re vi e w a n d a n n ual re-a p pr o val. 
1 2. 3  
S U B J E C T I N F O R M E D C O N S E N T 
Pri or t he i m ple me ntati o n of st u d y pr oce d ures, s u bj ects a n d pers o ns c o n d ucti n g t h e c o nse nt 
disc ussi o n will be re q uire d t o si g n a n d date t he I R B/I E C-a p pr o v e d I C F a n d eac h s u bject 
will b e gi v e n a c o p y. I n a d diti o n, t his i nf or mati o n will be rec or de d i n t he s u bject’s me dical 
rec or d (i.e., s o urce d oc u me nt). 
T he writte n c o nse nt d oc u me nt will e m b o d y t h e ele me nts of i nf or me d c o nse nt as descri be d 
i n t h e HI P A A, W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki, F D A 2 1 C F R Part 
5 0. 2 5, I C H G C P, a n d i n acc or da n ce wit h a n y l ocal re g ulati o ns. T he i n vesti gat or is 
res p o nsi ble f or t he pre parati o n, c o nte nt, a n d I R B/I E C a p pr o val of t h e I C F. T he I C F m ust 


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 4 9 of 6 0 
be a p pr o ve d b y t h e site- d esi g nate d I R B/I E C a n d b e acce pt a ble t o K RI a n d  
 
. 
T he I C F m ust b e writte n i n a la n g ua ge f ull y c o m pre he nsi ble t o t he pr os pecti v e s u bject. T he 
i n vesti gat or or desi g nee will gi v e t h e s u bj ect a de q uate o p p ort u nit y t o rea d it bef ore it is 
si g ne d a n d date d. I nf or mati o n pr o vi de d will b e gi ve n i n b ot h oral a n d writte n f or m 
w he ne ver p ossi ble a n d i n t he ma n ner d ee me d a p pr o priate b y t he I R B/I E C. S u bjects m ust 
be gi ve n a m ple o p p ort u nit y t o i n q uire a b o ut st u d y details. 
1 2. 4  
A M E N D M E N T S T O T H E P R O T O C O L 
A n a me n d m e nt m ust be a gree d t o i n writi n g b y K RI a n d 
, s u b mitt e d 
as a n I n vesti gati o nal Ne w Dr u g (I N D) a p plicati o n a me n d me nt, a n d s u b mitte d t o a n d 
a p pr o v e d b y t h e res pecti v e I R B/I E C f or eac h i n v esti gati o nal sit e bef ore it is i m ple me nt e d. 
Writte n a p pr o val of a pr ot oc ol a me n d me nt is n ot re q uire d pri or t o i m ple me ntati o n f or 
c ha n ges t o t h e pr ot o c ol, w hic h eli mi nate i m me diate hazar d t o t he s u bject; h o we ver, 
a p pr o v al m ust be o btai n e d as s o o n as p ossi ble t h ereafter. A p pr o v e d a me n d me nts m ust als o 
be si g ne d b y t he i n vesti gat or. 
1 2. 5  
S T U D Y I NI TI A TI O N 
T he i n vesti gat or m ust n ot e nr oll a n y s u bjects pri or t o t h e c o m pleti o n of a f or mal meeti n g 
c o n d ucte d b y a re prese ntati ve of 
( or K RI). T his meeti n g will 
i ncl u de a d etaile d re vie w of t h e st u d y pr ot oc ol a n d C R F/e C R Fs. St u d y gel will n ot be 
s u p plie d t o a n i n vesti gat or u ntil all t he n ecessar y pre-st u d y re q uire m e nts ha ve bee n 
c o m plete d a n d esse ntial si g ne d d oc u me nts are re cei v e d b y 
, as 
a p plica ble, a n d K RI. 
1 2. 6
S T U D Y M O NI T O RI N G 
It is t he res p o nsi bilit y of t he i n vesti gat or t o e ns ure t hat t h e st u d y is c o n d ucte d i n acc or da nce 
wit h t h e pr ot oc ol, I C H/ F D A G C Ps, a p plica ble re g ulat or y re q uire me nts, HI P A A, a n d t he 
c urre nt Declarati o n of Helsi n ki. Vali d data are t o be e ntere d i nt o t he C R Fs/e C R Fs. 
M o nit ori n g acti vities will b e c o n d ucte d as d escri be d i n a n a p pr o ve d M o nit ori n g Pl a n. 
O versi g ht visits ma y be c o n d ucte d b y K RI Cli nical O perati o ns t o assess m o nit ori n g
perf or ma n ce. 
T o ac hi e ve t his o bj ecti ve, t he m o nit or’s d uties are t o ai d t h e i n vesti gat or a n d, at t he s a me 
ti m e, K RI i n t he mai nte na nce of acc urat e, c o m plete, le gi ble, well- or ga nize d a n d easil y 
retrie va bl e data. T he m o nit or will re vie w t h e pr ot oc ol wit h t h e i n vesti gat or. I n a d diti o n, 
t he m o nit or will e x plai n t he i n vesti gat or’s re p orti n g res p o nsi bilities a n d all a p plica ble 
re g ulati o ns c o n cer ni n g t he cli nical e val u ati o n of t he st u d y gel. 
T he i n vesti gat or will per mit t he re prese nt ati ves of K RI a n d
 t o 
m o nit or a n d o versee t he st u d y as fre q ue ntl y as 
 ( or K RI) dee ms is 
necessar y t o deter mi n e t h at data rec or di n g a n d pr ot oc ol a d here nce are acce pta ble. T he 
C R Fs/e C R Fs a n d rel ate d s o urce d oc u me nts will be re vi e we d i n detail b y t h e m o nit or at 
eac h visit, i n acc or da n ce wit h rel e va nt Sta n dar d O perati n g Pr oce d ures ( S O Ps), I C H G C P
g ui da nce, a n d F D A G C P re g ulati o ns. T his i ncl u des res ults of tests perf or me d as a 
re q uire me nt f or parti ci p ati o n i n t his st u d y a n d a n y ot h er m e dic al rec or ds re q uire d t o 


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 0 of 6 0 
c o nfir m i nf or mati o n c o ntai n e d i n t he C R Fs, s uc h as past me dical hist or y a n d sec o n d ar y 
dia g n oses. T he i n vesti gat or a n d staff will be e x pecte d t o c o o perate wit h t he m o nit or/ K RI
a n d pr o vi de a n y missi n g i nf or mati o n, w he ne ver p ossi ble. 
All m o nit ori n g a n d K RI o versi g ht acti vities will b e re p orte d a n d arc hi ve d. A n y iss ues 
i de ntifie d will be re p orte d a n d f oll o we d- u p u ntil res ol ve d. I n a d diti o n, eac h m o nit ori n g 
visit will be i d e ntifie d at t he i n vesti gati o nal site b y t h e m o nit or’s / K RI’s si g nat ure a n d dat e 
o n t he st u d y-s pecific m o nit ori n g l o g. 
1 2. 7 
C A S E R E P O R T F O R M
All s u bject data ge nerate d d uri n g t h e st u d y will be rec or de d o n t he C R F/ e C R F. 
T he i n vesti gat or will e ns ure t hat all d ata are e ntere d pr o m ptl y, le gi bl y, c o m pletel y, 
acc uratel y a n d c o nf or m t o s o urce d oc u me nts, i n acc or da nce wit h s pecifi c i nstr ucti o ns 
acc o m p a n yi n g t he C R Fs/e C R Fs, d esi g ne d s p ecificall y f or t his st u d y a n d s u p plie d b y   
 
 f or eac h s u bject.  
 will o nl y c o nsi der t h e C R Fs/e C R Fs t o be c o m plete after t he y are 
re vie we d a n d si g ne d b y t he i n vesti gat or, i n dicati n g his/ her ass ura nce of t h e acc urac y of all 
rec or d e d dat a. It is e x p ecte d t hat t he i n vesti gat or a n d staff will c o o p erate wit h t he 
m o nit ori n g tea m a n d pr o vi de missi n g data i n a ti mel y ma n ner. 
1 2. 8 
V E RI FI C A TI O N P R O C E D U R E S 
I n f ulfill m e nt of t h eir o bli g ati o ns t o K RI a n d t o v erif y c o m plia nce wit h t his pr ot oc ol, I C H 
G C P g ui d a nce, a n d F D A G C P re g ul ati o ns, t he i n vesti gat or will per mit 
 
, t h e I R Bs/I E Cs, t h e m o nit or, a n d re g ulat or y a ut h oriti es t o ha ve direct access t o 
t he s u bj ect’s me dical rec or ds. 
It is t he i n vesti gat or’s o bli gati o n t o e ns ure d oc u me ntati o n of all rele v a nt data i n t he 
s u bject’s me dical rec or d, C R Fs/e C R Fs, a n d o n st u d y f or ms, w he n a p plica bl e, acc or di n g t o 
pr oce d ures pr o vi de d i n t he pr ot o c ol. 
T he i n vesti gat or will mai ntai n a S u bject I d e ntifi cati o n C o de List t o e na ble u na m bi g u o us 
i de ntificati o n of t h e s u bjects (s u bject na mes a n d c orres p o n di n g s u bject n u m bers). T he 
S u bject I d e ntificati o n C o de List is a n esse ntial d oc u me nt a n d as s uc h m ust be mai ntai ne d 
acc or di n g t o t he I C H G C P g ui deli n es. 
1 2. 9 
R E T E N TI O N O F R E C O R D S 
All d oc u me ntati o n pertai ni n g t o t h e st u d y will be retai ne d b y K RI a n d 
 
i n acc or da nce wit h U. S. F D A re g ulati o ns a n d t he I C H G C P g ui d a nce d oc u me nt. 
will pr o vi de eac h i n vesti gat or wit h a st u d y bi n der, w hic h will be 
use d t o file t he I n v esti gat or’s 
Br oc h ure; pr ot oc ol; dr u g acc o u nta bilit y rec or ds; 
c orres p o n d e nce 
wit h t he I R B/I E C, 
K RI, a n d 
; a n d ot her 
st u d y-relate d d oc u m e nts. 
T he i n vesti gat or a grees t o kee p rec or ds a n d t h ose d oc u me nts t h at i ncl u de ( b ut are n ot 
li mite d t o) t he i de ntificati o n of all partici pati n g s u bjects, me dical rec or ds, st u d y-s pecific 
s o urce d oc u me nts, s o urce w or ks heets, all ori gi n al si g ne d a n d date d I C Fs, c o pi es of all 


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 1 of 6 0 
C R Fs/e C R Fs, q uer y res p o nses, a n d detaile d rec or ds of dr u g dis p ositi o n, t o e na ble 
e val uati o ns or a u dits fr o m re g ulat or y a ut h orities a n d K RI or its desi g nees. 
T he i n vesti gat or a n d 
will retai n rec or ds re q uire d t o be mai nt ai ne d 
u n der fe d eral re g ul ati o ns f or a peri o d of 2 years f oll o wi n g t he date a mar keti n g a p plicati o n 
is a p pr o ve d f or t h e dr u g f or t h e i n dicati o n f or w hic h it is bei n g i n v esti gate d; or, if n o 
a p plicati o n is t o b e file d or if t he a p plicati o n is n ot a p pr o ve d f or s uc h i n dicati o n, u ntil 
2 years after t he i n vesti gati o n is dis c o nti n ue d a n d F D A is n otifie d. H o we ver, t hese 
d oc u me nts
will be retai n e d f or a l o n ger peri o d if re q uire d b y t he a p plica ble re g ulat or y 
re q uire me nt(s) or if nee de d b y K RI. I n a d diti o n, t he i n vesti g at or m ust ma ke pr o visi o n f or 
t he s u bject’s me dical rec or ds t o be k e pt f or t h e s a m e peri o d of ti me. 
S u bjects’ me dical rec or ds a n d ot her ori gi nal data will be arc hi v e d i n acc or da n ce wit h 
a p plica ble re g ulati o ns a n d re q uire me nts est a blis he d b y t he i n vesti gati o nal sites.
1 2. 1 0
I N S U R A N C E A N D I N D E M NI T Y 
K RI’s o bli gati o ns re g ar di n g i ns ura nce a n d i n de m nificati o n are d escri be d i n ot h er 
d oc u me nts or a gree me nts. 
1 2. 1 1
A U DI T 
It is t he res p o nsi bilit y of 
a n d K RI t o perf or m a u dits (if a p plica ble), 
as part of i m ple me nti n g q ualit y ass ura nce. T h e p ur p ose of a n a u dit, w hic h is i n de pe n d e nt 
of a n d se parate fr o m r o uti ne m o nit ori n g or q ualit y c o ntr ol f u ncti o ns, is t o e val uate trial 
c o n d uct a n d c o m plia nce wit h t he pr ot oc ol, S O Ps, I C H/ F D A G C Ps, HI P A A, a n d ot her 
a p plica ble re g ul at or y re q uire me nts. T he a u dit or a n d re g ulat or y a ut h oriti es will re q uire 
direct access t o t he s u bject’s me dical rec or ds a n d all st u d y rec or ds. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 2 of 6 0 
1 3. 0
U S E O F I N F O R M A TI O N
1 3. 1 
G E N E R A L A S P E C T S 
All i nf or mati o n c o ncer ni n g 
a n d K RI, s u c h as pate nt a p plicati o ns, 
f or m ula, 
ma n ufact uri n g pr ocesses, basic scie ntific data or f or m ulati o n i nf or mati o n 
s u p plie d b y K RI a n d n ot pre vi o usl y p u blis he d, are c o nsi dere d c o nfi de ntial a n d will re mai n 
t he s ole pr o pert y of K RI. T h e i n vesti gat or a grees t o us e t his i nf or m ati o n o nl y i n 
acc o m plis hi n g t his st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut t h e writte n c o nse nt 
of K RI, e xce pt f or official re prese nt ati v es, s uc h as re g ulat or y a ut h orities.
It is u n derst o o d b y t he i n vesti g at or t hat t he i nf or m ati o n de vel o pe d i n t his cli nical st u d y, i n 
c o n necti o n wit h t he d e vel o p me nt of K- 2 8 5 will be use d b y K RI a n d, t h eref ore, ma y b e 
discl ose d b y K RI as re q uire d t o ot her cli nical i n vesti gat ors, ot her p har mace uti cal 
c o m pa nies a n d t o ot her g o ver n m e nt a ge n cies. I n or d er t o all o w f or t he use of t he 
i nf or mati o n deri v e d fr o m cli nical st u dies, it is u n derst o o d t hat t here is a n o bli gati o n t o 
pr o vi de t o K RI c o m plete test res ults a n d all data c o m pile d i n t his st u d y. 
1 3. 2
S U B J E C T C O N FI D E N TI A LI T Y A N D D A T A P R O T E C TI O N 
K o wa Researc h I nstit ute, I n c. a n d its desi g nees affir m a n d u p h ol d t he pri nci ple of t he 
s u bject’s ri g ht t o pr otecti o n a gai nst i n vasi o n of pri vac y. T hr o u g h o ut t his st u d y, all d ata will 
be li n ke d t o t he C R F/ e C R F via a u ni q ue i de ntificati o n n u m ber a n d t h e s u bject's i nitials. 
T he d at a will be bli n de d c orr es p o n di n gly i n all d at a a n alyses . 
H o we ver, i n c o m pli a nce wit h t h e g ui d eli n es a n d re g ulati o ns of t he U S F D A c o ncer ni n g 
t he acce pta n ce of cli nical st u dies i n s u p p ort of I N D a p plicati o ns a n d t he I C H G C P ( w het h er 
perf or me d i n t h e U nite d States or else w here), a n d i n f ulfill me nt of its o bli g ati o ns t o K RI
t o verif y c o m plia nce wit h t his pr ot o c ol, K RI’s desi g nee re q uir es t h at t h e i n vesti gat or t o 
per mit its m o nit or, re prese ntati ves fr o m t h e F D A, K RI’s d esi g nate d a u dit ors, I R Bs/I E Cs, 
a n d ot her g o ver n me ntal re g ulat or y a ut h oriti es t o re vie w t he s u bject’s pri m ar y m e dical 
rec or ds (s o urce data or d oc u m e nts) i n cl u di n g, b ut n ot li mite d t o la b orat or y test res ult 
re p orts, E C G re p orts, a d missi o n a n d disc har g e s u m m aries f or h os pital a d missi o ns 
occ urri n g d uri n g a s u bj ect’s st u d y partici pati o n, a n d a ut o ps y re p orts rel ate d t o deat hs 
occ urri n g d uri n g t he st u d y. 
S h o ul d access t o s uc h m e dical rec or ds re q uir e a wai ver or a ut h orizati o n se parate fr o m t he 
state me nt of i nf or me d c o nse nt, t he i n vesti g at or will o btai n s uc h per missi o n i n writi n g fr o m 
t he s u bject b ef ore t he s u bject is e ntere d i nt o t he st u d y. 
1 3. 3
FI N A L R E P O R T A N D P U B LI C A TI O N P O LI C Y 
All i nf or mati o n re g ar di n g t his st u d y will be ke pt strictl y c o nfi de ntial. All d ata deri v e d fr o m 
t he st u d y will be t h e pr o pert y of K RI. T he i n vesti gat or m ust u n derta ke n ot t o s u b mit a n y 
part of t h e data fr o m t his st u d y f or p u blicati o n wit h o ut pri or c o nse nt of K RI. K RI ma y 
discl ose data deri v e d fr o m t h e st u d y t o ot her i n vesti gat ors a n d dr u g re g ulat or y a ut h orities. 
After c o m pleti o n of t he st u d y, a n d as a gree d b y t h e i n vesti gat or a n d K RI, t he i n vesti gat or 
ma y se n d a draft m a n us cri pt t o K RI t o be re vie we d i n or der t o reac h a n a gree me nt re gar di n g 
p u blicati o n. T he i n vesti gat or m ust recei ve writt e n a p pr o v al fr o m K RI bef ore t h e fi n al 
versi o n of t h e m a n uscri pt is s u b mitte d f or p u blicati o n. 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 3 of 6 0 
At t he c o ncl usi o n of t h e st u d y, aft er t h e d ata are a nal yze d, K RI or its desi g n ee will pre pare 
a fi nal cli nical re p ort. 


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 4 of 6 0 
1 4. 0
R E F E R E N C E S
1.
Lai ne L. N o nster oi d al a nti-i nfla m mat or y dr u g gastr o pat h y. Gastr oi ntest E n d osc Cli n
N A m 1 9 9 6, 6: 4 8 9- 5 0 4.
2.
Bec ker J C, D o msc h k e W, P o hle T. C urre nt a p pr oac hes t o pre ve nt N S AI D-i n d uce d
gastr o pat h y – C O X selecti vit y a n d be y o n d. Br J Cli n P h ar mac ol. 2 0 0 4 Dece m ber;
5 8( 6): 5 8 7 – 6 0 0.
3.
J ü ni P. Are selecti ve C O X 2 i n hi bit ors s u peri or t o tra diti o nal n o nster oi d al
a ntii nfla m mat or y dr u gs? B MJ. 2 0 0 2 J u ne 1; 3 2 4( 7 3 4 9): 1 2 8 7 – 1 2 8 8.
4.
Mas o n L, M o ore R A, E d war ds J E, Derr y S, Mc Q ua y HJ. T o pical N S AI Ds f or ac ut e
pai n: a meta-a n al ysis. B M C Fa m Pract. 2 0 0 4 M a y 1 7; 5: 1 0.
5.
Oz M., El Ne brisi E. G., Ya n g, K- H. S., H o wart h F. C, a n d Al K ur y L T. C ell ular a n d
M olec ular T ar gets of Me nt h ol Acti o ns. Fr o nt. P h ar mac ol. 2 0 1 7; 8: 4 7 2.
6.
Ki m D H, Li m Y Y, Ki m H M, Ki m S Y, Ki m BJ. T he Safet y E val u ati o n of a P ote nt
A n gi o ge nic Acti v at or, S y nt hetic Pe pti de S F K L R Y- N H 2, f or t he S ki n A p plicati o n.
T o xic ol o gical Researc h. 2 0 1 2; 2 8: 5 1- 5 6.
7.
Gri mes D, L yssi kat os J. H u ma n Der m al Safet y T esti n g f or T o pical Dr u g Pr o d ucts.
F D A W or ks h o p. 2 0 1 8.


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 5 of 6 0 
1 5. 0
A P P E N DI C E S
 
1 5. 1 
A P P E N DI X 1
VI S U A L A N A L O G S C A L E ( E X A M P L E O F P A P E R V A S) 
 
 
Assess me nt of t he pai n i nte nsit y of D O M S at rest a n d w hile sta n di n g usi n g a 0 t o 1 0 0 p oi nt 
pai n V A S  
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 6 of 6 0 
VI S U A L A N A L O G S C A L E ( E X A M P L E O F E L E C T R O NI C V A S) 
 
 
Assess me nt of t he pai n i nte nsit y of D O M S at rest a n d w hile sta n di n g usi n g a 0 t o 1 0 0 p oi nt 
pai n V A S  
 
 
 
 
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 7 of 6 0 
1 5. 2 
A P P E N DI X 2
 
 
  
 
  
  
 
 
 
  
   
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 8 of 6 0 
1 5. 3 
A P P E N DI X 3
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L  
   
   
   
   
   
   
   
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol   
   
   
   
   
   
   
   
   
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 5 9 of 6 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


C O N FI D E N TI A L 
K o w a Rese arc h I nstit ute, I nc.  
K- 2 8 5- 2 0 1, St u d y Pr ot o c ol 
K- 2 8 5 
Versi o n 1. 0 1 0 A pril 2 0 2 0 
P a g e 6 0 of 6 0 
1 5. 4 
A P P E N DI X 4