Effectiveness of Topical Menthol as A Cooling Method During Exercise in A Recreational Runner Population
Phase: PHASE2
Conditions: Heat Stress, Athletic Performance
Sponsor: Taisho Pharmaceutical Indonesia

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RESEARCH PROTOCOL 
 
 
EFFECTIVENESS OF TOPICAL MENTHOL AS A COOLING METHOD 
DURING EXERCISE IN A RECREATIONAL RUNNER POPULATION  
 
Research Team:  
Specialist Doctors of Sports Medicine 
A. Andi Kurniawan, MD 
Angelica Anggunadi, MD 
Wawan Budisusilo, MD 
Albertus Quarino, MD 
Monica Surjanto, MD 
 
 
Work closely with: 
PT Taisho Pharmaceutical Indonesia TBK 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. GENERAL INFORMATION 
Research Title  
: EFFECTIVENESS OF TOPICAL MENTHOL AS A COOLING 
METHOD DURING EXERCISE IN A POPULATION OF  RUNNERS  
Clinical Trial Phase 
 
: Pre-Marketing Phase for new Indications 
Protocol Version Number 
: CTP.Mentol/V004/V/2023 
Protocol Version Date 
: May 19, 2023 
Principal Investigator  
: A. Andi Kurniawan, MD 
 
 
 
 
(Contact number: +62 878-8839-1980) 
 
Research Team 
 
: Angelica Anggunadi, MD 
 
 
 
 
  Wawan Budisusilo, MD 
 
 
 
 
  Albertus Quarino, MD 
 
 
 
 
  Monica Surjanto, MD 
 
Research Site Coordinator 
: Theresia Indriani Prima Chesar, MD 
 
 
 
 
(Contact number: +62 812-9583-8147) 
 Nisrina Nindriya, MD 
(Contact number: +62 812-2173-4814) 
 
Statistical Consultant  
: Prof. Dra Arini Setiawati, Ph.D. 
 
Sponsor 
 
 
: Ni Putu Ardini, MD - PT Taisho Pharmaceutical Indonesia TBK 
 
 
 
 
Millenium Centennial Center 8th Floor 
 
 
 
 
Jalan Jend. Sudirman Kav. 25 Jakarta, Indonesia 
 
 
 
 
(Contact Number: +62 85888337997)  
 
Research site  
 
: Eminence Elite Clinic - Elite Club 
Jl. Epicentrum Utama Raya 
Jl.H.R.Rasuna Said No.Kav C 22 
Karet Kuningan Kec.Setiabudi, Jakarta, Indonesia 
 
Clinical Trial Location  
: GOR Soemantri Athletic Field, Jakarta, Indonesia 
 
 
 
 
 
 

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2. BACKGROUND INFORMATION 
2.1 Products under study 
This research will use products produced by PT Taisho Pharmaceutical Indonesia Tbk with 
the following details: 
 Product brand  
: Counterpain® COOL 
 Active substance content: Menthol 4% 
 Registration number : POM QD. 111709501 
 Approved indications: To relieve pain in muscles due to exercise, sprains, bruises or 
back pain. 
 Proposal indication in this study: Counterpain COOL with COOL Sensation, as a 
cooling method when exercising in hot air environments. And to relieve pain in 
muscles due to exercise, sprains, bruises or back pain. 
 
2.2 Summary of other relevant clinical trials 
Currently, there are no clinical trials using the studied products to support cooling methods 
during exercise in hot environments in Indonesia. However, in various other countries, 
clinical trials have been conducted using topical products containing Menthol and the 
results support the use of menthol as a cooling method during exercise in hot air 
environments.  
In 2018, 17 healthy men (n=17) between the ages of 18 and 35 were recruited to take part 
in a study conducted by Mitchell Snell (titled "Influence of menthol on human temperature 
perception, regulation and energy expenditure") at Salem State University. Subjects rested 
supine in a controlled environment at 30℃ and 50% relative humidity. Subjects rested for 
30 minutes before menthol or placebo gel was applied to establish baseline temperature 
and metabolic values. Placebo gels without menthol and those containing 4.13% Menthol 
(Biofreeze, Performance Health, Warrenville, IL, USA) were applied to the anterior surface of 
participants while resting in the supine position at 30 minutes to 60 minutes. Outcomes 
collected were core body temperature (Tre), RER (Respiratory Exchange Ratio), absolute 
VO2, relative VO2, supraclavicular skin temperature, skin blood perfusion, and thermal 
sensation. Some measures showed no significant response to menthol, however, the reason 
remains unclear. Two variables that showed significant changes due to menthol application 
were core body temperature and thermal sensation. Menthol seemed to make the body 
feel cooler (lower thermal sensation score), but at the same time caused it to store more 
heat (increased rectal temperature).  
Another study conducted by D Jason Gillis, et al (titled "The influence of menthol dose on 
human temperature regulation and perception") in 2020 assessed the effect of high (H, 
4.13%), medium (M, 2.0%) and low (L, 0.1%) concentrations of menthol on temperature 
perception and regulation, compared to a placebo (P). Sixteen participants underwent the 

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conditions on four separate days. Each test participant rested supine (Environmental 
conditions: 30°C, 50% rh) for 30 minutes before 40 mL of L, M, H or P gel was applied to the 
anterior upper body, then rested 30 minutes thereafter. Primary parameters assessed 
included thermal sensation (TS), thermal comfort (TC), irritation (IRR), rectal temperature 
(Tre), skin temperature (chest, forearm, thigh, calf), and EMG (trapezius, pectoralis major, 
sternocleidomastoid).  This study showed that menthol exerts perceptual and 
thermoregulatory effects regardless of skin temperature. The perceptual cooling effect was 
also dependent on the concentration of menthol administered, with the greatest effect 
exhibited by menthol of medium concentration. Changes in core body temperature were 
also shown to be dependent on menthol concentration. 
 
2.3 Summary of known risks and benefits 
Referring to previous clinical trials on menthol gel, it is known that the application of 
menthol gel influences thermal sensation and changes in core body temperature. The risk of 
irritation with menthol application may occur depending on the dose administered.  
 
2.4 Description and justification for mode of administration, dosage, dosage regimen and 
period of administration 
The test drug consists of:  
• Test Drug 
Light blue gel with the trademark Counterpain COOL® (License Number: POM QD. 111 
709 501) containing the active substance Menthol 4%. 
• Placebo 
Light blue gel where the active ingredient Menthol is replaced by purified water.  
 
Each Subject will receive a cross-over application of 4% Menthol gel and placebo with the 
order of application randomized using a random number table and a minimum wash out 
period of 7 days+ 1 day after the first application. The test drug, i.e. 4% Menthol gel or 
placebo, will be applied by rubbing on the neck area, the front side of the upper arm and 
the front side of the upper leg. The neck area was chosen because there is a carotid artery in 
the neck area, which is said to have an impact on changes in body temperature in the 
hypothalamus. In addition, the upper arm and upper leg areas were chosen because they 
are the extremity areas closest to the core of the body and perform a lot of movement while 
running. Some journals concluded that the application of cooling methods in the hand and 
thigh area is effective for cooling methods.  
The application is adjusted to the Per (Mid) Cooling method, where the Subject will start 
applying the test drug while running on lap 7 (along kilometer 2.5 to 2.8).  

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 dose of the test drug, 4% Menthol gel or placebo, was administered by following the 
dosage of topical drugs in general, as follows:2 
• 2 grams (2.25 inches or 5.7cm) for the neck 
• 4 grams (4.5 inches or 11.4cm) for each upper extremity (including upper arm or 
forearm) and lower extremity 
The total dose given is not more than the maximum total dose limit of 32 grams in a day of 
use. 
The test drug dose card consists of 3 dose cards consisting of dose cards for the neck, right 
and left upper arms, right and left upper limbs. 
 
2.5 Researcher statement 
The research team leader and the rest of the research team agree to conduct the study in 
accordance with the protocol and any amendments and in accordance with current ICH GCP 
guidelines, be responsible for conducting and supervising the study as a whole, ensure that 
all associates, colleagues and employees assisting in conducting the study are informed of 
their obligations, and agree to conduct the study in full compliance with the laws and 
regulations of the country in which the study is conducted and the Declaration of Helsinki. 
 
2.6 Population description 
The subjects of this study were recreational runners who were trained and selected from 
running clubs aged 18-45 years, domiciled in Jakarta and its surroundings, and met the 
inclusion criteria and did not have exclusion criteria. The recreational runners selected from 
this running club were runners who already had the experience of completing a marathon 
before by providing certificates/medals/other evidence. And had a personal best of under 
one hour on a 10-kilometer run (which would be confirmed during the screening of 
potential subjects through history taking) in the past 6 months.  
 
2.7 Literature reference 
Exposure to heat during exercise causes an increase in body temperature (core and skin 
temperature), impaired thermal perception (sensation and comfort), and dehydration that 
will affect the cardiovascular system, central nervous system, and musculoskeletal function. 
This results in impaired sports performance. Over the past few decades, various cooling 
techniques have been developed with the aim of offsetting exercise-induced increases in 
core body temperature and improving thermal perception. 
Cooling techniques can be divided into internal and external cooling. Internal cooling aims 
to alleviate thermal strain by lowering the core body temperature, such as through the 

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consumption of cold drinks. While external cooling techniques, such as the use of cooling 
garments, cold-water immersion, or fans, aim to reduce thermal strain through increasing 
the core-to-skin temperature gradient and increasing thermal perception. Both cooling 
techniques can be combined to provide a greater effect, both physiologically and 
perceptually. 
Cooling interventions can increase heat storage capacity (pre-cooling), reduce exercise-
induced increases in core body temperature (mid-cooling), and accelerate recovery after 
intense exercise (post-cooling). Cooling interventions are known to improve exercise 
performance, such as time trial performance and time to exhaustion, in hot environmental 
conditions (>30OC) or conditions where prolonged exercise is performed. 
Mid-cooling interventions aim to reduce the increase in core temperature during exercise. It 
is known that the effects of pre-cooling interventions usually fade by 20-25 minutes after 
the start of exercise. This suggests that the benefits of pre-cooling mostly occur during the 
initial phase of resistance training. However, exercise intensity, heat production, and 
thermal strain are higher during exercise than at rest or warm-up, thus emphasizing the 
greater potential ergogenic benefits of mid-cooling than pre-cooling. The mechanism of 
improving sports performance through mid-cooling by reducing cardiovascular strain, 
lowering skin temperature, improving central nervous system function and increasing 
thermal perception. The application of mid-cooling methods in athletes can extend the 
duration of the benefits of cooling interventions. Mid-cooling effectively increases time to 
exhaustion and is also effective in self-paced exercise. Some of the mid-cooling methods that 
can be used include cooling packs, ice vests, consumption of cold drinks or ice slurry, fans 
(with or without mist), water spray, and interventions using menthol in the form of 
mouthwash, spray, or topical gel. Ice slurry drinks are considered the most effective mid-
cooling method, but consuming large volumes of cold drinks may induce physical complaints 
such as gastrointestinal distress, nausea, "brain freeze" or headache. The use of ice vests, 
fans, and water sprays are also considered effective in laboratory conditions, but are not 
practical in competition. 
Menthol is a non-thermal cooling stimulus that acts on receptors without lowering 
temperature when applied to the skin and mucosal surfaces.(4)(7) Menthol causes a sensation 
of freshness, coolness, and nasal patency through stimulation of transient receptor potential 
melastatin 8 (TRPM 8) which functions as a cold receptor.4,20,4(7)(,4)8 Activation of these 
sensory pathways sends information to the brain thus reducing the perception of thermal 
strain that occurs. 
The use of menthol as a cooling intervention during exercise has been widely encountered. 
Methods used can be internal cooling, such as mouth rinse and additives in cold drinks, or 
external, such as sprays and topical gels.4 Topical application of placebo and mouth rinse is 
ergogenic in endurance exercise in hot environments, improving performance and 

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perception, with different effects on body temperature regulation. Their use can be through 
a single application with a high concentration and repeated applications. 
 
3. PURPOSE AND OBJECTIVES OF CLINICAL TRIALS 
In general, to determine the effect of topical menthol application as a cooling method when 
exercising in a hot air temperature environment. 
3.1 Primary Objective: 
To determine the effect of topical menthol application as a cooling method during exercise 
by finding out the difference in thermal sensation between the menthol gel topical applied 
group and placebo.  
 
3.2 Secondary Objectives: 
To determine the effect of topical menthol application on various other parameters as a 
cooling method during exercise, namely by knowing the difference in body temperature, the 
difference in heart rate frequency and the difference in physical performance and intensity 
during exercise and also knowing the perception (acceptance) of comfort and irritation 
scores between the groups applied topical menthol gel and placebo. 
In addition, the safety of the drug will also be assessed by finding out all adverse events that 
occur with topical menthol application and placebo after running. 
 
4. CLINICAL TRIAL DESIGN 
4.1 Clinical Trial Endpoints 
The final outcomes of the clinical trial to be determined from this study are 
4.1.1 Primary result 
✓ Difference in mean thermal sensation scale between topical 
application of menthol gel and placebo 
 
4.1.2 Secondary result 
✓ Difference in mean body temperature between topical application of 
menthol gel and placebo 
✓ Difference in mean heart rate frequency between topical application 
of menthol gel and placebo 
✓ Mean difference in highest heart rate frequency between topical 
application of menthol gel and placebo 
✓ Differences in physical performance in vertical jumping (difference in 
mean jump height between topical application of menthol gel and 
placebo) 

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✓ Mean difference in physical intensity in terms of Rating Perceived 
Exertion (RPE) between topical application of menthol gel and placebo 
✓ Difference in mean duration (time) of running between topical 
application of menthol gel and placebo 
✓ Mean difference in perceived comfort between topical application of 
menthol gel and placebo 
✓ Difference in proportion of skin irritation category on the applied area 
between topical application of menthol gel and placebo 
✓ Knowing the security profile, both non-serious and serious in nature 
 
4.2 Research Design 
This was a randomized, cross-over, double-blind study at one site: Eminence Clinic, which 
compared the application of 4% Menthol gel versus placebo gel. Running activities were 
carried out at the Athletic Field of GOR Soemantri.  
 
4.3 Description to avoid bias 
4.3.1 Randomization to Test Drug and Placebo 
A randomization list of Subjects will be generated by the Statistical Consultant. Application 
of Test Drug and Placebo will follow the random number table.  Each Subject will receive the 
test drug following the random number table (M.G. Kendall and B. Babington random 
number table. Cambridge University. 1954).  In the event of adverse events in the Subjects, 
at the request of the Research Team, the confidentiality of the use of the Test Drug and the 
Placebo can be disclosed. 
 
4.3.2 Impersonation 
The test drug and placebo are in the form of light blue gel. 
The test drug and placebo packaging tubes to be used in this study will be covered by 
packaging stickers. The research team is not allowed to have access to the test drug and 
placebo. Subjects are also not allowed to have access to the test drug and placebo.  
The Research Site Coordinator will apply the test drug to the dose card according to the 
dose indicated on the dose card according to randomization. And will give it to the subjects 
at the stopping posts (3 stopping posts). So that both the research team and subjects only 
receive dose cards that have been applied to the test drug or placebo according to 
randomization.  
 
4.4 Description of the treatment and dosage and its completeness of the product under 
study  
4.4.1 The test drug consists of:  
• Test Drug 

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Light blue gel with the trademark Counterpain COOL® (License Number: POM QD. 111 
709 501) containing the active substance Menthol 4%. 
• Placebo 
Light blue gel where the active ingredient Menthol is replaced by purified water.  
 
4.4.2 How and where to apply the gel 
Each Subject will receive a cross-over application of 4% Menthol gel and placebo with the 
order of application randomized using a random number table and a minimum wash out 
period of 7 days+ 1 day after the first application 
The test drug, i.e. 4% Menthol gel or placebo, will be applied by rubbing on the neck area, 
the front side of the upper arm and the front side of the upper leg. The neck area was 
chosen because there is a carotid artery in the neck area, which is said to have an impact on 
changes in body temperature in the hypothalamus. In addition, the upper arm and upper leg 
areas were chosen because they are the extremity areas closest to the core of the body and 
perform a lot of movement while running. Some journals concluded that the application of 
cooling methods in the hand and thigh area is effective for cooling methods.  
The application is adjusted to the Per (Mid) Cooling method, where the Subject will start 
applying the test drug while running on lap 7 (along kilometer 2.5 to 2.8).  
 
 
Description: 
 = where dose cards are distributed by the Site Coordinator to subjects 
 dose of the test drug, 4% Menthol gel or placebo, was administered by following the 
dosage of topical drugs in general, as follows:2 
• 2 grams (2.25 inches or 5.7cm) for the neck 
• 4 grams (4.5 inches or 11.4cm) for each upper extremity (including upper arm or 
forearm) and lower extremity 
The total dose given is not more than the maximum total dose limit of 32 grams in a day of 
use. 
The test drug dose card consists of 3 dose cards consisting of dose cards for the neck, right 
and left upper arms, right and left upper limbs. 
 

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4.4.3 Tube packaging stickers 
The packaging sticker will be used to cover the Test Drug and Placebo tubes. Only the 
Research Site Coordinator will have access to the test drug and placebo. The test drug and 
placebo will be stored at the research site in accordance with  recommended temperature 
of 30°C. A cooling box will be provided to store the test drug and placebo at the research 
site if the air temperature exceeds 30°C.  
 
 
 
TOPICAL DOSING CARD 
TOPICAL DOSING CARD 
TOPICAL DOSING CARD 
NECK 
RIGHT UPPER ARM 
LEFT UPPER ARM 
RIGHT UPPER LEG 
LEFT UPPER LEG 
Exp. date 
Np. Batch: 
Exp. date 
Exp. date 
For CLINICAL TEST only 
Clinical trial drug (light blue gel) 
Only to be applied on the dose card. 
Batch No: 
Exp date: 
For CLINICAL TEST only 
Placebo (light blue gel) 
Only to be applied on the dose card. 
Batch No: 
Exp date: 

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4.5 Duration of Research 
4.5.1 Research Schedule  
The study runs from May 2023 to December 2023. Each subject will require 5 visits with a 
wash-out period of 7 days+1 day. So, in total, each subject will need +3 weeks to complete 
the study.  
Running activities will be held at the Athletics Field, every Saturday and Sunday for two 
months. Only the three deepest tracks will be used for this activity. During the research 
activities, the Athletic Field will be closed to the public.  
 
 
Subject 
1 
Screening 
Subject 
2 
Screening 
Intervention 
Period 1 
Intervention 
Period 2 
Research  
Visit 
1 
2 
3 
4 
5 
Day 
1 
2 
9 
(Wash-
out) 
16 
20 
Electronic Form 
V 
 
 
 
 
Informed Consent Subject 
V 
 
 
 
 
Anamnesis 
and 
PAR-Q 
Questionnaire 
V 
 
 
 
 
Physical 
examination, 
blood 
pressure, 
blood 
sugar and resting ECG, 
Covid 19 
V 
 
 
 
 
Bleep Test 
 
V 
 
 
 
Intervention 
Period 
Preparation Education 
 
V 
 
 
 
Blood 
Pressure 
Check 
Before Running 
 
 
V 
V 
 
Education on how to apply 
test products 
 
 
V 
V 
 
Weight and Height Check 
 
 
V 
V 
 
Hydration Status 
 
 
V 
V 
 
Heart Rate 
 
 
V 
V 
 
Skin 
and 
Tympanic  
 
V 
V 
 

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Temperature 
Vertical Jump 
 
 
V 
V 
 
Test Drug Intervention 
 
 
V 
V 
 
Physical 
Checkup 
After 
Running 
 
 
V 
V 
 
Body Weight 
 
 
V 
V 
 
Skin 
and 
Tympanic 
Temperature 
 
 
V 
V 
 
Heart rate 
 
 
V 
V 
 
Vertical Jump 
 
 
V 
V 
 
RPE 
 
 
V 
V 
 
Running duration 
 
 
V 
V 
 
Thermal sensation, comfort 
and irritation 
 
 
V 
V 
 
Occurrence of Side Effects 
 
 
V 
V 
 
Finish 
 
 
 
 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.5.2 Research Flow 
 
 
4.6 Description of Termination Rules 
All studies were stopped or interrupted by the following procedures. 
1. When an entire study is terminated or discontinued, the  Sponsor immediately 
notifies all principal investigators involved in the study and the regulatory agency of 
that and the detailed reasons in writing. 
2. When the Sponsor decides to terminate or discontinue the entire study and notifies 
the PI of the decision, the PI immediately notifies the institutional review board 
about it in writing and explains the details of the termination or discontinuation to 
the institutional review board. 
Registration of prospective participants via electronic form 
Explanation & informed consent for participants 
Day 1 screening: history taking, PAR-Q, physical examination, blood pressure, resting ECG, and 
glucose test 
Day 2 screening: bleep test 
Explanation & education for participants 
Selected participants 
Arrangement of the 1st running activity schedule 
1. 
Blood pressure & blood sugar checks 
2. 
Participant explanation of test drug application 
3. 
Randomization of the test drug according to the list 
4. 
Stretching for participants 
5. 
Assessment of parameters before running: 
a. 
weight, height, BMI 
b. 
hydration status based on urine color 
c. 
skin and tympanic temperature 
d. 
heart rate 
e. 
vertical jump 
6. 
application of trial materials along kilometer 2.5 to 2.8 
7. 
parameters assessed after running: 
a. 
running duration 
b. 
body weight 
c. 
skin and tympanic temperature 
d. 
heart rate 
e. 
vertical jump 
f. 
fatigue level (RPE) 
g. 
thermal sensation, comfort, and irritation 
8. 
side effect assessment 
2nd running activity: same as 1st running activity 
Data analysis 

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3. When the principal investigators were notified of the discontinuation or termination 
of the entire study, they immediately informed the subjects who received the study 
treatment to that effect and took appropriate actions including switching to another 
therapy. 
 
4.7 Accountability procedures for the product under study 
The test drug and placebo will be stored at the research site in accordance with the 
recommended temperature of below 30°C. A cooling box will be provided to store the test 
drug and placebo at the research site if the air temperature exceeds 30°C.  
 
4.8 Maintain random code 
The study site coordinator has full access to the randomization and is responsible for the 
administration of test drugs in the field. 
The research team did not have access to randomization and test drugs.  
 
4.9 Data identification 
Individuals interested in becoming Subjects will be required to fill out an electronic 
registration form, which asks for identity data (name, date of birth, address, education, 
occupation, ethnicity, and contact phone number). 
The research site coordinator will assign a unique code number to each Subject. The unique 
code number will be recorded in the examination status of the Subject.  
 
5 SUBJECT SELECTION AND TERMINATION 
5.1 Inclusion Criteria:  
- 
Adults, 18 - 45 years old 
- 
Have a personal best 10-kilometer run time of under one hour (which will be 
confirmed during the screening of prospective Subjects through history taking) in the 
last 6 months. 
- 
Doing running training at least 3 times/week for the past 1 year 
- 
Have a level of heart-lung endurance or VO2max that is at least included in the 
average criteria (known through examination: Bleep test) 
- 
Meets Subject screening criteria by answering "No" to all questions on the Physical 
Activity Readiness Questionnaire (PAR-Q) questionnaire. 
- 
Have normal resting ECG and normal GDS results on screening of prospective 
Subjects. 
- 
At the time of the study, the body temperature was within the normal range 
 
5.2 Exclusion Criteria: 

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- 
Pregnant and/or breastfeeding women 
- 
Have had a musculoskeletal injury in the last three months and still have symptoms 
or complaints 
- 
Are experiencing acute infectious disorders, such as gastrointestinal, respiratory 
infections 
- 
During treatment for chronic diseases (e.g. high blood pressure or hypertension, 
diabetes or diabetes mellitus, heart disease) 
- 
Have a history of hypersensitivity or allergy to menthol or skin-applied products 
(especially gel-based products) 
- 
Has a history of cold allergy 
- 
Have a positive COVID-19 test result at the time of screening. 
 
5.3 Subject Termination Criteria  
Criteria for Subjects who were unable to continue the study: 
- 
The subject was not at the research site at the time of data collection. 
- 
The subject decided not to continue participating in the study. 
- 
Subjects had COVID-19 infection during the study period 
- 
The subject had an acute injury or inflammation during the study period that made 
them unable to participate in the study according to the research team 
 
6 SUBJECT TREATMENT 
 
6.1 Treatment to be given 
The test drug consists of:  
• Test Drug 
Light blue gel with the trademark Counterpain COOL® (License Number: POM QD. 111 
709 501) containing the active substance Menthol 4%. 
• Placebo 
Light blue gel where the active ingredient Menthol is replaced by purified water.  
 
6.2 Allowable and unallowable treatments 
6.2.1 Allowed and disallowed medicines 
Medicines that are allowed to be consumed are vitamins and minerals within reasonable 
limits. The drugs that are not allowed to be consumed are a list of drugs that are on the 
World Anti-Doping Agency (WADA) list such as: 
o Drugs that belong to the Anabolic group  
o Drugs that belong to the group of peptide hormones and growth hormones 
o Drugs belonging to the metabolic hormone group 

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o Drugs that belong to the Beta agonist group 
o Drugs that belong to the Diuretics group 
o Drugs that belong to the Stimulant group 
o Drugs that belong to the Narcotic group 
o Glucocorticoid drugs 
 
6.2.2 Medicines for first aid 
In this study, Subjects are likely to experience several kinds of health problems due to the 
intervention provided, namely musculoskeletal injuries, wounds or exertional heat illness 
due to running activities, or skin health problems related to the experimental materials 
applied. To anticipate these various health problems, the Research Team provides various 
equipment and medicines that can be used to provide appropriate first aid.  
No. 
Equipment/Medicine 
Total 
1 
Topical medication 
 
 
a. Voltaren gel (anti-inflammatory) 
1 tube 50 grams 
 
b. Kloretil Spray 
2 cans 
 
c. Counterpain cream 
2 tubes 120 grams 
 
d. Mofacort 
ointment 
(Mometasone 
furoate 0.1%) 
1 tube 
2 
Wound care 
 
 
a. Betadine antiseptic solution 
1 bottle (30 mL) 
 
b. Sterile gauze 
2 boxes 
 
c. 1-inch micropore 
1 piece 
 
d. Hansaplast plaster 
20 pieces 
 
e. Hansaplast Jumbo Plaster 
10 pieces 
3 
Oral medication 
 
 
a. Diclofenac sodium 25 mg 
1 strip 
 
b. Eperisone HCl 
1 strip 
 
c. Domperidone 
1 strip 
4 
Injectable drugs 
 

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a. Epinefrine 
2 ampoules 
 
b. Dexamethasone 5 mg/mL 
2 ampoules 
 
c. Sodium chloride infusion solution 0.9% 
1 colf (500 mL) 
 
d. Lactated Ringer's infusion solution 
1 colf (500 mL) 
5 
Miscellaneous equipment 
 
 
a. Oxycan 
3 tubes 
 
b. Ice cubes 
1 box/day 
 
c. Plastic bag with zip 
1 pack 
 
d. Plastic wrap 
1 piece 
 
e. Elastic bandage Tensocrepe 7.5 cm 
1 piece 
 
f. Elastic bandage Tensocrepe 10 cm 
1 piece 
 
g. Elastic bandage Tensocrepe 15 cm 
1 piece 
 
h. 3 cc syringe 
2 pieces 
 
i. Alcohol swab 
1 box (100 pieces) 
 
j. Scissors 
1 piece 
 
k. KN95 Mask 
3 boxes 
 
l. Gloves/handscoon 
1 box 
 
m. AED 
1 unit 
 
6.3 Procedures to monitor Subject compliance  
The research site coordinator ensures that the Subjects follow the rules set out in this study. 
The research site coordinator will provide education to Subjects on H-1, research day and 
H+1 as follows: 
a. Subject preparation education: 
• Adequate rest the night before participating in research activities, which is at 
least 8 hours of night rest 
• Breakfast is required, 2 hours prior to the running activity 
• Wear appropriate sports shoes 
• Avoid drinking caffeine-containing beverages such as coffee, tea, cola, 
chocolate, and do not consume alcohol before the study. 

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• Remind the Subjects about the drugs they can and cannot take during the 
study period. 
b. Education on the day of intervention: 
• Stretching according to the video shown 
• See how the test drug is applied through the video shown 
• Explaining how to fill in the analog visual score: thermal sensation and 
comfort acceptance. 
• Explain reporting if there are complaints or symptoms during the study time, 
you can immediately report them to the research team.  
c. Education on the day after the intervention: 
• If there are complaints or symptoms during the study time, you can 
immediately report to the research team.  
 
 
7. FINAL OUTCOME EFFICACY ASSESSMENT 
7.1 Specification of result parameters 
7.1.1 Primary result parameters 
Thermal Sensation Check of the Subject 
Education on how to fill out the thermal sensation visual analog score form will be given to 
each research subject on the intervention day before the running activity is carried out. 
Thermal sensation is the ability to distinguish temperature differences. 
Examination Thermal sensation on the skin will be measured using a visual analog scale. 
Subjects were asked to provide an assessment of thermal sensation according to the 
translation of thermal sensation that has been validated by ISO 10551:  
 
 
 
 
In this study, it will use a thermal sensation examination with reference to the American 
Society of Heating Refrigeration and Air conditioning Engineers (ASHRAE) standard 55-2004. 
Visual Analogue Scale ASHRAE refers to 7 scale score assessment namely "cold", "cool", 
"slightly cool", "neutral", "slightly warm", "warm" and "hot". 
Subjects will rate the visual analog scale as follows: 
 
 

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After filling in the visual analog scale, the assessment of the visual analog scale score 
conducted by the researcher is as follows below:  
 
 
 
 
The assessment of the Thermal Sensation score corresponds to the scale in millimeters 
(mm) as follows:  
 
 
7.1.2 Secondary result parameters 
a. Body Temperature 
Measurement of skin and tympanic temperature in accordance with the procedure is 
carried out twice during each running activity. The first measurement was taken when the 
Subject was standing in the starting line area. The second measurement was taken 
immediately after the Subject finished running 
Skin temperature measurements will be taken in 5 areas: calf, thigh, abdomen, upper arm, 
lower neck (close to the chest).  
 
b. Heart Rate 

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Heart rate (HR) was recorded using a Polar Heart Rate Monitor before the start of the 
exercise protocol until the completion of the exercise. Upon completion of the exercise, the 
equipment was immediately removed. From the results of the heart rate monitoring, the 
following two things were recorded: 
• Average heart rate during activity 
• Highest heart rate during exertion 
 
c. Physical performance ability / Vertical Jump 
The vertical jump examination is carried out after the subject warms up in the form of 
jogging or running 1 lap and doing static stretching according to the guidelines of the 
Research Team. Vertical jump will also be done after the subject completes a 5 km running 
session.  
• The vertical jump height is the difference between two marked points on the 
wall. All Subjects jumped three times, with a minimum interval of 45 seconds 
between jumps. The data used was the highest vertical jump (cm). 
 
d. Physical Exercise Intensity Assessment using Rating Perceived Exertion (RPE) 
Rating of Perceived Exertion (RPE) is a scale created by Gunnar Borg's in 1982, and aims to 
measure and determine the intensity or effort expended during physical activity, based on a 
person's subjective perception that is quantified. RPE is highly correlated with heart rate, 
maximal oxygen uptake, and lactic acid levels during physical activity. 
 
e. Running Duration 
The researcher calculated the amount of time taken by the Subject to complete a 5-
kilometer run (in minutes). 
 
f. Comfort perception (acceptance) assessment 
Education on how to fill out the thermal sensation visual analog score form will be given to 
each research subject on the intervention day before the running activity is carried out. 
BS EN ISO 7730 defines thermal comfort as '...a state of mind that expresses satisfaction 
with the thermal environment.' 
According to the Big Indonesian Dictionary (KBBI), comfort is a state of comfort, freshness, 
or coolness. 
ISO 10551-2019 measures the perception (acceptance) of comfort measured using the 
following scale: "Comfortable", "Slightly uncomfortable", "Uncomfortable", "Very 
uncomfortable", "Extremely uncomfortable".  

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After filling in the visual analog scale, the assessment of the visual analog scale score 
conducted by the researcher is as follows below:  
 
 
 
The assessment of the comfort perception score corresponds to a scale in millimeters (mm) 
as follows:  
 
 
g. Examination of irritation by the researcher is when the subject has finished running 
activities (finish), using the International Contact Dermatitis Research Group (ICDRG) 
score as follows: 
Comfortable 
 
Uncomfortable 
 
Extremely uncomfortable 
Comfortable 
 
Uncomfortable 
 
Extremely uncomfortable 

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Note: Table of European Society of Contact Dermatitis guideline for diagnostic patch testing 
- recommendations on best practice.2015 
 
 
7.2 Safety assessment  
7.2.1 Definition of AE 
In this study, adverse events (AEs) refer to all unwanted medical events in Subjects 
administered the medicinal product. AEs can be unwanted symptoms or signs (including 
abnormal laboratory findings), or transient illness, whether or not related to the 
(investigational) medicinal product. 
 
7.2.2 AE Observation 
The researcher asks the Subject about AEs and checks for abnormal changes on physical 
examination. When an AE occurred during the study (i.e. within the observation and 
treatment period), the Investigator entered the items indicated in the "Evaluation Method 
and Criteria for AEs and other items necessary for the assessment of the safety of the study 
drug in the case report form and followed up the AE until it recovered. 
 
7.2.3 Evaluation Method and AE Criteria 
a. AE name 
Names of symptoms, findings, and diseases or names of laboratory or other tests are 
identified. 
 
b. Start Date 
The day on which the AE was observed was determined. The day of onset is defined as 
follows. When symptoms or signs are observed and the cause is subsequently identified: 
The day on which the symptom or sign was first observed. 
 
c. Severity 

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The severity of AEs is differentiated based on the following 3-point scale: 
• Mild: An event that is easily tolerated by the Subject, causes minimal discomfort and 
does not interfere with daily activities. 
• Moderate: An event that is unpleasant enough to interfere with normal daily 
activities. 
• Severe: An event that prevents normal daily activities. 
 
d. Seriousness 
The seriousness of AE can be divided into: 
• Seriously 
• Not Serious 
 
e. Measures Taken for Study Medicine 
Among the 3 action steps taken for the following study drugs, the one that was applied was 
included in the case report form. 
• None (continued/treatment completed) 
• Dose interruption 
• Discontinued 
 
f. AE Maintenance 
AE treatment is investigated until the end of AE treatment. The names of all drugs used or 
all therapies used will be investigated and included in the case report form. However, this 
does not apply when follow-up examination is stopped based on sufficient medical reasons 
or when follow-up becomes impossible for reasons including death not caused by the AE or 
transfer to another clinic or hospital 
In case of skin irritation such as allergic contact dermatitis, the first treatment is to 
immediately clean the area with clean cold water, compress with betadine using sterile 
gauze, after that provide treatment according to the symptoms, for example topical 
calamine can be given for itching, topical corticosteroid preparations to relieve 
inflammation and antibiotics if there is a possibility of bacterial infection. The Subject will 
then be referred to a Referral Hospital for further treatment by a competent Doctor. (see 
list of first aid medicines point 6.2.2). 
Injuries related to heat-related illness will be treated according to the symptoms and if 
necessary, will be referred to the Referral Hospital for further treatment. 
 
 
g. AE Trip Results 
Classified into 4 categories as follows:  
• Recover 
• Improving 
• Unchanged 

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• Worsening 
 
h. Result Date 
Outcome day is defined as the last day on which the Investigator can directly confirm or 
classify the outcome. Follow-up investigations are conducted until the event recovers. 
However, when it is deemed unnecessary to follow up the complaint until it recovers, the 
specified day need not be considered as the outcome day. When the outcome day cannot 
be accurately determined due to reasons including missed site visits, the day on which the 
outcome is confirmed or assessed over the phone or by mail is considered the outcome day. 
 
i. Causal Relationship with Study Drugs and Definition of ADRs 
Causal relationships with study drugs are classified into 4 categories as follows:  
• Definitely 
• Very likely 
• May 
• Not related 
 
7.2.4 Serious side effects  
7.2.4.1 Definition of a Serious AE 
A serious AE among AEs is defined as follows. 
1. Fatal (death) 
2. Life-threatening (may cause death) 
3. Requires hospitalization or extended hospitalization for treatment 
4. Causes permanent or actual disability or dysfunction 
5. Causes congenital abnormalities 
6. Other significant medical events, i.e., significant events that expose the patient to 
risk or require treatment to avoid the above outcomes (1) to (5) even if they are not 
life-threatening or cause death or immediate hospitalization. 
 
7.2.4.2 Response to Serious AE Alert 
1. When a serious AE occurs, the PI immediately notifies the Sponsor (monitor) verbally 
or by phone, email or fax and reports details in writing at a later date. In these cases, 
the principal investigator identifies unexpected ADRs (the characteristics and 
severity of which correspond to the information in the investigator brochure) among 
the serious AEs to be reported. 
2. When the Sponsor and institutional review board requested additional information 
(autopsy reports, terminal stage medical records, and other necessary information) 
regarding the reported serious AEs, the principal investigator provided this 
information. 
3. The sponsor promptly notified all principal investigators involved in the study of all 
events that should be reported to BPOM RI immediately. 

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7.2.4.3 Handling of Serious AE Events 
a. Anaphylactic Shock 
1. Position the patient lying supine (pregnant patient on the left side) with the 
legs elevated. 
2. Check Airway, Breathing, Circulation, Disability, Exposure (whether history of 
severe allergic reaction, rapid onset, respiratory compromise or hypotension, 
or organ failure, with skin changes). 
3. If there is an exposure, identify and stop contact with the allergen.  
4. Give 02 8 L/min. Place an intravenous line. 
5. 
Give 0.3-0.5 ml intramuscular injection of adrenaline/epinephrine 1:1,000 IM 
in the lateral thigh. 
6. Repeat 10-15 minutes if there is no clinical improvement. Maximum of 3 
doses. 
7. If there is hypotension or tachycardia, fluid 1 liter 
8. Diphenhydramine is given to treat additional symptoms such as pruritus, 
erythema, and urticaria at a dose of 1.25 mg/kg, maximum 50 mg IM. Give it 
once. Given only after epinephrine has been administered. 
 
     b. Hypovolemic Shock 
The initial management of patients with no hemorrhagic hypovolemic shock is: 
▪ 
determining fluid deficit 
▪ 
Overcome shock by giving crystalloid fluid (RL fluid or NaCl 0.9%) 20 mL/kgBB in 
30 - 60 minutes, can be repeated. 
▪ 
The remainder of the fluid deficit can be given in percentages: 50% in the first 8 
hours and 50% in the following 16 hours. 
▪ 
Clinical signs of hypovolemia have been resolved / hydration, if urine production: 
0.5 - 1 mL / kg / hour 
 
Infusion Fluid (Isotonic Balanced Full Electrolyte Solutions) 
Indications for administration in all cases of shock, when cardiac preload is reduced 
due to reduced intravascular volume or obstruction. The mechanism of action is by 
replacing fluid loss due to electrolyte imbalance or volume shift, increasing stroke 
volume by increasing cardiac preload. 
Side effects can occur volume overload, pulmonary edema , peripheral edema. The 
initial dose of 10-20 mL/kg IV can be given continuously depending on the effect and 
patient response. 
 
Administration of Vasoconstrictors, Positive Inotropic Agents, and Vasodilators 
• Epinephrine 

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Indications for epinephrine administration are in all types of shock, when the use of 
other catecholamines fails to achieve the desired state of vasoconstriction and 
increase inotropic: cardiopulmonary resuscitation, anaphylactic shock. The 
mechanism of action of epinephrine causes constriction through α1-receptor-
mediated vasoconstriction and β1-receptor-mediated positive inotropic and β2-
receptor-mediated bronchodilation. 
Side effects that may occur are myocardial ischemia, stress cardiomyopathy, 
tachyarrhythmias, oliguria/anuria. 
The dose of epinephrine is 0.3-0.6 mg IM, can be given continuously based on effect 
and need: 0.05 to 1.0 (up to a maximum dose of 5.0) μg/kg/min IV administration 
during cardiopulmonary resuscitation: 1 mg IV. every 3-5 minutes. 
• Dobutamine 
Indications for the administration of dobutamine in all types of shock with 
ventricular pump function insufficiency, the mechanism of action of dobutamine is 
mainly β1-receptor mediated positive inotropic effect, side effects that can occur are 
increased heart rate ≥ 30 / min, increased blood pressure ≥ 50 mmHg, headache, 
cardiac arrhythmias, the possibility of a decrease in blood pressure caused by β2-
receptor-mediated vasodilation. 
The dose of dobutamine can be given continuously depending on the effect and 
needs of each patient i.e.: 2.5 to 5 (with a maximum dose of 10) μg/kg per min IV. 
• Norepinephrine 
Indications norepinephrine is administered in all types of shock with decreased 
peripheral resistance. The mechanism of action is mainly α1-receptor mediated 
vasoconstriction, (low) positive inotropic effects. Possible side effects are peripheral 
ischemia, increased blood pressure, reflex bradycardia, and cardiac arrhythmias. 
Continuous doses are given depending on effect and need i.e.: 0.1-1.0 μg/kg/min IV. 
bolus administration: 5-10 μg IV 
 
c.  Neurogenic Shock 
The management of neurogenic shock includes three aspects: 
• Hemodynamic stabilization with target means arterial pressure (MAP) and 
cerebral perfusion pressure of >85-90 mmHg and >70 mmHg within 7 days. 
Hypotension needs to be treated immediately with target mean arterial pressure 
(MAP) and cerebral perfusion pressure of >85-90 mmHg and >70 mmHg within 7 
days. In neurogenic shock with traumatic etiology, hypotension may result from 
hemorrhagic shock rather than neurogenic shock. For this reason, hypotension 
treatment needs to begin with a fluid challenge or administration of crystalloid 
fluids (lactated ringer or NaCl 0.9%) or colloids up to a maximum of 2 L. Mannitol 
administration needs to be avoided in patients with suspicion of traumatic brain 
injury or spinal cord injury. 

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Second-line therapy for the management of hypotension in neurogenic shock is 
vasopressor and inotropic agents. Norepinephrine is preferred as phenylephrine 
may cause reflex bradycardia. Therefore, norepinephrine is preferred. 
Insert a urine catheter to monitor urine output and to decompress the 
neurogenic bladder. Urine output should be maintained at >0.5-1 ml/kgBB/hour. 
Patients should be subjected to continuous cardiac monitoring including ECG, 
blood pressure, and oxygen saturation monitoring. Hospitalize the patient in the 
ICU. 
 
• Prevention of further spinal cord damage 
To prevent further spinal cord damage, the following steps can be taken: 
o Oxygenation and/or ventilator use 
o Stabilization of cervical vertebrae 
o Surgery for decompression and shock repair 
o Corticosteroid administration has shown potential benefit in animal 
studies but has not been shown to be beneficial in clinical trials and may 
increase the risk of complications. 
 
• Management of bradycardia or another arrhythmia 
Management of bradycardia can be done by administering atropine, 
glycopyrrolate, or isoproterenol. If the bradycardia does not respond to the drugs 
given, methylxanthines such as theophylline and aminophylline or propantheline 
can be given. In addition to bradycardia, another arrhythmia such as AV block, or 
atrial fibrillation may also occur. Treat according to the principles of handling 
each type of arrhythmia. 
 
d.  Cardiogenic Shock 
Cardiogenic shock can be caused by acute coronary syndrome and its mechanical 
complications (such as chordae rupture, interventricular septal (IVS) rupture, and ventricular 
wall rupture), heart valve abnormalities, and severe heart failure in other myocardial 
disorders. It is known that there is impaired consciousness ranging from mild to severe 
conditions, decreased diuresis, may be accompanied by cold sweat, weak pulse, there are 
signs of hypoperfusion such as (cold extremity skin touch, tachycardia, weak pulse, 
hypotension, reduced bowel noise, oliguria), there are signs of increased preload such as 
increased JVP or wet rales at basal, wet and cold hemodynamic profile. 
Acute phase management in the ED or ICVCU 
• Total bedrest 
• Perform cardiac resuscitation in case of cardiac arrest 
• Sedation with midazolam, propofol or morphine 
• Oxygen support (NRM or CPAP, intubation in case of respiratory failure) 
• IVFD insertion 

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• If there is a rhythm disturbance such as tachycardia/bradyarrhythmia, treat it 
immediately with anti-arhythmic preparations or pacemaker, over drive or 
cardioversion. 
• Invasive or non-invasive monitoring to determine the status of preload, SVR 
and cardiac output (CO). 
• If preload is low, a fluid challenge of 1-4 cc/bodyweight in kg/10 minutes is 
given until preload is confirmed. 
• If CO is low with high SVR but MAP is still <70 mmHg, inotropic vasodilator 
(dobutamine) or inodilator (milrinone) preparations should be given. IABP 
placement should be recommended in shock patients with acute coronary 
syndrome. 
• If CO is high with low SVR, then vasopressor preparations such as 
noradrenaline or adrenaline or dopamine are given. 
• Low dose dopamine can be given in oliguria. 
• In refractory cardiogenic shock consider insertion of IABP, ECMO or LVAD as 
definitive bridging therapy. 
• Definitive therapy such as PCI, valve replacement surgery, BMV (in MS), 
urgent CABG should be performed immediately, or heart transplantation if 
possible. 
• All cardiogenic shock patients should be admitted to the CVCU. 
 
 
8 STATISTICS 
8.1 Statistical Methods 
Univariate analysis was conducted to see the description of each dependent and 
independent variable. For variables that are numerical variables, a distribution test will be 
conducted. If the variable has a normal distribution, the data will be presented in the form 
of mean and standard deviation. Meanwhile, if the variable has an abnormal distribution, 
the data will be presented in the form of median and minimum and maximum values. 
Variables that are nominal or ordinal variables will be presented in the form of a frequency 
distribution for each category.  
Bivariate analysis will be conducted according to the following specific objectives: 
1. To analyze whether there is a difference in variables that are numerical variables, a 
paired T-test is conducted. If the paired T-test does not meet the requirements, the 
Wilcoxon test will be conducted. 
2. For variables that are nominal or ordinal variables, the Chi-square test is performed. 
If the Chi-square test is not eligible, Fisher's exact test will be performed. 
 
 
8.2 Number of subjects 
8.2.1 Subject calculation (thermal sensation) 

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The study design was cross over, with the aim of seeing the thermal sensation between the 
groups given menthol gel and placebo gel.  
Where for standard deviation, the largest standard deviation of various thermal sensation 
data due to the use of menthol in physical exercise is selected. 
 
 
 
 
 
 
 
 
The formula is as follows: 
 
• 
N = number of subjects 
• 
α = 0.05, then Zα = 1.96 
• 
Research power = 0.9, then Zβ = 1.282 
• 
SDd = Standard deviation of the mean difference in thermal sensation in both 
treatment groups = 3.47 
• 
X1-X2= difference in thermal sensation between the two treatment groups that is 
considered clinically meaningful = 3 (based on the clinical judgment of the 

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researchers, where in general, in the medical world, a difference of more than 15% is 
considered a meaningful difference [for example in terms of differences in left and 
right-side muscle strength]). 
 
N 
= (1,96+1,282)2 x 3,472 
 
                   32 
N 
= 14.06→ 15  
 
By calculating the dropout calculation, assuming the dropout is 10%, using the formula:  
𝑁′ = 
𝑁
1 −𝑓 
Therefore, the number of subjects is 16.67 = 17 subjects per group. 
 
8.2.2 Subject calculation (temperature change) 
The study design was cross over, with the aim of seeing the temperature difference 
between the groups given menthol gel and placebo gel.  
Where for the standard deviation, the largest standard deviation is selected from various 
data on temperature changes due to the use of menthol in physical exercise. 
 
 
The formula is as follows: 

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• 
N = number of subjects 
• 
α = 0.05, then Zα = 1.96 
• 
Research power = 0.9, then Zβ = 1.282 
• 
SDd = Standard deviation of the mean difference in body temperature changes in the 
two treatment groups = 0.840C 
• 
X1-X2= difference in body temperature reduction between the two treatment 
groups that is considered clinically meaningful = 0.50C (based on the clinical 
judgment of the researchers) 
N 
= (1,96+1,282)2 x 0,8412 
 
                   0,52 
N 
= 29.66→ 30  
 
By calculating the dropout calculation, assuming the dropout is 10%, using the formula:  
𝑁′ = 
𝑁
1 −𝑓 
 
Therefore, the number of subjects is 33.33 = 34 subjects per group. 
 
8.2.3 Conclusion Number of subjects  
Based on the calculation of the number of subjects above, the minimum number of subjects 
recruited in accordance with the primary objective is 17 subjects.  
In order to be able to analyze all objectives, both primary and secondary, and following the 
existing randomization method, the number of subjects to be recruited in this study was 36 
subjects.  
 
 
8.3 Criteria for stopping a clinical trial 
The sponsor immediately discusses discontinuation or termination of the study with the 
medical expert when the following criteria are met and continuation of the study at all study 
sites is deemed difficult or meaningless. 
1. When an "unexpected" serious AE (illness, impairment, death) occurs. 
2. When information indicating that the "expected" occurrence of significant AEs 
including the number of incidents, frequency, and conditions of occurrence cannot 
be predicted based on the investigator's brochure is obtained. 
3. When information indicating that trends in the occurrence of ADRs including the 
number of incidents, frequency, and conditions for occurrence are changing 
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4. When information is obtained that indicates or does not indicate the superiority of 
the test drug over the comparator 
5. When other information that affects the continuation of the research is obtained. 
 
 
9 . DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
9.1 Direct Access to Source Documents 
Principal investigators accept monitoring and auditing by the Sponsor and inspection by 
institutional review boards and regulatory bodies and make all study-related records 
including source documents available for direct access. 
9.2 Direct Access Method 
Each study site and Sponsor determined the method of direct access through discussion. 
 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor responsibly conducts quality assurance based on standard operating 
procedures and maintains a quality control system to ensure that research is conducted and 
data are generated, recorded, and reported in accordance with the protocol, 
pharmaceutical affairs laws, and GCP. 
 
10.1 Study Quality Control 
The Sponsor implements quality control at each step of data handling to ensure the 
reliability of all study-related data and appropriate processing. Monitors assigned by the 
Sponsor conduct monitoring (including direct access to study-related records such as source 
documents) in accordance with standard operating procedures and confirm that research is 
being conducted appropriately at the study site in accordance with protocols, standard 
operating procedures, and GCP. The monitor, the person in charge of the quality control 
system, the person in charge of data management, and the person in charge of statistical 
analysis perform quality control at each step of data handling according to standard 
operating procedures established by the Sponsor. 
 
10.2 Study Quality Assurance 
The Sponsor assures the quality of research by establishing an audit department that is 
independent of the department conducting the research. To ensure the quality of the 
research, personnel responsible for audits conduct audits at appropriate times at the 
Sponsor as well as at research sites and other facilities involved in the research as necessary, 
in accordance with the Sponsor's standard operating procedures. 
 
10.3 Study Completion 
The study completion day for each Subject was defined as "the day on which observations 
of all items specified in the protocol were completed or the termination day for the Subject" 

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and the study completion day for each study site as "the last day of research data collection 
at the study site in question." Once the study and observations specified in the protocol 
were completed for the last subject at the study site in question, the principal investigator 
immediately notified the institutional review board and sponsor of the completion of the 
study in writing and reported an outline of the study results based on the prepared report. 
 
 
11 ETHIC 
11.1 Study Overview 
The study was reviewed by institutional review boards selected by each study site, whether 
or not the implementation was appropriate from the perspective of ethical, scientific and 
medical adequacy. 
 
11.2 Overview of Continuing Studies 
The adequacy of continued implementation of this study at specific study sites is reviewed 
once a year or more frequently, or in the following cases. 
1. When the Sponsor notifies the PI of a serious and unexpected ADR or other event 
2. When PIs report serious AEs or other events 
3. When the PI reports revised consent forms and other written information to the 
Subjects 
4. When the principal investigator submits an overview of the current status of the 
research for review regarding the continuation of the research 
5. Other matters that the principal investigator felt needed to be reviewed regarding 
the continuation of her research 
The PI requests the opinion of the institutional review board on the adequacy of continuing 
the research at the research site in question. 
 
11.3 Matters Relating to the Protection of Privacy and Personal Information of Subjects 
To protect the privacy and personal information of the Subject, the Subject is identified by 
the Subject ID. 
In the preparation and handling of case report forms and monitoring, auditing, and other 
tasks performed by the Sponsor, as well as when study results are published, attention is 
paid to the protection of the privacy and personal information of subjects. 
 
 
12 DATA HANDLING AND DOCUMENT STORAGE 
12.1 Principal Investigator 
Essential documents should be retained until at least 2 years after the last approval of the 
marketing application related to the test drug and until no marketing application is pending 
or under consideration or at least 2 years have elapsed since the formal cessation of clinical 
development of the investigational product. However, these documents should be retained 

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for a longer period, if required by applicable regulatory requirements or by agreement with 
the Sponsor. 
 
12.2 Sponsor 
1. Sponsor-specific critical documents should be retained until at least 2 years after the 
last approval of a marketing application in the ICH region and until there are no 
pending or planned marketing applications in the ICH region or at least 2 years have 
passed since the formal cessation of clinical development of the investigational 
product. These documents should be retained for longer periods but only if required 
by applicable regulatory requirements or if required by the Sponsor. 
2. In the event that retention of documents that should be retained by the principal 
investigator or assessment body becomes unnecessary, the Sponsor notifies the 
assessment body through the Investigator. 
 
13 FINANCE AND INSURANCE 
13.1 Finance  
The sponsor paid for this research based on the contract with each research site. 
 
13.2 Insurance 
The sponsor takes necessary measures including purchasing insurance policies to 
compensate for the treatment of subject health hazards caused by the research and other 
losses. 
 
14 PUBLICATION POLICY 
This study data is owned by the Research team and the Sponsor. In this case the Sponsor is 
free to use the information obtained in this study for purposes including applications for 
marketing approval related to the test drug and also for marketing related to the test drug.  
 
 
15 OPERATIONAL DEFINITIONS 
 
Variables 
Operational 
Definition 
Measureme
nt tool 
How to measure 
Measurement unit 
Variable 
scale 
Gender 
Determination of the 
gender 
identity 
recorded on the KTP 
(Identity Card) of each 
research subject 
Data on ID 
card 
Check the suitability 
of the ID card 
Male and female 
Nominal 
Age 
The biological age of 
the subject calculated 
from the date of birth 
in units of years 
Data on ID 
card 
Check suitability on 
ID card 
Year 
Numeric
al 
Body weight 
Subject's 
weight 
measured in minimal 
Body scales 
The subject stands 
upright on the scale 
Unit kilogram 
Numeric
al 

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clothing 
without 
using 
footwear, the results 
on the scale are seen 
Height 
Height of the subject 
measured from the 
soles of the feet to the 
tip of the head in a 
vertical plane 
Stadiometer 
The subject stands 
upright barefoot with 
the back of the head, 
upper back, buttocks 
and heels against the 
wall. 
The 
gaze 
is 
forward and the chin 
is parallel to the floor. 
Then, 
the 
stadiometer 
plate 
was placed directly 
above the Subject's 
head. 
Unit cm 
Numeric
al 
Blood 
Pressure 
Examination with a 
special device called a 
sphygmomanometer, 
which 
aims 
to 
measure the pressure 
in the arterial blood 
vessels 
when 
the 
heart beats.  
Sphygmoma
nometer 
The subject is seated 
and relaxed, arm at 
heart level, cuff is 
placed, 
and 
blood 
pressure 
is 
calculated. 
JNC VIII Scale 
Normal 
BP 
Systolic 
<120 mmHg; Diastolic 
<80 mmHg 
Prehypertension: 
Systolic 120 - 139 
mmHg ; Diastolic 80 -
89 mmHg 
Hypertension 
gr.1: 
Systolic 
140 
-159 
mmHg ; Diastolic 90 - 
99 mmHg 
Hypertension 
gr.2: 
Systolic > 160 mmHg ; 
Diastolic > 100 mmHg 
Ordinal 
Instantaneou
s Blood Sugar 
a blood glucose test 
that can be done at 
any time without the 
need to fast first. used 
as a screening for 
diabetes, also done 
routinely to monitor 
blood glucose levels.  
Timed Blood 
Sugar Strips 
and 
Examiner 
Wash your hands 
thoroughly  
Place 
the 
lancet 
needle 
into 
the 
lancing device. 
Insert the test strip 
into 
the 
glucose 
meter. 
Wipe your fingertips 
with 
an 
alcohol-
treated 
cotton 
swab. 
Prick your fingertip 
with a lancet to 
allow blood to be 
drawn. 
Place 
a 
drop 
of 
blood on the drip 
blood sugar level < 
200 
mg/dL 
and 
without 
classic 
symptoms of diabetes 
mellitus 
through 
history taking 
Numeric
al 

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strip and wait for 
the results. Usually, 
a number indicating 
your 
blood 
sugar 
level 
will 
appear 
within 
a 
few 
seconds 
on 
the 
meter screen. 
 
Electrocardio
graphy (ECG) 
 Tests 
to 
evaluate 
heart health, including 
knowing 
and 
measuring whether a 
person's heart rate is 
normal or not. 
An electrical 
impulse 
detection 
machine 
called 
an 
electrocardi
ograph 
During 
the 
examination, 
electrodes 
are 
attached to the chest, 
arms and legs. There 
are usually 10 or 12 
electrodes, made of 
plastic, and small in 
size. Each electrode 
cable is connected to 
an ECG machine to 
record 
the 
heart's 
electrical activity. 
P wave 
Normal values: 
Width ≤ 0.12 seconds 
High ≤ 0.3 mV 
Always (+) in lead II 
Always (-) in aVR leads 
 
PR Interval 
Measured from the 
beginning of the P 
wave to the beginning 
of the QRS wave. 
Normal values range 
from 
0.12-0.20 
seconds. 
 
QRS 
wave 
(QRS 
complex) 
Normal values: width 
0.04 - 0.12 seconds, 
height depending on 
the lead. 
Q wave: first negative 
deflection 
of 
QRS 
wave 
Normal values: width 
< 0.04 s, depth < 1/3 
of R wave. If depth > 
1/3 of R wave height, 
pathological Q. 
The R wave is the first 
positive deflection of 
the 
QRS 
wave. 
Generally, 
in 
leads 
aVR, V1 and V2, the S 
wave is deeper, while 
in leads V4, V5 and V6 
it 
disappears 
or 
decreases in depth. 
 
Category 

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T wave 
Represents 
the 
ventricular 
repolarization process. 
Generally positive T 
wave, in almost all 
leads except in aVR 
 
U-wave 
Is a positive deflection 
after the T wave and 
before the next P 
wave.  
 
 
Body 
mass 
index 
Indicators 
for 
determining 
nutritional status  
Body scales 
and 
stadiometer 
The ratio of body 
weight (in kilograms / 
kg) to the square of 
height 
(in 
square 
meters / m2) 
< 
18.5 
kg/m2 
: 
underweight 
18.5-22.9 
kg/m2 
: 
normal 
≥ 
23 
kg/m2: 
overweight 
≥ 25 kg/m2 : obese 
Ordinal 
Hydration 
status before 
running 
An overview of SP's 
water 
in 
and 
out 
balance 
before 
the 
running intervention 
Urine color 
degree table 
Subjects were asked 
to 
collect 
urine 
samples in the urine 
pot provided. Then 
the subject's urine 
color is matched with 
the urine color table 
 
1-3 : good hydration 
4-6 : less well 
hydrated 
7-8 : fluid deficiency. 
*This urine color is in 
accordance with PURI, 
Practical Manual for 
Meeting 
Fluid 
Requirements 
in 
Physical 
Training. 
PDSKO. First Edition. 
2014 
Ordinal 
Hydration 
status 
after 
running 
An overview of SP's 
water 
in 
and 
out 
balance 
after 
the 
running intervention 
Body scales 
The percentage of SP 
body weight loss was 
calculated using the 
formula: 
(𝐵𝐵 𝑠𝑒𝑏𝑒𝑙𝑢𝑚 𝑏𝑒𝑟𝑙𝑎𝑟𝑖−𝐵𝐵 𝑠𝑒𝑡𝑒𝑙𝑎ℎ 𝑏
𝐵𝐵 𝑠𝑒𝑏𝑒𝑙𝑢𝑚 𝑏𝑒𝑟𝑙𝑎𝑟𝑖
× 100% 
≤ 2% : not dehydrated 
> 2% : dehydration31 
Category 
Vertical jump 
One of the fitness 
parameters 
to 
measure leg explosive 
Talcum 
powder 
The subject places 
their powdered finger 
against the wall while 
cm 
Numeric
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power is by measuring 
jump height.  
standing 
upright 
facing sideways with 
the wall on their right 
side, then the right 
shoulder is maximally 
induced 
with 
the 
right arm and hand in 
a maximal extension 
position; the subject 
will mark the highest 
point that can be 
reached 
with 
the 
finger in the standing 
position.  
After that, the subject 
will be asked to jump 
as high as possible. At 
the highest point of 
the jump, the subject 
should 
extend 
the 
right hand to the wall 
to 
mark 
the 
maximum height of 
the 
jump 
with 
a 
powdered finger.  
The 
vertical 
jump 
height 
is 
the 
difference 
between 
two points marked on 
the wall. All subjects 
jumped three times, 
with 
a 
minimum 
interval of 45 seconds 
between jumps. The 
data used was the 
highest vertical jump 
data.  
WBGT 
Temperature 
(Wet 
Bulb 
Globe 
Temperature
) 
A 
measurement 
of 
heat stress by direct 
sunlight, which takes 
into 
account: 
temperature, 
humidity, wind speed, 
sun angle, and clouds 
(solar radiation). 
WBGT 
Turn 
the 
power 
on/off to the ON 
position. Select the 
unit 
of 
measurement. 
Select 
outdoor/indoor. 
Take 
temperature 
measurements 
on 
the 
measuring 
target 
(place). 
<18oC : safe 
18-24 oC : alert 
24-28 oC : more alert 
28-30 oC : dangerous 
>30 
oC: 
extremely 
dangerous 
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Record 
the 
measurement 
results. 
 
 
 
Heart-lung 
endurance 
level 
The 
level 
of 
cardiopulmonary 
fitness as measured by 
the 
calculation 
of 
VO2max 
Bleep Test 
Subjects were asked 
to run from one end 
or markers cones to 
the other end or 
markers 
cones 
20 
meters 
away 
by 
following the rhythm 
of the "beep" sound 
from the recording 
tape. The rhythm of 
this "beep" sound will 
become faster over 
time. If the subject 
failed to reach the 
markers cones before 
the "beep" sound was 
heard twice in a row, 
the 
subject 
was 
declared 
to 
have 
completed the test, 
and the number of 
laps was taken from 
the last lap that could 
reach 
the 
line. 
VO2max values were 
determined based on 
the 
Multistage 
Fitness Test (Bleep 
Test) prediction table. 
VO2max 
category: 
very poor, poor, fair, 
good, excellent 
Ordinal 
Body 
temperature 
The hot and cold state 
of the body measured 
by 
using 
a 
thermometer 
Thermomet
er 
Pull the top of the 
earlobe up and back. 
Gently insert the tip 
of the thermometer 
into the ear canal and 
aim the sensor at the 
eardrum. Once the 
thermometer is in 
position, turn it on 
and wait for an alert 
to appear indicating 
the scan is complete. 
Remove the 
Low-grade: 
37.3 
to 
38.0 C (99.1 to 100.4 
F) 
Moderate-grade: 38.1 
to 39.0 C (100.6 to 
102.2 F) 
High-grade: 39.1 to 41 
C (102.4 to 105.8 F) 
Hyperthermia: 
Greater than 41 C 
(105.8 F) 
 
interval 

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thermometer from 
the ear and read the 
temperature. 
Average skin 
temperature will be 
measured in 5 areas: 
calf, thigh, abdomen, 
upper arm and lower 
neck (near chest). 
Reference: Mekjavic 
IB. Life 2021, 11,  
Running 
duration 
The amount of time it 
takes to complete a 5-
kilometer run 
Timing 
device 
(stopwatch) 
The researcher 
calculated the 
amount of time 
needed to complete a 
5-kilometer run. 
Minutes 
Numeric
al 
Average 
heart 
rate 
during a run 
Average 
heart 
rate 
during activity 
Heart 
rate 
monitor 
The researcher reads 
the results of the 
analysis 
of 
the 
subject's heart rate 
data recording on the 
device connected to 
the 
heart 
rate 
monitor used. 
Beats per minute 
Numeric
al 
Highest heart 
rate during a 
run 
Highest 
heart 
rate 
during exertion 
Heart 
rate 
monitor 
The researcher reads 
the results of the 
analysis 
of 
the 
subject's heart rate 
data recording on the 
device connected to 
the 
heart 
rate 
monitor used. 
Beats per minute 
Numeric
al 
Thermal 
sensation 
Assessment 
of 
the 
temperature 
sensation felt by the 
subject  
ASHRAE 
thermal 
sensation 
visual 
analogue  
ISO 10551 
Subjective 
assessment 
of 
temperature 
sensation 
asked 
directly to the subject 
based on the scale 
7 scale rating score: 
cold, cool, slightly 
cool, neutral, slightly 
warm, warm, hot 
ordinal 
RPE (Rating 
of Perceived 
Exertion) 
Fatigue 
perception 
index  
Borg scale 6-
20 
Subjective 
assessment of fatigue 
perception 
asked 
directly to the subject 
6 means no muscle 
fatigue at all and 20 
means 
maximum 
muscle effort/fatigue. 
ordinal 
Perception 
comfort 
Thermal comfort is a 
satisfaction 
mind 
experienced 
human 
against 
conditions 
temperature in the 
surrounding 
environment. Thermal 
ISO 10551 
Subjects were asked 
to 
provide 
a 
subjective 
assessment 
of 
the 
level of comfort 
5 scale rating score: 
comfortable, 
somewhat 
uncomfortable, 
uncomfortable, 
very 
uncomfortable, 
extremely 
Ordinal 

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comfort 
benchmarks 
include 
a 
balance 
between temperature  
air and temperature 
human body 
uncomfortable. 
Irritation 
Irritation of the skin to 
which the test drug is 
applied 
Internationa
l 
Contact 
Dermatitis 
Research 
Group 
(ICDRG) 
score 
The 
researcher 
inspects 
the 
area 
where the test drug is 
applied. 
Category 
 
 
 
 

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APPENDIX ATTACHMENT 
 
Test Drug Dosing Card 
 
 
 
 
Signaling the administration of the test drug by the Research Coordinator to the 
Subject 
 
 
 
 
TOPICAL DOSING CARD 
TOPICAL DOSING CARD 
TOPICAL DOSING CARD 
NECK 
RIGHT UPPER ARM 
LEFT UPPER ARM 
RIGHT UPPER LEG 
LEFT UPPER LEG 
Exp. date 
Np. Batch: 
Exp. date 
Exp. date 

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Annex 2. List of other medicines prepared 
No. 
Equipment/Medicine 
Total 
1 
Topical medication 
 
 
a. Voltaren gel (anti-inflammatory) 
1 tube 50 grams 
 
b. Chloretyl Spray 
2 cans 
 
c. Counterpain cream 
2 tubes 120 grams 
 
d. Mofacort ointment (Mometasone furoate 
0.1%) 
1 tube 
2 
Wound care 
 
 
a. Betadine antiseptic solution 
1 bottle (30 mL) 
 
b. Sterile gauze 
2 boxes 
 
c. 1-inch micropore 
1 piece 
 
d. Hansaplast plaster 
20 pieces 
 
e. Hansaplast Jumbo Plaster 
10 pieces 
3 
Oral medication 
 
 
a. Diclofenac sodium 25 mg 
1 strip 
 
b. Eperisone HCl 
1 strip 
 
c. Domperidone 
1 strip 
4 
Injectable drugs 
 
 
a. Epinefrine 
2 ampoules 
 
b. Dexamethasone 5 mg/mL 
2 ampoules 
 
c. Sodium chloride infusion solution 0.9% 
1 colf (500 mL) 
 
d. Lactated Ringer's infusion solution 
1 colf (500 mL) 
5 
Miscellaneous equipment 
 
 
a. Oxycan 
3 tubes 
 
b. Ice cubes 
1 box/day 
 
c. Plastic bag with zip 
1 pack 
 
d. Plastic wrap 
1 piece 
 
e. Elastic bandage Tensocrepe 7.5 cm 
1 piece 
 
f. Elastic bandage Tensocrepe 10 cm 
1 piece 
 
g. Elastic bandage Tensocrepe 15 cm 
1 piece 
 
h. 3 cc syringe 
2 pieces 
 
i. Alcohol swab 
1 box (100 pieces) 
 
j. Scissors 
1 piece 
 
k. KN95 Mask 
3 boxes 
 
l. Gloves/handscoon 
1 box 
 
m. AED 
1 unit 
 
 

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Appendix 3 
VISUAL ANALOG SCORE 
 
Subject Code Number 
: .......................................................................... 
 
Day   
 
 
: .......................................................................... 
 
Date  
 
 
: .......................................................................... 
 
 
THERMAL SENSATION ANALOG VISUAL SCORE 
The following below is a visual analog score to measure thermal sensation after applying the 
test drug. 
Circle the area of the visual analog according to the sensation you feel associated with the 
application of the test drug at the exact point or image of the visual analog.  
If your form is incorrect, please request a new form. 
EXAMPLE: 
 
 
 
 
---------------------------------------------------------------------------------------------------------------- 
Filling Sheet  
AFTER THE APPLICATION OF THE TEST DRUG, THEN MY CONCLUSION IS: 
 
 
 
 
 

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VISUAL ANALOG SCORE 
 
Subject Code Number 
: .......................................................................... 
 
Day   
 
 
: .......................................................................... 
 
Date  
 
 
: .......................................................................... 
 
 
VISUAL ANALOG COMFORT SCORE 
The following below is a visual analog score to measure comfort after applying the test drug. 
Circle the area of the visual analog according to how comfortable you feel with the 
application of the test drug on the image of the visual analog.  
If your entry is incorrect, please request a new form again. 
 
EXAMPLE: 
 
 
 
 
---------------------------------------------------------------------------------------------------------------- 
Filling Sheet  
AFTER THE APPLICATION OF THE TEST DRUG, THEN MY CONCLUSION IS: 
 
 
 
 
 
 
Comfortable 
 
 
Uncomfortable 
 
Extremely uncomfortable 
Comfortable 
 
 
Uncomfortable  
Extremely uncomfortable 

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Appendix 4 
Sheet 4 
SCREENING SHEET FOR PROSPECTIVE SUBJECTS 
 
Identity 
Research Code 
 
Name (Initials) 
 
Date of birth 
_______ / ___________ / ________ (date / month / year) 
Age (years) 
 
Gender 
Male/Female*) 
Address 
 
 
 
Phone/Mobile 
 
 
Interview 
Personal best 10 km running duration 
(minutes) 
 < 1 hour 
 
Health 
Musculoskeletal injury in the last 3 
months 
 There is: 
 None 
 
 
 There are still complaints  No complaints 
In the treatment period of chronic 
diseases (HT, DM, heart disease, etc.) 
 Yes 
 No 
History of hypersensitivity or allergy 
to topical products 
 Yes 
 No 
History of cold allergy 
 Yes 
 No 
 
 
Hijab 
 Yes 
 No 
 
Bleep test 
Results 
Level: 
Balikan: 
VO2max 
 
 
Criteria: 
 
 
 
 

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PAR-Q+ Questionnaire 
This questionnaire was used to confirm the completion of the electronic form previously 
completed by the Subject. 
SECTION 1 - GENERAL HEALTH 
Please read each question below carefully and answer as honestly as possible. by marking✓ 
for the appropriate YES or NO answer. 
1. Has your doctor ever diagnosed you with heart 
disease OR high blood pressure? 
 Yes 
 No 
2. Do you ever feel chest pain at rest, during daily 
activities, OR during physical activity? 
 Yes 
 No 
3. 
Have you lost your balance due to dizziness OR 
have you fainted in the past 12 months? Please 
answer NO if the feeling of dizziness is 
associated with heavy breathing (including 
during strenuous physical exercise). 
 Yes 
 No 
4. 
Have 
you 
been 
diagnosed 
with 
any 
chronic/annual health problems (other than heart 
disease and high blood pressure)? 
 Yes 
 No 
5. 
Are you currently taking any medications 
prescribed by your doctor for chronic/annual 
health problems? 
 Yes 
 No 
6. 
Do you have any bone or joint problems that get 
worse with physical activity? Please answer NO 
if you have had joint problems in the past, but 
they do not limit your ability to do physical 
activity now. For example, knee, ankle, 
shoulder, or other joints. 
 Yes 
 No 
7. Has your doctor told you that you can only do 
medically supervised physical activity? 
 Yes 
 No 
If you answered NO to any of the questions above, you are safe to engage in physical 
activity. 
If you answered YES to one or more of the above questions, CONTINUE TO PART 2. 
 
 

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SECTION 2 - CHRONIC HEALTH PROBLEMS 
Please read each question below carefully and answer as honestly as possible. by marking✓ 
for the appropriate YES or NO answer. 
1 Do you suffer from arthritis, osteoporosis, or back 
problems? 
 Yes  
 No 
 
if yes, go to question 1a-1c 
if not, go to question 2 
 
1a 
Are you having difficulty managing this 
condition with medication or other therapies 
from your doctor? (answer NO if you are not 
currently on medication or other therapies). 
 Yes 
 No 
1b 
Do you have joint problems that cause pain, 
recovering from a fracture or fractures due to 
bone 
loss 
(osteoporosis) 
or 
cancer, 
spondylolisthesis, and/or spinal disconnection 
or fracture of the spine or part of the spine. 
 Yes 
 No 
1c 
Have you had steroid injections, or taken 
steroid tablets regularly for more than 3 
months? 
 Yes 
 No 
2 Do you have cancer? 
 Yes 
 No 
 
if yes, go to question 2a-2b 
if not, go to question 3 
 
2a 
Do you have any of the following cancers: 
lung/airway (bronchogenic cancer), multiple 
myeloma, (plasma cell cancer), head and neck? 
 Yes 
 No 
2b 
Are you currently undergoing treatment for 
cancer 
(e.g. 
chemotherapy 
or 
irradiation/radiotherapy)? 
 Yes 
 No 
 
 

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3 
Do you suffer from heart disease or vascular 
disease? Including coronary heart disease, high 
blood pressure, heart failure, heart rhythm 
disorders. 
 Yes 
 No 
 
if yes, go to question 3a-3e 
if not, go to question 4 
 
3a 
Are you having difficulty managing this 
condition with medication or other therapies 
from your doctor? (answer NO if you are not 
currently on medication or other therapies). 
 Yes 
 No 
3b 
Do you have any heart rhythm irregularities 
that require medical attention (e.g. atrial 
fibrillation, 
premature 
ventricular 
contraction)? 
 Yes 
 No 
3c Do you have chronic heart failure? 
 Yes 
 No 
3d 
Is your resting blood pressure equal to or 
greater than 160/90 mmHg with or without 
medication? (Answer YES if you do not 
know what your resting blood pressure is). 
 Yes 
 No 
3e 
Have you been diagnosed with coronary 
heart disease and not engaged in regular 
physical activity in the past 2 months? 
 Yes 
 No 
4 
Do you have any metabolic problems? Including 
type 1 diabetes, type 2 diabetes, pre-diabetes. 
 Yes 
 No 
 
if yes, go to question 4a-4c 
if not, go to question 5 
 
4a 
Is your blood sugar often higher than 13.0 
mmol/L 
(equivalent 
to 
234 
mg/dL)? 
(Answer YES if you are not sure) 
 Yes 
 No 
4b 
Do you have signs or symptoms of diabetic 
complications such as heart or vascular 
disease and/or complications affecting the 
eyes, kidneys, and feeling/sensation in the 
toes and feet? 
 Yes 
 No 
4c 
Do you have any metabolic problems (e.g. 
thyroid disorders, diabetes in pregnancy, 
chronic kidney disease, liver disorders)? 
 Yes 
 No 
5 
Do you have a mental problem or learning 
disorder? 
Including 
Alzheimer's 
disease, 
dementia, depression, anxiety disorders, eating 
disorders, 
psychotic 
disorders, 
intellectual 
disability, Down syndrome. 
 Yes 
 No 
 
if yes, go to question 5a-5b 
if not, go to question 6 
 
5a 
Are you having difficulty managing this 
condition with medication or other therapies 
from your doctor? (answer NO if you are not 
 Yes 
 No 

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currently on medication or other therapies). 
5b Do you also have back problems that affect 
your nerves and muscles? 
 Yes 
 No 
6 
Do you have any respiratory problems? These 
include chronic obstructive pulmonary disease, 
asthma, high pulmonary blood pressure. 
 Yes 
 No 
 
if yes, go to question 6a-6d 
if not, go to question 7 
 
6a 
Are you having difficulty managing this 
condition with medication or other therapies 
from your doctor? (answer NO if you are not 
currently on medication or other therapies). 
 Yes 
 No 
6b 
Has your doctor ever stated that your blood 
oxygen level is low during rest or physical 
exercise, and/or you need supplemental 
oxygen therapy. 
 Yes 
 No 
6c 
If you have asthma, do you currently have 
symptoms of chest tightness, wheezing, 
heavy breathing, persistent coughing (more 
than 2 days per week), or have you used 
your back-up medication (medication for 
attacks) more than twice in the last week? 
 Yes 
 No 
6d Has your doctor told you that the blood 
pressure in your pulmonary veins is high? 
 Yes 
 No 
7 
Do you have a spinal cord injury? This includes 
paralysis of both arms and legs (tetraplegia) and 
both legs (paraplegia). 
 Yes 
 No 
 
if yes, go to question 7a-7c 
if no, go to question 8 
 
7a 
Are you having difficulty managing this 
condition with medication or other therapies 
from your doctor? (answer NO if you are not 
currently on medication or other therapies). 
 Yes 
 No 
7b 
Do you often experience very low blood 
pressure 
resulting 
in 
dizziness, 
lightheadedness, and/or fainting? 
 Yes 
 No 
7c 
Has your doctor ever told you that your 
blood pressure is suddenly high? (known as 
Autonomic Dysreflexia) 
 Yes 
 No 
8 
Have you ever had a stroke? This includes 
Transient Ischemic Attack (TIA) or cerebral 
vascular disorders. 
 Yes 
 No 
 
if yes, go to question 8a-8c 
if no, go to question 9 
 
8a Are you having difficulty managing this 
condition with medication or other therapies  Yes 
 No 

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from your doctor? (answer NO if you are not 
currently on medication or other therapies). 
8b Do you have difficulty walking or moving? 
 Yes 
 No 
8c Have you had a stroke or nerve or muscle 
disorder in the last 6 months? 
 Yes 
 No 
9. 
Do you have any medical problems not listed 
above, or do you have two chronic/annual health 
problems? 
 Yes 
 No 
 
if yes, go to question 9a-9c 
if not, go to page 5 
 
9a 
Have you experienced blackouts, fainting, or 
loss of consciousness as a result of a head 
injury in the past 12 months OR have you 
had a concussion in the past 12 months? 
 Yes 
 No 
9b 
Do you have any medical problems that are 
not listed (e.g. epilepsy/ayan, neurological 
disorders, renal disorders)? 
 Yes 
 No 
9c Do you currently have two chronic/annual 
health problems? 
 Yes 
 No 
 
 

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Appendix 4 
EXPLANATION SHEET TO RESEARCH SUBJECTS 
 
We as a Research Team from Sports Medicine Specialists are conducting research with the title: 
Effectiveness of Topical Menthol as an Exercise Cooling Method in a Population of Recreational 
Runners. 
 
Therefore, at this time, we are providing information about the subject recruitment process   to be part of 
this study.  
 
1. 
Research objectives 
Knowing the effect of using topical menthol application as a cooling method during exercise. 
 
2. 
Reasons for choosing Mr / Mrs / Brother / Sister 
1. 
18- 45 years old 
2. 
Have a personal best 10 km running time < 1 hour in the last 6 months 
3. 
Doing running training at least 3 times/week for the past 1 year 
4. 
No musculoskeletal injuries (muscle, joint, bone injuries) in the past 3 months 
5. 
No acute infectious disorders such as gastrointestinal infections and respiratory infections 
6. 
Not under treatment for chronic diseases such as hypertension, Diabetes Mellitus, and heart 
disease 
7. 
No history of hypersensitivity or allergy to gel-based topical products, products containing 
menthol 
8. 
No history of allergy to cold 
9. 
Not currently infected with COVID-19 
10. Not a pregnant or breastfeeding woman 
 
3. Research procedure 
Overall, the study process will consist of 2 intervention periods of test drug administration. In the 
subject recruitment process, you will undergo the following activities: 
a. The research team will ask you to confirm the results of the electronic registration form and 
the PAR-Q questionnaire (physical activity readiness questionnaire). 
b. Then, the research team will carry out a physical examination, blood pressure examination, 
resting ECG examination and current blood sugar and Covid 19 on Mr / Mrs / Brother / 
Sister. 
c. If all tests on the first day are normal, you will be scheduled to take the Bleep Test on the 
second day of screening. 
d. On the second day of screening, you will be directed to do static stretching as guided by the 
Research Team and warm up by running 1 lap (400 m). 
e. Mr / Mrs / Brothers / Sisters will be asked for their willingness to do the Bleep test to 
measure the level of pulmonary heart fitness by running from one end or markers cones to 
the other end or markers cones within 20 meters by following the rhythm of the "beep" 
sound from the recording tape. 

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f. If your Bleep Test results fall into the minimum sufficient category, then you will be given 
education and an explanation of the research procedures to be carried out. 
g. If all criteria are met, you will receive education related to this study such as: the time of 
the study day, preparation before running activities, education related to data that will be 
assessed on the day of the study and actions that need to be reported to the research team.  
h. On the first day of the study, the research team will conduct a Covid-19 antigen 
examination on Mr / Mrs / Brother / Sister. 
i. 
Furthermore, the research team will check your blood pressure before running and you will 
be given education about the application of the trial materials. 
j. 
Then, you will be asked to take measurements of several parameters, namely weight, 
height, body mass index, hydration status (by collecting urine in the pot provided), and 
vertical jump (measuring the height of the jump to measure leg explosive power), followed 
by body temperature checks at 5 areas and ears. 
k. Before doing the running activity, you are directed to do static stretching according to the 
guidance of the Research Team and warm up by jogging or running for 1 lap (400 m). 
l. 
After that, you will run 5 km as fast as you can.  
m. At kilometers 2.5 to 2.8, you will apply the prepared menthol-containing gel or placebo to 
your neck, right and left upper arms, right and left quadriceps, while continuing to run.  
n. After running, you will be measured for body weight, ear temperature, heart rate, vertical 
jump, fatigue level, temperature sensation and perceived comfort of use and irritation 
check. 
o. You will also be asked to immediately report any complaints or symptoms of health 
problems or injuries that occur after the study. 
 
4. Risks, side effects and management 
There is a risk of injury and heat related illness when you run. If this occurs, the screening will be 
stopped if there are complaints that interfere with the screening process. In addition, the Researcher 
who is a Sports Medicine Specialist and the Rapid Reaction Medical Team will provide appropriate 
first aid if there is an emergency condition, in this case contacting the ambulance according to the 
nearest referral hospital and preparing an AED. If you need further treatment at the hospital, the 
Sponsor provides insurance that can cover the cost of your treatment. 
 
5. Benefits 
The benefit that you can get is a health check and fitness check with a doctor 
 
6. Compensation 
There is no special incentive for you to participate in this process. However, the Research Team 
will provide transportation costs of IDR 300,000 and a reimbursement fee for the time you have 
given in participating in this study of IDR 300,000 per intervention period. The fee will be 
provided on the 2nd research day. 
 
7. Confidentiality 
All data collected in this study will be kept confidential. Presentation of research results at 
scientific meetings/conferences and publication in scientific journals will not include your name.  

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8. Subject Obligations 
As a Subject, you are obliged to follow the rules or instructions for the screening process of 
prospective Subjects as written above. If there is anything that is not clear, you can ask further to 
the research team.  
 
 
9. Right to refuse and resign 
You do not have to participate in this study if you do not want to. And even if you have agreed to 
participate in this study, you have the right to withdraw from this study at any time.  
 
10. Additional Information 
Mr./Ms./Mrs./Brothers/Sisters are given the opportunity to ask all things that are not clear in 
connection with the screening process of this prospective Subject. If at any time you need further 
explanation, you can contact Dr. Theresia Indriani Prima Chesar at 081295838147 and Dr. Nisrina 
Nindriya at 081221734814. 
 
 
 
 
 

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INFORMED CONSENT FORM FOR SUBJECT PARTICIPATION 
 
 
All these explanations have been provided to me and all my questions have been answered by 
_________________________. I understand that if I need clarification, I can ask Dr. Theresia Indriani 
Prima Chesar and Dr. Nisrina Nindriya. 
 
Certificate of Consent 
 
I have read all the explanations about this 
screening of Subject candidates. I have been given 
the opportunity to ask questions and all my 
questions have been answered clearly. I am willing 
to participate in this research study voluntarily. 
 
 
____________________________ 
Subject Name 
 
 
____________________________ 
Signature of Subject 
 
Tanggal_________________________ 
day/month/year 
 
I confirm that participants have been given 
the opportunity to ask questions regarding 
this screening of potential Subjects, and all 
questions have been answered correctly. I 
confirm that consent has been 
given 
willingly. 
 
 
____________________________ 
Name of researcher/approver  
 
 
____________________________ 
Signature of researcher/approver  
 
Tanggal_________________________ 
day/month/year 
 
 

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If the Subject is illiterate: 
A witness who is not illiterate should sign (if possible, this person should be chosen by the research 
subject/participant, not his/her parents, and should not have any relationship with the research team). The 
illiterate research subject/participant must also include his/her fingerprints.  
 
I have witnessed the reading of the consent form to the Subject/participant accurately, and have 
been given the opportunity to ask questions. I confirm that the Subject/participant has given his/her 
consent freely.  
 
Witness name ____________________________ 
AND      
 
Subject's fingerprints 
Witness signature _____________________ 
Tanggal ________________________ 
                  date/month/year 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 7 
WITHDRAWAL FORM FROM RESEARCH 
 
After reading and listening to the explanation of the research to be conducted by the Sports 
Medicine Specialist Research Team with the title "The Effectiveness of Topical Menthol as a Cooling 
Method During Exercise in a Population of Recreational Runners" and the information has been well 
understood by me regarding the benefits, actions to be taken, advantages and possible 
inconveniences that may be encountered, I: 
Name 
 
: ..................................................................... 
Age 
 
: ..................................................................... 
Gender 
: ..................................................................... 
Address  
: ..................................................................... 
Phone No. : ..................................................................... 
I hereby withdraw from the research without any coercion from any party and I will not sue if 
something happens in the future. 
 
Jakarta, ___________________ 
 
 
Subject Signature________  
 
 
Witness Signature________ 
Subject Name: 
 
 
 
 
Witness Name: ______________ 
 
 

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Appendix 7 
Research Status 
Effectiveness of Topical Menthol as an Exercise Cooling Method in a Population of 
Recreational Runners 
 
Subject Identity 
Sequence number 
: 
Name (Initials) 
:  
Date of birth (Age) 
: 
Gender 
 
: Male/Female 
Address 
 
: 
Last education  
: 
Jobs 
 
 
: 
Nationality 
 
:  
Phone No. 
 
: 
Email address  
: 
 
Copy of Identification Card (KTP) 
 
Yes 
 
No 
 
Anamnesis 
Complaints in the last few months (please mark √ ) 
fever ( ) nausea ( ) vomiting ( ) diarrhea ( ) cough ( ) runny nose ( ) tightness ( ) chest pain ( ) 
palpitations ( ) cold sweat ( ) others __________ 
Disease History 
 
 : Hypertension ( ), Diabetes Mellitus ( ), Heart Disease ( ) 
 
 
 
 
   Musculoskeletal injury ( ) 
Allergy History 
 
 :  
Medications being taken: 
Exercise routine 
 
 : ___ Yes. If yes, frequency: 
 
 
 
 
   ___ No  
 
 
 
 

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Fulfillment of Inclusion and Exclusion Criteria 
 
 
No. 
Inclusion Criteria 
Yes 
No 
1 
Adults, 18 years old - 45 years old 
 
 
2 
Have a personal best 10-kilometer run time under one hour 
(which will be confirmed during the screening of prospective 
Subjects through history taking) in the last 6 months. 
 
 
3 
Doing running training at least 3 times/week for the past 1 
year 
 
 
4 
Have a level of heart-lung endurance or VO2max that is at 
least included in the average criteria (known through 
examination: Bleep test) 
 
 
5 
Meets Subject screening criteria by answering "No" to all 
questions on the Physical Activity Readiness Quesstionnaire 
(PAR-Q) questionnaire. 
 
 
6 
Have normal resting ECG and normal GDS results on 
screening of prospective Subjects. 
 
 
7 
At the time of the study, the body temperature was within 
the normal range. 
 
 
 
 
 
No. 
Exclusion Criteria: 
Yes 
No 
1 
Pregnant and/or breastfeeding women 
2 
Have had a musculoskeletal injury in the last three months 
and still have symptoms or complaints 
3 
Are experiencing acute infectious disorders, such as 
gastrointestinal, respiratory infections 
4 
During treatment for chronic diseases (e.g. high blood 
pressure or hypertension, diabetes or diabetes mellitus, heart 
disease) 
5 
Have a history of hypersensitivity or allergy to menthol or 
skin-applied products (especially gel-based products) 
6 
Has a history of cold allergy 
7 
Have a Positive Covid-19 test at the time of screening. 
 
 
 
 
 
 
 
 

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Inspection Result 
● Before running 
Core body temperature 
 
:  
oC 
Skin surface temperature 
 
: 
 
Calves  
 
 
: 
oC 
 
Thighs  
 
 
:  
oC 
 
Stomach 
 
 
:  
oC 
 
Upper arm 
 
 
:  
oC 
 
Neck   
 
 
:  
oC 
Heart rate frequency  
 
: 
times/minute 
Blood pressure 
 
 
: 
mmHg 
Body weight  
 
 
:  
kg 
Height  
 
 
 
:    
cm 
Body mass index 
 
 
: 
kg/m2 
Vertical jump  
 
 
: 
cm 
Hydration status* 
 
 
: 
 
 
● After running 
Core body temperature 
 
:  
oC 
Skin surface temperature 
 
: 
 
Calves  
 
 
: 
oC 
 
Thighs  
 
 
:  
oC 
 
Stomach 
 
 
:  
oC 
 
Upper arm 
 
 
:  
oC 
 
Neck   
 
 
:  
oC 
Max heart rate frequency 
 
: 
times/minute 
Average heart rate frequency  
: 
times/minute 
Blood pressure 
 
 
: 
mmHg 
Body weight  
 
 
: 
kg 
Vertical jump  
 
 
: 
cm 
Hydration status* 
 
 
 
: 
 
Cold temperature sensation (please circle "O"): 
 
 
 
 

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Perceived comfort level 
(please circle "O"): 
 
 
 
 
Skin Irritation Check: 
 
- 
?+ 
+ 
++ 
+++ 
IR 
Negative 
Doubtful 
Weak 
Positive 
Strong 
Positive 
Extreme 
Positive 
Irritant 
Reaction 
 
 
 
 
 
Comfortable 
 
Uncomfortable 
 
Extremely uncomfortable 

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Appendix 9 
ELECTRONIC FORM 

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