A Human Repeat Insult Patch Test (HRIPT) in Healthy Subjects to Assess the Cutaneous Irritation and Sensitization Potential of a Cosmetic Facial Product
Phase: NA
Conditions: Skin Care
Sponsor: GlaxoSmithKline

Copyright:  GlaxoSmithKline.  An unpublished work subject to trade secret 
protection.  This work contains confidential and proprietary information of 
GlaxoSmithKline and should not be copied, circulated, or distributed to persons not 
employed by GlaxoSmithKline unless specifically authorized.  Unauthorized 
disclosure of this work is expressly prohibited.
Clinical Protocol
207585
 
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CONFIDENTIAL
SUMMARY INFORMATION
Title:
A Human Repeat Insult Patch Test (HRIPT) in Healthy 
Subjects to Assess the Cutaneous Irritation and 
Sensitisation Potentialof a Cosmetic Facial Product.
Protocol Number:
207585
Sponsor:
GlaxoSmithKline Consumer Healthcare (GSKCH)
Rua Hungria, 1240 4º andar, Jardim Europa
São Paulo/SP –Brazil, CEP 01455-000
Tel: 
Product Name:
Facial micellar cleanser
Development Phase:
N/A
Expert Advice Outside of Normal 
Working Hours:
Tel: 
 (US)
Key Protocol Authors:
PRIMARY CONTACT
Clinical Research Scientist:
, MSc
GlaxoSmithKline Consumer Healthcare 
(GSKCH)
St. Georges Avenue, Weybridge, Surrey, 
KT13 0DE. UK
Tel. 
PRIMARY CONTACT
Clinical Study Manager:
GlaxoSmithKline Consumer Healthcare 
(GSKCH)
Rua Hungria, 1240 4º andar, Jardim
Europa
São Paulo/SP –Brazil, CEP 01455-000
Tel: 
Biostatistician:
Other Protocol Authors:
Clinical Supplies:
Data Manager:
Medical Expert:
, MD, Ph.D
 
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Study Site Name & Address:
AZIDUS BRASIL PESQUISA 
CIENTÍFICA E DESENVOLVIMENTO 
LTDA.
Rua: General Osório, 507 -Vila Martina 
-Valinhos –SP –Brazil 
CEP: 13271-130
Study Site Telephone Number:
Study Examiner(s):
Study examiner (s)will be assigned 
according to the site schedule (before 
First Subject First Visit) and documented 
in the site file.
Dermatologist:
Study Dermatologistwill be assigned 
according to the site schedule (before 
First Subject First Visit) and documented 
in the site file.
 
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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT 
PAGE
I confirm agreement to conduct the study in compliance with the protocol and any 
amendments and according to the current ICH GCP guidelines.
I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure site staff receives all appropriate information throughout the study.
I agree to conduct this study in full conformance with the laws and regulations of 
the country in which the research is conducted.
Investigator Name:
Investigator Qualifications:
Investigator Signature:
Date of Signature/ Agreement:
DD/MMM/YYYY
 
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Table of Content
SUMMARY INFORMATION...............................................2
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT 
PAGE..............................................................................4
Table of Content......................................................................5
PROCESS FOR AMENDING THE PROTOCOL...............9
PROTOCOL AMENDMENT PAGE....................................10
PROTOCOL SYNOPSIS FOR STUDY 207585...................14
1. INTRODUCTION...............................................................19
2. OBJECTIVE(S) AND ENDPOINT(S)...............................20
3. STUDY PLAN.....................................................................20
3.1. Study Design.......................................................................20
3.2. Subject Restrictions...........................................................22
3.3. Type and Planned Number of Subjects............................23
3.4. Study Design and Application Amount Justification.......23
4. SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA........................................27
4.1. Inclusion Criteria...............................................................27
4.2. Exclusion Criteria..............................................................28
4.3. Screening/ Baseline Failures..............................................30
4.4. Withdrawal/ Stopping Criteria.........................................30
4.5. Subject Replacement..........................................................31
4.6. Subject and Study Completion..........................................31
5. PRODUCT INFORMATION.............................................31
5.1. Study Product.....................................................................31
5.2. Application Schedule.........................................................32
 
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5.3. Product Assignment...........................................................33
5.3.1 Randomisation....................................................................33
5.3.2 Blinding...............................................................................33
5.3.3 Code Breaks........................................................................34
5.4. Packaging and Labelling...................................................34
5.4.1. Accountability of Product.................................................34
5.4.2. Storage of Product............................................................35
6. STUDY ASSESSMENTS AND PROCEDURES..............35
6.1. Visit 1 -Screening Visit......................................................35
6.1.1 Telephone Screening..........................................................35
6.1.2. InformedConsent.............................................................35
6.1.3. Demographics....................................................................36
6.1.4 Dermatologist Assessment.................................................36
6.1.5. Medical History and Concomitant Medication...............36
6.2. Visit 2 -Baseline Visit To Visit 14.....................................36
6.2.1 Application of patches........................................................37
6.2.2 Patch Assessments..............................................................38
6.3. Visit 15 -Last Subject Last Visit (LSLV).........................40
6.3.1. Study Conclusion...............................................................40
7. SAFETY ASSESSMENTS..................................................40
7.1. Definitions of an Adverse Event and Serious Adverse
Event.................................................................................40
7.1.1. Adverse Events..................................................................40
7.1.2. Serious Adverse Events.....................................................42
7.2. Recording Adverse Events and Serious Adverse Events.43
7.3. Evaluating Adverse Events and Serious Adverse Events44
7.4. Reporting Adverse Events and Serious Adverse Events..45
7.5. Follow-up of Adverse Events and Serious Adverse Events
..........................................................................................46
 
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7.6. Collection of Pregnancy Information................................48
7.6.1. Time Period for Collecting of Pregnancy Information...48
7.6.2. Action to be Taken if Pregnancy Occurs.........................48
8. DATA MANAGEMENT....................................................48
8.1. Source Documents/ Data....................................................49
8.2. Electronic Case Report Form............................................49
8.3. Data Handling....................................................................50
8.3.1. Data Queries......................................................................50
9. STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES....................................................................50
9.1 Sample Size Determination.................................................50
9.2. General Considerations.....................................................51
9.2.1. Definition of Analysis Populations...................................51
9.2.2. Exclusion of Data from Analysis......................................51
9.2.3. Criteria for Evaluation.....................................................51
9.2.4. Handling of Dropouts and Missing Data.........................51
9.3. Statistical Methods and Analytical Plan...........................51
9.3.1. Demographic and Baseline Characteristics.....................52
9.3.2. Primary Analysis(es).........................................................52
9.3.3. Safety Analysis(es).............................................................52
10. STUDY GOVERNANCE CONSIDERATIONS.............52
10.1. Posting of Information on Publicly Available Clinical 
Trials Registers................................................................52
10.2. Regulatory and Ethical Considerations, Including the 
Informed Consent............................................................53
10.3. Quality Control (Study Monitoring)...............................53
10.4. Quality Assurance............................................................54
10.5. Conditions for Terminating the Study............................54
 
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10.6. Records Retention............................................................55
10.7. Provision of Study Results to Investigators, posting of 
Information on PubliclyAvailable Clinical Trials 
Registers and Publication................................................56
11. REFERENCES..................................................................56
12. APPENDICES...................................................................58
12.1. Appendix 1 -Abbreviations and Trademarks................58
12.2. Appendix 2 –Dermal Response Score.............................59
12.3. Appendix 3 -Fitzpatrick Skin Type Grading.................61
 
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PROCESS FOR AMENDING THE PROTOCOL
Protocol modifications to ongoing studies which could potentially adversely affect the 
safety of subjects or which alter the scope of the investigation, the scientific quality of 
the study, the experimental design, dosages, duration of therapy, assessment 
variables, the number of subjects treated, or subject selection criteria are considered 
major/substantial amendments and must be made only after appropriate consultation 
between an appropriate representative of GSKCH and the investigator.
Details of amendments to the protocols should be recorded on the following page. 
Protocol modifications must be prepared by a representative of GSKCH.  All changes 
must be justified in the Reason for Amendment section of the following Protocol 
Amendment Page. Approval of amendments will be made by the original protocol 
signatories or their appropriate designees.
All major/substantial protocol modifications must be reviewed and approved by the 
appropriate IRBin accordance with local requirements, before the revised edition can 
be implemented. 
All non-substantial/ minor/ administrative amendments should be submitted to the 
IRBas per country specific requirements. In some countries pre-approval of a minor 
amendment is not required and will just be held on file by the sponsor and 
investigator.
 
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PROTOCOL AMENDMENT PAGE
Details of all amendments should be recorded in the table below. Affected sections should be listed in the table; the actual 
amendment/ change should be made in the relevant section of the main protocol. 
To highlight the change, the following features will be used: 
To addtext:Use of CAPITAL LETTERS, BOLD AND UNDERLINE
To delete text: Use of Strikethrough e.g. strikethrough
Amendment 
No. & New 
Protocol 
Version No.
Type of Amendment
Reason for Amendment
Other 
Documents 
Requiring 
Amendment
Section(s) Amended 
PI Amendment 
Agreement
Signature & 
Date
Amendment 
No.:
Non-Substantial/Minor    
Informed 
Consent   
Yes No
Safety 
Statement     
Yes No
CRF                       
Yes No
Signature:
Protocol 
Version 
No.:
Substantial/ Major           
Date:
Amendment 
No.:
Non-Substantial/Minor    
Informed 
Consent   
Yes No
Safety 
Statement     
Yes No
CRF                       
Yes No
Signature:
Protocol 
Version 
No.:
Substantial/ Major           
Date:
 
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Amendment 
No. & New 
Protocol 
Version No.
Type of Amendment
Reason for Amendment
Other 
Documents 
Requiring 
Amendment
Section(s)Amended 
PI Amendment 
Agreement
Signature & 
Date
Amendment 
No.:
Non-Substantial/Minor    
Informed 
Consent   
Yes No
Safety 
Statement     
Yes No
CRF                       
Yes No
Signature:
Protocol 
Version 
No.:
Substantial/ Major           
Date:
Amendment 
No.:
Non-Substantial/Minor    
Informed 
Consent   
Yes No
Safety 
Statement     
Yes No
CRF                       
Yes No
Signature:
Protocol 
Version 
No.:
Substantial/ Major           
Date:
 
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SCHEDULE OF EVENTS
Study Phase
Screening
Induction
Rest
Challenge
Study Week
-
Week 1
Week 2
Week 3
Week 
4-5
Week 6
                      Study Day            
Procedure/
Assessment
VISIT 1 
DAY -14 
to 
DAY 0
VISIT 2
DAY 1
VISIT 3
DAY 3
VISIT 4
DAY 5
VISIT 5
DAY 8
VISIT 6
DAY 10
VISIT 7
DAY 12
VISIT 8
DAY 15
VISIT 9 
DAY 17
VISIT 10
DAY 19
VISIT 11
DAY 22 
VISIT 12
DAY 36
VISIT 13
DAY 38
VISIT 14
DAY 39
VISIT 15
DAY 40
Day of Week
-
Mon
Wed
Fri Mon
Wed
Fri Mon
Wed
Fri
Mon
Mon
Wed
Thu
Fri
Informed Consent
X
Demographics
X
Medical History
X
Current/Concomitant medication 
review 
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fitzpatrick Skin Type 
Assessment
X
Inclusion/Exclusion Criteria
X 
Xa
Dermatologist Assessment 
a
X 
X
X
Subject Eligibility
X
X
Continued Eligibility
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomisation
X
Patch Application b
X 
X 
X 
X 
X 
X 
X 
X 
X
Xf
Patch Removalc
X 
X 
X 
X 
X 
X 
X 
X 
Xe
Xi
Grading/Assessment of the patch 
sites 
d
X g
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
X i
Xj
Xj
Adverse Eventsk
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Study Conclusion/Discharge 
from Study/
X
 
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Note: Visit 1 and Visit2 could occur on the same day but Visit 2 must be within 
14 days of Visit 1.
a.Performed by a qualified dermatologist(Inclusion criteria 3c)
b.Subjects will report to the study site 10times during the Induction Phase (9 patch 
applications).  The patches will remain in place for 48(±2) hours during the week.  
Patches applied on Friday will remain in place for approximately72(±2)hours until 
Monday.
c.30 minutes (up to 1 hour)after each patch removal, a trained blinded assessorwill 
perform an assessment of all test sites for irritation symptoms using the scoring 
system detailed in Appendix 2.
d.A trained (by a dermatologist) blinded assessorwill perform assessments of all test 
sites for symptoms of irritation using the scoring system detailed in Appendix 2.
e.Visit 11 (Day 22)will be the final Induction Phase patch removal and 
grading/assessment.
f.Challenge Phase patch application(after 2 week Rest Phase), Visit 12 (Day 36).The 
challenge patchwill be applied to a naïve site and remain in place for 48(±2) hours.
g.Visit 2 (Day 1) Baseline assessments of the patch sites will be performed prior to the 
patch application.
h.Visit 12 (Day 36) assessments of the naïve challenge patch sitewill be performed 
prior to the challenge patch application. 
i.30 minutes (up to 1 hour)following Challenge patch removal a trained blinded 
assessorwill perform an assessment of the Challengetest sitefor irritation 
symptoms using the scoring system detailed in Appendix 2.
j.Further evaluationsofnaïve patch removal sitewill take place 24 (±2) and 48 (±2)
hours after patch removal (e.g., apply the patch on Monday, remove thechallenge 
patch on Wednesday, and evaluate the sites on Wednesday, Thursdayand Friday).
k.Subjects are asked to report any adverse events from Visit 2 (or Visit 1 if patch 
application occurs at Visit 1) and the use of any concomitant medications 
throughout the study.
 
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PROTOCOL SYNOPSIS FOR STUDY 207585
Brief Summary
A cosmetic product that isfreely available to the consumer must be safe when applied
under normal or reasonably foreseeable conditions of use. Asa general requirement, 
the safetyand compatibilityof a newformulationshouldbe confirmed before it is 
commercialised (Guidelineforthe Safety Evaluation of Cosmetic Products; Agência 
Nacional de Vigilância Sanitária, ANVISA, 2012).
Compatibility studies, performed aspatch tests, aim to confirm the local tolerance of
topical cosmetic productsduring the first application to the skin,therefore providing 
assurancethat the product is safe for useunder maximized conditions (ANVISA, 
2012).
The human repeatedinsult patch test (HRIPT) is a long standing, standard methodto 
determine whether a defined exposure to a product will elicit a dermal irritant or 
allergic response under exaggerated conditions of exposure.  It is also routinely used 
and accepted as an appropriate methodology to establish the sensitisation potential of 
topical products (e.g. by the FDA in the U.S.).  The HRIPT requires approximately 
six weeks per a subject and involves three phases: Induction, Rest and Challenge, and 
is based on the modified Draize test. (Draize, 1944)
In this study the test material and the positive control of saline solutionare applied 
under a semi-occlusive patch to a subject’s upper back. The first phase of the study is 
an Induction Phase; a knownamount of product is applied over adefined surface area 
of skin (amountper unit area) under asemi-occlusive patch.  Each patchwill remain 
on the skin for 48 (±2)hours (weekdays) or 72 (±2) hours (including inclusive 
weekends) during this phase. The patch will be removed and the site will be assessed 
then a new patch will be applied to the same site.After the Induction Phase, subjects 
will enter a Rest Phase of 2 weeks duration, during which no patches are applied.  
After the Rest Phase, subjects will return to the clinical site for the Challenge Phase.  
In this phase a challenge patch of both the test product and control is applied to virgin 
skin for 48 (±2) hours then assessed 30 minutes (maximum 1 hour) 24 (± 2) hours and 
48 (±2) hours after patch removal.
Theobjectiveof this clinical studyis to assess the irritation and sensitisationpotential 
of acosmetic test productafter repeated patch applications to healthy humansubjects 
by following a conventional HRIPT methodologyunder supervision of a 
dermatologist.
 
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Objective(s) and Endpoint(s)
Objective(s)
Endpoint(s)
Primary
To determine the irritation and contact 
sensitisation potential of a cosmetic facial 
skin productafter repeated patch 
applications to the skin of healthy 
subjects.
Trained assessorassessment of local 
tolerance through visual assessment of 
cutaneous irritation viathe combined 
dermal responseand other effects scores 
over the induction and challenge phase.
Secondary
To evaluate the general safety of a 
cosmetic facial skin product.
Assessment of frequency and severity of 
Adverse Events
Study Design
Overall Design
Test site randomized, assessor-blinded, single-center, Human Repeated Insult Patch 
Test (HRIPT) in healthy subjects to assess the cutaneous irritation and sensitisation 
potentialof a cosmetic facial product, by following a conventional HRIPT 
methodologyunder supervision of a dermatologist.
Day -14 to 0  / Visit 1 -Screening Visit
NOTE: Visit 1 and Visit 2 could be combined
The following assessments will be conducted:
1. Subject Informed Consent taken
2. Subject demographics collected
3. Medical history details
4. Details of current and concomitant medication collected 
5. Fitzpatrick Skin Type Assessment (Appendix 3) 
6. Inclusion/Exclusion criteria 
7. Dermatologist determination for eligibility to participate in the study
(including visual examination of the dorsum scapular region)
8. Subject Eligibility
Days 1 to 22 /Visit 2 -Visit 11 -Induction Phase (3 Weeks)
NOTE: Visit 1 and Visit 2 could be combined
Thefollowing assessments will be conducted:
1. Continued eligibility check
2. Current/Concomitant Medicationsreview
3. Inclusion/Exclusion criteria review(3c only at Visit 2 if Visit 1 and 2 are not 
combined).
 
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4. Dermatologist determination for continued eligibility to participate in the study 
(Visit 2/Day 1 only -if visits not combined).
5. Test Site Designation and Randomisation (Visit 2/Day 1 only).
6. Baseline grading/assessment of test sites(Visit 2/Day 1 only) as per Appendix 
2.
7. Patch applications (9 patch applications to the same test site, over3 
consecutiveweeks with patches applied on alternate weekdays).
8. Patch removal after 48 (± 2) hours or 72 (± 2) hours over inclusive weekends.
9. Reaction grading/assessmentperformed by a qualified staff member, as per 
Appendix 2.
10.Adverse event assessment
Note: 30 minutes (maximum of 1 hour) after patch removal,sites will be 
graded/evaluated, then patches will be reapplied to the same sites.
Day 22-Day 36 / Visit 11 –Visit 12 -Rest Phase (2 Weeks) 
No Patch Application  
Days 36to 39 / Visit 12 to Visit 14 -Challenge Phase
The following assessments will be conducted:
1. Continued eligibility check
2. Current/Concomitant Medicationsreview
3. Grading/assessmentof naïve challenge patchsite performed by a qualified 
staff member.(As per Appendix 2). Prior to Challenge patch application.
(Visit 12/Day 36).
4. Challenge Phase patch application to naïve site (Visit 12/Day 36).
5. Patch removal 48 (± 2) or 72 (± 2) hours over inclusive weekends after 
application. (Visit 13/Day 38).
6. Reaction grading/assessment performed by a qualified staff member at 
approximately 30 minutes (maximum 1 hour) after patch removal.
7. 24(± 2) hours afterpatch removal(Visit 14/Day 39) subjects will return for 
assessment performed by a qualified staff member.
8. Adverse event assessment. 
Day40 / Visit 15–End of Study
The following assessments will be conducted:
1. Current/Concomitant Medicationsreview
2. Adverse event assessment.
3. 48 (± 2) hours after patch removal (Visit 15/Day 40) final challenge patch site 
assessment performed by a qualified staff member.
4. Dermatologist final assessment.
5. Subject discharge from the study site following completion of all study 
 
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procedures. 
Typeand Planned Number of Subjects
Approximately 280 healthy subjects will be screened to randomize at least 240 
subjects to ensure 200 evaluablesubjects complete the entire study.If no reaction is 
observed in 200 subjects, there is a 95% certainty that the actual rate of reaction in the 
wider population is <1.8%.
Diagnosis and Main Criteria for Inclusion
Healthy male and female volunteers aged 18 to 65 with no dermatological disorders, 
with a Fitzpatrick skin phototype I to IVwill be enrolled into this study. 
Product Information
Test Product 
Reference Product 
Product Name 
Facial micellar cleanser
Saline Solution: Sodium 
Chloride (NaCl; 0.9%)
Product Formulation 
Code (MFC)
N/A
Site to supply
Product Format
200ml clear PET Bottle
N/A
Application Quantity
0.02 millilitres/square 
centimetre (ml/cm
2)
0.02 ml/cm
2
Route of Administration
Topical dermal application via semi occlusive patch
Application  Instructions
Applied on-site by technician
Statistical Methods
The focus of the statistical analysis will be the evaluationof the frequency and level
of irritation and sensitisation responsesofthe investigational product. All subjects 
with any product applied will be included in the analysis population.
Individual observations will be assessed based onAppendix 2and a narrative 
description of all skin responses, both in the induction and challenge phases,will be 
provided.  A frequency tabulation of the number of subjects with any skin response 
versus those without any skin response will be presented by
 treatment group for both 
the induction and challenge phases of the study. If there are subjects with non-zero 
dermal response or superficial irritation scores, a combined dermal and others effects 
 
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CCI

score will be determined across all time points over the induction and challenges 
phases as well as at each assessment time point and summarised using descriptive 
statistics.
No interim or subgroup analyses are planned.
Adverse Events (AE) will be tabulated according to the current version of the 
Medical Dictionary for Regulatory Activities (MedDRA). Frequencies and 
percentages will be presented overall, for each system organ class, and for each 
preferred term. Summaries of treatment-emergent AEs, treatment-related AEs, AEs 
leading to discontinuation, and serious AEs will be completed. For treatment-related 
AEs, these will alsobe presented by treatment/test site.
Detailed methodology for summary and statistical analyses of the data collected in 
this study will be documented in a Statistical Analysis Plan, which will be maintained 
and signed off prior to study unblinding.  
 
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1. INTRODUCTION
In recent years the cosmetic industry has grown considerably, along with its concern
for developing safe and effective products. This industry awareness, and consumer
and regulatory agency requirements have led cosmetic manufacturers to adopt
procedures that provide them with a better understanding of their products. This 
includesthe conduct of clinical tests to assess safety and efficacy, which are often 
coordinatedby dermatologists or other experts before marketing a product. These 
proceduresprovide greater assurance of safety for the companies, increase their 
credibility, andincrease confidence among consumers.
A cosmetic product that is freely available to the consumer must be safe when applied
under normal or reasonablyforeseeable conditions of use (ANVISA, 2012). Thus, the
raw materials used in the product formulation must be of proven safety and with
established use in the cosmetic industry. As a general requirement, the safety of the
final formulation must also be confirmed before it is marketed.
Skin contact with topical products such as cosmeticsmay triggerdifferent types of 
reactions including eczematouscontact dermatitis, urticaria, acneand spots. Contact 
dermatitis can arise from two mechanisms: primary irritation,through the action of 
irritant substances; or sensitisation, in the presence of anallergenic ingredient.
Clinical studiesto evaluate the irritation and sensitisation potential of a product must 
take intoaccount a number of variables: components used in the formulation, 
ingredientconcentration, absorption, amount applied,skin condition, application 
directions andfrequency, aswell as the cumulative effect (Dooms-Goossens, 1993).
The objective of suchcompatibility studies,performed by applying materials to the 
skin under a patch, isto evaluate potentialuntoward effectsduring exaggerated 
application to the skin to provideassurance that the product is well tolerated and safe 
for use. A common method to assess the potential of topically applied product to 
cause irritation or sensitisation involved repeatedpatch applications of a product to 
the skin (Basketter, 2008).  
Theobjectiveof this clinical studyis to assess the irritation and sensitisationpotential 
of a cosmetic test productafter repeated semi-occlusive patch applications to healthy 
humansubjects by following a conventional HRIPT methodologyunder supervision 
of a dermatologist.
 
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2. OBJECTIVE(S)AND ENDPOINT(S)
Objective(s)
Endpoint(s)
Primary
To determine the irritation and contact 
sensitisation potential of a cosmetic facial 
skin product after repeated patch 
applications to the skin of healthy 
subjects.
Trained assessorassessment of local 
tolerance through visual assessment of 
cutaneous irritation via the combined 
dermal responseand other effects scores 
over the induction and challenge phase.
Secondary
To evaluate the general safety of a
cosmetic facial skin product.
Assessment of frequency and severity of 
Adverse Events
3. STUDY PLAN
3.1. Study Design
Overall Design
Test site randomized, assessor-blinded, single-center, Human Repeated Insult Patch 
Test (HRIPT) in healthy subjects to assess the cutaneous irritation and sensitisation 
potentialof acosmetic facial product, by following a conventional HRIPT 
methodologyunder supervision of a dermatologist.
Day -14 to 0  / Visit 1 -Screening Visit
NOTE: Visit 1 and Visit 2 could be combined
The following assessments will be conducted:
1. Subject Informed Consent taken
2. Subject demographics collected
3. Medical history details
4. Details of current and concomitant medication collected 
5. Fitzpatrick Skin Type Assessment (Appendix 3) 
6. Inclusion/Exclusion criteria 
7. Dermatologist determination for eligibility to participate in the study
(including visual examination of the dorsum scapular region)
8. Subject Eligibility
Days 1 to 22 /Visit 2 -Visit 11  -Induction Phase (3 Weeks)
NOTE: Visit 1 and Visit 2 could be combined
The following assessments will be conducted:
1. Continued eligibility check
 
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2. Current/Concomitant Medicationsreview
3. Inclusion/Exclusion criteria review(3c only at Visit 2 if Visit 1 and 2 are not 
combined).
4. Dermatologist determination for continued eligibility to participate in the study 
(Visit 2/Day1 only -if visits not combined).
5. Test Site Designation and Randomisation (Visit 2/Day 1 only).
6. Baseline grading/assessment of test sites(Visit 2/Day 1 only) as per Appendix 
2.
7. Patch applications (9 patch applications to the same test site, over3 
consecutiveweeks with patches applied on alternate weekdays).
8. Patch removal after 48 (± 2) hours or 72 (± 2) hours over inclusive weekends.
9. Reaction grading/assessmentperformed by a qualified staff member, as per 
Appendix 2.
10.Adverse event assessment
Note: 30minutes (maximum of 1 hour) after patch removal,sites will be 
graded/evaluated, then patches will be reapplied to the same sites.
Day 22-Day 36 / Visit 11 –Visit 12 -Rest Phase (2 Weeks) 
No Patch Application  
Days 36to 39 / Visit 12 to Visit 14 -Challenge Phase
The following assessments will be conducted:
1. Continued eligibility check
2. Current/Concomitant Medicationsreview
3. Grading/assessmentof naïve challenge patch site performed by a qualified 
staff member. (As per Appendix 2). Prior to Challenge patch application. 
(Visit 12/Day 36).
4. Challenge Phase patch application to naïve site (Visit 12/Day 36).
5. Patch removal 48 (± 2) or 72 (± 2) hours over inclusive weekends after 
application. (Visit 13/Day 38).
6. Reaction grading/assessment performed by a qualified staff member at 
approximately 30 minutes (maximum 1 hour) after patch removal.
7. 24(± 2) hours afterpatch removal(Visit 14/Day 39) subjects will return for 
assessment performed by a qualified staff member.
8. Adverse event assessment. 
Day40 / Visit 15 –End of Study
The following assessments will be conducted:
6. Current/Concomitant Medicationsreview
7. Adverse event assessment.
8. 48 (± 2) hours after patch removal (Visit 15/Day 40) final challenge patch site 
 
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assessment performed by a qualified staff member.
9. Dermatologist final assessment.
10.Subject discharge from the study site following completion of all study 
procedures. 
3.2. Subject Restrictions
Lifestyle/ Dietary
During the entire study (Screening –Last Subject Last Visit (LSLV))the following 
should be avoided:
1. Applyingany other product to the test site (dorsum).
2. Use of cosmetics, moisturisers, and other topical products on the back area.
3. Changingany cosmetic habits, including personal hygiene.
4. Changingdietaryhabits.
5. Gettingthe patch test site wet: during showers or bathing, in pools or 
lakes/ocean, sauna or activities that cause excessive sweating. The study site 
will provide instructions on how to shower or bathe throughout the study.
6. Removingthe patches.
7. Wearingtight or restrictive clothingthat can remove the patch through friction 
or cause redness.
8. Exposure to artificial ultraviolet (UV) light or cosmetic procedures (includes 
tanning beds, Intense Pulsed Light, etc.) are prohibited on the test areas for the 
duration of the study.
9. Introduction of new products during the study including but not limited to 
soap, laundry detergent, or fabric softener.
10.Engaging in activities that result in excessive sweating.
11.Missing the first day of application during the Induction Phase, or the day of 
application during the Challenge Phase.
 
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12.Missing 2 or more consecutive visits or more than 2 alternate visits.
Medications and Treatments
During the entire study (Screening –LSLV)the following medications and treatments 
should be avoided:
1. Having any body aesthetic or dermatological treatments performed.
2. Changinghormone treatment.
3. Changingcontraceptive method.
4. Use of the following medications:
a. Systemic or topicalcorticosteroids
b. Systemic or topical immunosuppressive drugs
c. Systemic or topical antihistamines,Vitamin A acid and its derivatives, 
or non-steroidal anti-inflammatory drugs 
d. Concomitant topical treatment at test sites
3.3. Type and Planned Number of Subjects
Approximately 280 healthy subjects will be screened to randomize at least 240 
subjects to ensure 200 evaluablesubjects complete the entire study. If noreaction is 
observed in 200 subjects, there is a 95% certainty that the actual rate of reaction in the 
wider population is <1.8%.
Healthy male and female subjects ages 18 to 65 with no dermatological disorders, 
with a Fitzpatrick skin phototype I to IV will be enrolled into this study.
3.4. Study Design and Application AmountJustification
Study Design:
This will be a single-center, randomised, assessorblind study in healthy subjects aged 
18 to 65years. Subjects will be exposed to repeated insult dermal semi-occlusive 
patch applicationof acosmetic facial skin productand negative control(saline 
 
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solution).
Screening: 
During screening subjects will sign an informed consent document and then a 
dermatological assessment will be conducted to ensure subjects have no 
dermatological conditions ontheir dorsum (backs) that might impact subject safety or 
study results and to ensure subjects have aFitzpatrick Phototype I to IV.
Each subject’s medical history and medication history will be reviewed, as well as 
inclusion/exclusion criteria. After which, site staff will review lifestyle guidelinesand 
directions with eligible subjects.
Induction Phase: 
Visit 2/Day 1 of the induction phase could be combined with Visit 1.
On Day 1 ofthe Induction Phase, eligible subjects will return to the study site and 
another dermatological assessment will be conductedto ensure subject continued 
eligibility (if Visits 1 and 2 are not combined), as well as a review of concomitant 
medications since screening. Test sites will be designated above the waist between
the left scapula and waistline and away from the spinal mid-line. The site of 
application of the products will then be randomly assigned. Baseline 
grading/assessment of the test sites will then be performed. 
There will be a total of 9patch applications,over 3 consecutive weeks during the 
induction phase, with patches applied on alternate weekdays each week (Monday, 
Wednesday, and Friday). Each patch will containthe test product and saline solution. 
Each patchwillremain in place for 48(± 2) hours onweekdays and 72 hours on 
weekends.  The patch will be removedand the areawillbe cleaned with saline 
solution.  After 30 minutes (maximum of 1 hour) the sitewill be graded/evaluatedas 
per the scale in Appendix 2.A new patchof both test product and saline solution will 
then be reapplied to the same site.
Rest Phase: 
Afterthe last patch removaland grading/evaluation of the Induction Phase,subjects 
will enter a Rest Phase of2 weeks.  During this time there will be no product patch 
applications.
 
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Challenge Phase:
After completing the Rest Phase, subjects will return for the Challenge Phase.  A 
naïve site (previously un-patched area) will be selectedfor the Challenge patch, this 
areawill be graded/evaluated prior to any patch application. A patch with the test 
product and saline solutionwill then be randomly applied to the selected previously 
untreated areas of skin according to the subject’s random assignment as determined 
on Day 1 of the Induction phase.  After 48 (± 2) hours, each subject will return for 
Challenge patch removal, the sitewillbe cleaned with saline solutionand 
graded/evaluated after 30 minutes (maximum of 1 hour).  Subjects will return after 24 
(± 2) hours and 48 (± 2) hours post patch removal for further grading/assessment. 
End of Study:
After the 48(± 2) hour grading/assessment, a final clinical assessment by a qualified 
dermatologist will be performed to confirm it is medically appropriate to exit the 
subject from the study.After all study assessments are completed, subjects will be 
discharged from the study site. 
Adverse events and concomitant medications will be assessed throughout the study. 
Patch Assessments:  
The results of the patch site assessments (Appendix 2) will be presented as individual 
responses to each test product and the negative control (saline solution) at each 
assessment time point. All responses will be reviewed in context of the grading scale.
Assessment of the patch sites will be conducted once at Baseline (Visit 2/Day 1) prior 
to any patch applicationsand then a further 8times post-baseline during the Induction 
Phase, once during the Rest Phase(for the final Induction Phase patch removal), and
fourtimes during the Challenge Phase (prior to Challenge patch application and post) 
by a blinded assessor(a qualified staff member).  
Any skin response at a patched site will be clinically assessed using the criteria 
recommended by the US Department of health and Human Services Food and Drug 
Administration (FDA), 1999.
Each of the scores represents an effect that is localised in a representative portion of 
the patch area, defined as 25% or more of the patch test site. Individual observations 
will be recorded in tables and a narrative description of all skin responses (any 
 
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score>0) will be provided. Superficial irritation scores are only provided if there is a 
dermal response score >0.
Each Superficial Irritation Score should be reported as a letter. The combined score 
will equal the sum of the dermal response score plus the numerical equivalent of the 
superficial irritation score (e.g.  dermal response score=3 and superficial irritation 
score=”C” implies a combined score of 3 + 2 = 5).
If a subject develops a combined score of 3 or greaterat any pointduring the 
Induction phase, the patch will be applied to an adjacent naïve site for the next 
application. If a combined score of 3 or greater occurs at the naïve site, no further 
patch applications will be made. Such reactive subjects willhowever, receive patches 
on naïve test sites during the challenge phase of the study unless, in the opinion of the 
Investigator, it would be unwise to do so.  
Dermal irritation or sensitisation reactionswithinthe patch area (i.e., irritation 
reactions outlined in Appendix 2) will not be recorded as AEs during the study. 
Reactions to the patch itself will also not be recorded as AEs.Unexpected reactions 
(e.g., rash, hives) will be recorded as AEs. These responses are expected in these 
study conditions and will be disregarded in evaluations, using the negative control 
(saline solution) as the standard for determining the expected degree of reaction.
Application Amount Justification:
The prerequisite for a patch test is the requirement that the whole test site is covered 
with the test product, without spreading or overlapping into other test sites. Previous 
work (Isaksson, 2007) has shown that the optimal dose to fulfil these requirements is 
0.02ml/cm2.
The test product will be distributed over the patch test filter paper discs (semi-
occlusive patch application) in the amountof 0.02 ml, and applied to designated sites 
on the back.  A sodium chloride (NaCl) saline solution (0.9%) will be used as the 
negative control and will also be applied to the back through semi-occlusive 
application. 
The semi-occlusive patches are made ofa hypoallergenic material with round 
chambers (or cells) of an absorbent material. Standardized amounts will be applied in 
these cells, approximately 0.02 ml(if application with a pipette is possible) or 20 mg 
(if applicationwith a pipette is not possible, in this study, only products of the 
sponsor, GlaxoSmithKline will be tested. One of the patch cells will contain the 
 
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control and, therefore, will be filled in with saline solution, and one of the other cells 
will be filled with the test product. 
The study will be conducted under the supervision of a qualified dermatologist.  
Prospective subjects will be assessed by the qualified staff member as a prerequisite 
to enrollment, and again at study end.
4. SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse 
events, and other pertinent information on the GSK investigational product or other 
study treatment that may impact subject eligibility is provided in the Safety 
Statement.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is
essential.
4.1. Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. CONSENT
Demonstrates understanding of the study procedures, restrictions and willingness to 
participate as evidenced by voluntary written informed consent and has received a 
signed and dated copyof the informed consent form. 
2. AGE
Aged between 18 and 65 years inclusive.
3. GENERAL HEALTH
a.)Good general and mental health with, in the opinion of the investigator or 
medically qualified designee no clinically significant and relevant 
abnormalities in medical history or upon physical examination.
b.)Healthy, intact skin at the proposed application site; dorsum (scapular region).
c.)Clinical assessment for eligibility (at Visit 1 and Visit 2–if not combined) by 
 
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a dermatologist to ensure subject is free of clinically relevant dermatological 
conditions.
4. SKIN TYPE
Fitzpatrick phototype I to IV(see Appendix 3).
5. COMPLIANCE
Agreement to comply with the procedures and requirements of the study andto attend 
the scheduled assessmentvisits.
4.2. Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. PREGNANCY
Women who are known to be pregnant or who are intending to become pregnant over 
the duration of the study. 
2. BREAST-FEEDING
Women who are breast-feeding
3. CONCURRENT MEDICATION/ MEDICAL HISTORY 
a) Any history of significant dermatological diseases or conditions or medical 
conditions known to alter skin appearance or physiologic response (e.g. 
diabetes,) which could, in the opinion of the Investigator, preclude topical 
application of the investigational products and/or interfere with the evaluation 
of the test site reaction. 
b) Presence of open sores, pimples, or cysts at the application site. 
c) Active dermatosis (local or disseminated) that might interfere with the results 
of the study.
d) Considered immune compromised. 
e) History of diseases aggravated or triggered by
 ultraviolet radiation.
f) Participants with dermatographism.
g) Currently using any medication which in the opinion of the investigator, may 
 
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affect the evaluation of the study product, or place the subject at undue risk.
h) Use of the following topical or systemic medications: immunosuppressants, 
antihistamines, non-hormonal anti-inflammatory drugs, and corticosteroids up 
to 2 weeks before screening visit.
i) Oral or topical treatment with vitamin A acid and/or its derivatives up to 1 
month before the screening visit.
j) Intention of being vaccinated during the study period or has been vaccinated 
within 3 weeks of the screening visit.
k) Currently receiving allergy injections, or received an allergy injection within 7 
days prior to Visit 1, or expects to begin injections during study participation
4. ALLERGY/ INTOLERANCE
a) Previous history of atopy, allergic reactions, irritation or intense discomfort 
feelings to topical-use products, cosmetics or medication.
b) Study subjectswith a history of allergy to the study material/product, 
hypoallergenic tape, or to the cotton patches.
c) History of sensitisation in a previous patch study.
5. CLINICALSTUDY/ EXPERIMENTAL PRODUCT
a) Participation in another clinical study (including cosmetic studies) or receipt 
of an investigational drug within 30days of the screening visit.
b) Previous participation in this study.
6. SUBSTANCE ABUSE
Recent history (within the last 5years) of alcohol or other substance abuse.
7. DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
a) Intense sunlight exposure or sun tanning sessions up to 30days before the 
Screening evaluation.
b) Intention of bathing(in the sea or a pool), sauna, water sports,or activitiesthat 
 
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leadto intense sweating.
c) Any Subject who, in the judgment of the Investigator, should not participate in 
the study.
d) Any skin marks on the test site that might interfere with the evaluation of 
possible skin reactions (e.g. pigmentation disorders, vascular malformations, 
scars, tattoos, excessive hair, numerous freckles).
e) Prisoner or involuntary incarcerated subject.
f) Subject from an indigenous tribe.
8. PERSONNEL
An employee of the sponsor or the study site or members of their immediate family.
4.3. Screening/ Baseline Failures
Screen failures are defined as subjects who consent to participate in the study but are 
never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and any Serious Adverse 
Events. Re-screening of subjects considered previous screen failures will notbe 
allowed in this study.
4.4. Withdrawal/ Stopping Criteria
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons
If the reason for removal of a subject from the study is an AE or an abnormal 
laboratory test result, the principal specific event or test will be recorded on the 
electronic case report form (CRF).  If a subject is withdrawn from the study because 
of a product limiting AE, thorough efforts should be clearly made to document the 
outcome. Any AEs ongoing at the final visit will be followed up until resolved, the 
condition stabilizes, is otherwise explained, or the subject is lost to follow-up.
 
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The following actions must be taken in relation to a subject who fails to attend the 
clinic for a required study visit:
1. The site must attempt to contact the subject and re-schedule the missed 
visit as soon as possible. 
2. The site must counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the study. 
3. In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designeemust make every effort to regain contact with the subject (where 
possible, at least2 telephone calls). The contact attempt should be 
documented in the subject’s record. 
4. Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of 
“Lost to Follow-up”.
4.5. Subject Replacement
Subjects who withdraw from the study post-randomisation will notbe replaced.
4.6. Subject andStudy Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the date of the last subject’s last visit.
5. PRODUCT INFORMATION
5.1. Study Product
The following study productwill be supplied by the Clinical Supplies Department, 
GSKCH:
Test Product 
Reference Product 
Product Name 
Facial micellar cleanser
Saline Solution: Sodium 
Chloride (NaCl; 0.9%)
Product Formulation 
Code (MFC)
N/A
Site to supply
Product Format
200ml clear PET Bottle
N/A
 
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Application Quantity
0.02 ml/cm2
0.02 ml/cm
2
Route of Administration
Topical dermal application via semi occlusive patch
Application  Instructions
Applied on-site by technician
5.2. ApplicationSchedule
Induction Phase:
Visit 2/Day 1 of the induction phase could be combined with Visit 1.
On Day 1 ofthe Induction Phase, eligible subjects will return to the study site and 
another dermatological assessment will be conducted to ensure subject continued 
eligibility (if Visits 1 and 2 are not combined), as well as a review of concomitant 
medications since screening. The test site will be designated above the waist between 
the left scapula and waistline and away from the spinal mid-line. The site of 
application of the products will then be randomly assigned. Baseline 
grading/assessment of the test sites willthen be performed. 
There will be 9patch applicationsto the same test site with the test product and saline 
solutionover 3 consecutive weeks during the Induction phase, with patches applied 
on alternate weekdays each week (Monday, Wednesday, and Friday). Each patch 
willremain in place for 48 (± 2) hours on weekdays and 72(± 2) hourson weekends.  
The patcheswill be removedand the treated areas willbe cleanedwith saline
solution.  After 30 minutes (maximum of 1 hour) the sitewill be graded/evaluated, 
newpatches will be applied to the same site.
If a subject develops a combined score of 3 or greaterat any pointduring the 
Induction phase, the patch will be applied to an adjacent naïve site for the next 
application. If a combined score of 3 or greater occurs at the naïve site, no further 
patch applications will be made. Such reactive subjects willhowever, receive patches 
on naïve test sites during the challenge phase of the study unless, in the opinion of the 
Investigator, it would be unwise to doso.  
Rest Phase:
Afterthe last patch removaland grading/evaluation of the Induction Phase, subjects 
will enter a Rest Phase of2 weeks.  During this time there will be no patch 
applications.
 
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Challenge Phase:
After completing the Rest Phase, subjectswill return for the Challenge Phase.  The 
naïve sites for the Challenge patch will be graded/evaluated prior to any patch 
application.  The Challenge Patchwith both the test product and saline solutionwill 
be randomly applied to the selected previously untreated areaof skin on the back 
according to the subject’s random assignment on Day 1 of the Induction phase for 48 
(± 2) hours.  After on-site patch removal, the sitewillbe cleaned with saline solution
and graded/evaluated after 30 minutes (maximum of 1 hour).  Subjects will return 
after 24 (± 2) hours and 48 (± 2) hours post patch removal for further 
grading/assessmentsof the Challenge site.
End of Study:
After the 48(± 2) hour grading/assessment, a final clinical assessment by a qualified 
dermatologist will be performedto confirm it is medically appropriate to exit the 
subject from the study. After all study assessments are completed, subjects will be 
discharged from the study site. 
5.3. Product Assignment
Each subject will have the test productand the negative control applied to their backs
(dorsum region). The location for each study product application for each subject will 
be assignedin accordance with the randomisation schedule generated by the 
Biostatistics Department, GSKCH, prior to the start of the study, using validated 
internal software.
5.3.1Randomisation
A unique screening number will identify each subject screened for study 
participation.  Screening numbers will be assigned in ascending numerical order as 
each subject signs their consent form.  Subjects who meet all inclusion and exclusion 
criteria will be randomized according to the randomisation schedule.  Randomisation 
numbers will be assigned in ascending numerical order as each subject is determined 
to be fully eligible. The randomisation number will be associated with the random 
location assignment of product to test site.
5.3.2Blinding
The study statistician and other employees of the Sponsor who may influence study 
outcomes are blinded to the product allocation/test site location. Investigators 
 
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dispensing the product will be aware of each product’s location and must not divulge 
information to the study staff or assessors. The assessor performing the assessment of 
irritation will be blinded to the product allocation.
5.3.3Code Breaks
The blind must only be broken in an emergency where it is essential to know which 
product a subject received in order to give the appropriate medical care.  Wherever 
possible the Investigator (or designee) must contact the Sponsor prior to breaking the 
blind.  The investigator must document the reason for breaking the code and sign and 
date the appropriate document.
The study blind must be returned to GSKCH at the end of the study.
5.4. Packaging and Labelling
The contents of the label will be in accordance with all applicable regulatory 
requirements and will be the responsibility of the Clinical Supplies Department, 
GSKCH.
The facial micellar cleanser 
 will be supplied in 200 mlbottles andwill 
have a study label affixed by the Sponsor.Each study label will contain, but not be 
limited to, protocol number, product codeletterand directions for storage.
The investigator or designee will supply the salinesolution (Reference Product) with 
a study label affixed. Each study label will contain the information according to the 
site specific internal requirements.
Care should be taken with the supplied productand its labelso that it ismaintained in 
good condition.  It is important that all labels remain intact and legible for the 
duration of the study. 
5.4.1. Accountability of Product
The test productsupplied isfor use only in this clinical study and should not be used 
for any other purpose.
The investigator or designee will maintain a full record of study product 
accountability. A Product Dispensing Log must be kept current.
 
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The inventory must be available for inspection by the study monitor during the study. 
At the end of the study, study product supplies will be verified by the monitor.  Study 
product supplies will then be either collected by the study monitor or returned by the 
investigator or designee to the GSKCH Clinical Supplies Department or designated 
vendor.
5.4.2. Storageof Product
Study product supplies must be stored in compliance with the label requirements in a 
secure place with limitedor controlled access.
6. STUDY ASSESSMENTS AND PROCEDURES
This section lists the procedures and parameters of each planned study assessment.  
The exact timing of each assessment is listed in the Schedule of Events section.
Adherence to the study design requirements, including all assessments and 
procedures are essential and required for study conduct.
6.1. Visit 1 -Screening Visit
6.1.1 Telephone Screening
Prior to the screening visit, telephone screening of interested subjects may be 
conducted using a telephone script. This will be conducted by the site recruitment 
staff or designee.  
6.1.2. Informed Consent
The investigator, or designee, must obtain signed and dated (by the subject) informed 
consent from each subject participating in this study after adequate explanation of the 
aims, methods, objectives, and potential hazards of the study.
The investigator, or designee, must also explain to the subjects that they are 
completely free to refuse to enter the study or to withdraw from it at any time.  
Appropriate forms for documenting a signed and datedconsent will be provided by 
the investigator or by GSKCH.  The investigator, or designee, should sign and date 
the consent form to confirm that the consent process was completed correctly after 
the subject has signed.  The subject will be provided with a copy of their signed and 
dated consent form and any other written information which they are be instructed to 
retain.
 
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If, during a subject’s participation in the study, any new information becomes 
available that may affect the subject’s willingness to participate in the study, each 
ongoing subject should receive a copy of this new information and be re-consented 
into the study. Subjects should be provided with a copy ofthe signed and dated 
amended consent form. The date of consent will be recorded on the CRF.
After signing the Informed Consent Form (ICF), subjects will undergo all the 
screening assessments to confirm that they meet all the inclusion criteria and none of
the exclusion criteria. If the subject is considered eligible by the Investigator (or 
designee) to participate they are considered enrolled in the study.
6.1.3. Demographics
The following demographic parameters will be captured by the Investigator or 
designee and recorded on the CRF: year of birth, Fitzpatrick skin type(skin phototype 
classification, according to the Fitzpatrick classification, per Appendix 3), gender and 
race.
6.1.4 Dermatologist Assessment
For products with specific safety appeals, the study must be followed up by a 
specialist (ANVISA, 2012). A qualified dermatologist will assess the overall subject 
eligibility at the Screening Visit and continued eligibility in the study at Visit 2(if not 
combined) to ensure the subject is free of any pre-existing dermatological pathology.
Additionally a final assessment at Visit 15 by
 a qualified dermatologist will confirm it 
is medically appropriate to exit the subject from the study at the final visit. (Edward 
& Robillard, 2008).
6.1.5. Medical History and Concomitant Medication
Medical history will be assessed as related to the inclusion/exclusion criteria by the 
Investigator or medically qualified designee.  Details of any relevant medical or 
surgical history (within the lastyear), including allergies or drug sensitivity, will be 
recorded on the CRF.  Any concomitant therapy taken in the 30 days prior to the 
Screening Visit and throughout the study will also be recorded.
6.2. Visit 2 -Baseline VisitToVisit 14
Visit 2 may be combined with Visit 1 (Screening) but should be no more than 14days 
following Visit 1. 
 
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At Visit 2 any current and concomitant therapy takenwill be reviewed, and continued 
eligibility will be checked before any patch application (and randomisation of product 
application ordering). This will be reviewed again before each subsequent visit.
A qualified dermatologist will check for subject continued eligibility in the study(At 
Visit 2 only if Visits are not combined).
6.2.1Application of patches
The testproductand saline solution (0.02ml/cm2of each product) will be applied to a 
paper disc (or cell) contained within an adhesive patch. The number of cells available 
on the patch test tape can vary but in this study onewill be usedfor test product and 
one for the reference; saline solution).The patch is then applied ontothe dorsum 
(scapula region) of each subjectfor a period of 48± 2hours, the sequence of the 
product application to the cells will be randomly assigned to each subject according 
totherandomisation schedule.
Induction Phase: 
Visit 2/Day 1 of the induction phase could be combined with Visit 1.
On Day 1 ofthe Induction Phase, eligible subjects will return to the study site and 
another dermatological assessment will be conducted to ensure subject continued 
eligibility (if Visits 1 and 2 are not combined), as well as a review of concomitant 
medications since screening. The test site will be designated above the waist between 
the left scapula and waistline and away from the spinal mid-line. The site of 
application of the products will then be randomly assigned. Baseline 
grading/assessment of the test sites will then be performed. 
There will be 9patch applicationsto the same test site of boththe test product and 
saline solutionover 3 consecutive weeks during the induction phase, with a patch
applied on alternate weekdays each week (Monday, Wednesday, and Friday). Each 
patchwillremain in place for 48± 2hourson weekdays and 72 ± 2hours on 
weekends.The patchwill be removed and the treated areas willbe cleaned with 
saline solution.  After 30 minutes (maximum of 1 hour) the site will be 
graded/evaluated as per the scale in Appendix 2. A new patch will then be reapplied 
to the same site.
 
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Rest Phase:
Afterthe last patch removaland grading/evaluation of the Induction Phase, subjects 
will enter a Rest Phase of 2 weeks.  During this time there will be no product patch 
applications.
Challenge Phase:
After completing the Rest Phase, subjects will return for the Challenge Phase.  A 
naïvesite (previously un-patched area) will be selected for the Challenge patch, this 
area will be graded/evaluated prior to any patch application (according to Appendix 
2). AChallenge patchwith both the test product and saline solution will be randomly 
applied to thispreviously untreated areaof skin according to each subject’s random 
assignment as determined on Day 1 of the Induction phase.  After 48 (± 2) hours, 
each subject will return for Challenge patch removal,the site willbe cleaned with 
saline solution andgraded/evaluated after 30 minutes (maximum of 1 hour).  Subjects 
will return after 24 (± 2) hours and 48 (± 2) hours post Challenge patch removal for 
further grading/assessment. 
End of Study:
After the 48(± 2) hour grading/assessment, a final clinical assessment by a qualified 
dermatologist will be performed to confirm it is medically appropriate to exit the 
subject from the study. After all study assessments are completed, subjects will be 
discharged from the study site.  
6.2.2Patch Assessments 
An experienced trained assessor(s)will assess all patch sites for the duration of the 
studyaccording to the scoring scale in Appendix 2. Each patch will be removedand 
the treated areas willbe cleaned with saline solutionbefore visual assessment.  Where 
ever possible the same experienced trained assessor will perform all skinassessments 
for a given subject at each assessment time point.
A Baseline patch site assessment will be carried out at Visit 2 (or Visit 1 if visits 
combined) prior to any patch application. Patch assessments will then be performed at 
Visits 3 to 11 for the Induction Phase (every 48± 2hours following application).
Afterthe last grading/evaluation of the Induction Phase at Visit 11, subjects will enter 
a Rest Phase of2 weeks.
 
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After completing the Rest Phase, subjects will return for the Challenge Phase (Visit 
12).  Prior to the Challenge patch application the naïve patch sites will be assessed.
The challenge patchwill be randomly applied to previously untreated areas of skin 
for 48 ± 2hours.  After on-site patch removal (Visit 13), the patch site willbe cleaned 
with saline solution and graded/evaluated after 30 minutes(maximum of 1 hour).  
Subjects will return for further assessments after 24 ± 2hours(Visit 14) and 48 ±2
hours(Visit 15) post patch removal for further grading/assessment. 
Patch sites will be graded usinga magnifying glass with a fluorescent daylight lamp.
The assessor will beblinded to the treatment allocation location.
The results will be presented as individual responses to each test product at each 
assessment time point.
In any case of a positive reactionadermatologist will be available to perform 
secondary assessments and gradethe response with any further action as needed. This 
should occur thesame day as the initial assessment performed by the trained assessor.
The intensity of any visual signs of irritation will be recorded by the trained 
examiner, according to the quantity and grade of the reactions (Appendix 2) 
according to the skin appearance (Table 1) and other features indicative of irritation 
(Table 2) observed. The trained examiner is responsible for grading the reactions, and 
the trained examiner’s opinion on the interpretation of the results is final.
If a subject develops a combined score of 3 or greaterat any pointduring the 
Induction phase, the patch will be applied to an adjacent naïve site for the next 
application. If a combined score of 3 or greater occurs at the naïve site, no further 
patch applications will be made. Such reactive subjects willhowever, receive patches 
on naïve test sites during the challenge phase of the study unless, in the opinion of the 
Investigator, it would be unwise to do so.
Any observed response which can be denoted using the irritation criteria summarized 
in Appendix 2, will not be considered an adverse event. In addition any tape-related 
irritation will also not be noted as an AE. Only in case of unusual reactions, these 
reactions and the consequences upon the evaluation of the respective test areas will be 
documented as AE’s.
All responses will be reviewed in context of the grading scale in this protocol 
(Appendix 2).
 
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6.3. Visit 15-Last Subject Last Visit (LSLV)
At Visit 15 any current and concomitant therapy takenwill be reviewed, and 
continued eligibility will be checked. Final challenge site assessment 48 ± 2hours
(Visit 15) post patch removal (per Section 6.2.2) will take place.
A final evaluation by a qualified dermatologist will take place before the subject exits 
from the study(per Section6.1.4).
6.3.1. Study Conclusion
Subjects will be evaluated to determine if they completed all study procedures or if 
they were discontinued from the study early.  If the subject discontinued at any point 
during the study, the primary reason for withdrawal should be recorded on the Study 
Conclusion page of the CRF by selecting one of the options below.
1.
Subject did not meet study criteria
2.
Adverse Event
3.
Lost to Follow Up
4.
Protocol Violation
5.
Withdrawal of Consent
6.
Other
7. SAFETY ASSESSMENTS
7.1. Definitions of an Adverse Event and Serious Adverse Event 
7.1.1. Adverse Events
The investigator or site staff will be responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
Adverse Event Definition:
An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of an investigational or washout product, 
whether or not considered related to the investigational or washout product.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of an investigational or washout product.
 
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Events meeting AE definition include:
1. Any abnormal laboratory test results (if applicable) or other safety 
assessments, including those that worsen from baseline, and felt to be 
clinically significant in the medical and scientific judgment of the 
investigator.
2. Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition.
3. New condition(s) detected or diagnosed after study product administration 
even though it may have been present prior to the start of the study.
4. Signs, symptoms, or the clinical sequelae of a suspected interaction.
5. Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study product or a concomitant medication (overdose per se will not be 
reported as an AE/SAE).
Events NOT meeting definition of an AE include:
1. Any clinically significant abnormal laboratory findings (if applicable) or other 
abnormal safety assessments which are associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
subject’s condition. 
2. The disease/disorder/ condition being studied or expected progression, signs, 
or symptoms of the disease/disorder being studied, unless more severe than 
expected for the subject’s condition.. 
3. Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is an AE.
4. Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
5. Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
6. Any observed response which can be denoted using the irritation criteria 
summarized in Appendix 2, will not be considered an adverse event. In 
addition any tape-related irritation will also not be noted as an AE. Only in 
 
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case of unusual reactions, these reactions and the consequences upon the 
evaluation of the respective test areas will be documented as AE’s.
7.1.2. Serious Adverse Events
Serious Adverse Event is defined as any untoward medical occurrence that, at 
any dose:
A. Results in death
B. Is life-threatening
NOTE: The term 
'life-threatening
' in the definition of 
'serious
' refers to an 
event in which the subject was at risk of death at the time of the event.  It does 
not refer to an event, which hypothetically might have caused death, if it were 
more severe.
C. Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency 
ward for observation and/or treatment that would not have been appropriate in 
the physician’s office or out-patient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious.  When in doubt as to whether
“hospitalization” occurred or was necessary, the AE should be considered 
serious.
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
D. Results in disability/incapacity
NOTE: The term disability means a substantial disruption of a person’s ability 
to conduct normal life functions.
This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
E. Is a congenital anomaly/birth defect
F. Other Situations
Medical or scientific judgment should beexercised in deciding whether 
reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
 
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definition. These should also be considered serious.
Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development 
of drug dependency or drug abuse or reports of spontaneous abortion.
7.2. RecordingAdverse Eventsand Serious Adverse Events
Recording of adverse events and serious adverse events:
The investigator or site staff will be responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
The investigator or sitestaff will then record all relevant information regarding an 
AE/SAE in the CRF.
There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. Clinical AEs will 
be described by diagnosis and not by symptoms when possible (e.g., upper respiratory
 
tract infection, seasonal allergy, etc. instead of runny nose).
AEs will be collected from the start of the product application and until 5 days 
following last administration of the study product.
SAEs will be collected over the same time period as stated above for AEs.  However, 
any SAEs assessed as relatedto study participation (e.g., investigational product, 
protocol mandated procedures, invasive tests, or change in existing therapy) or related 
to a GSK concomitant medication will be recorded from the time a subject consents 
to participate in the study up to and including any follow-up contact.  
Medical conditions reported prior to the time period for reporting AEs/SAEs should 
be recorded as part of the subject’s medical history.
 
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7.3. Evaluating Adverse Eventsand Serious Adverse Events
Assessment of Intensity:
The investigator or designee will make an assessment of intensity for each AE and 
SAE reported during the study and will assign it to one of the following categories:
1. Mild:  An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
2. Moderate:  An event that is sufficiently discomforting to interfere with 
normal everyday activities
3. Severe:  An event that prevents normal everyday activities. AnAE that is 
assessed as severe will not be confused with an SAE. Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe.
Note: An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality:
The investigator is obligated to assess the relationship between study product and the 
occurrence of each AE/SAE.
A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
product will be considered and investigated.
The investigator will also consult the Safety Statementand/or Product Information, 
for marketed products, in the determination of his/her assessment.
For eachAE/SAE the investigator must document in the medical notes (source 
document) or CRF that he/she has reviewed the AE/SAE and has provided an 
assessment of causality.
 
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There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
7.4. Reporting Adverse Eventsand Serious Adverse Events
AE Reporting to GSKCH:
AEs will be recorded in the AE section of the CRF. 
Medical conditions recorded by the subject on a diary
 card or similar document that 
meet the definition of an AE must also be recorded in the AE section of the CRF, if 
not previously well-characterized by the investigator in the subject’s medical history. 
AEs elicited by the investigator in a standard manner at the study visits should also be 
recorded in the AE section of the CRF.  The investigator or designee must ask the 
subject the following question during each visit including any follow-up visits:  
“Have you felt unwell, experienced any symptoms or taken any medication (since 
your last visit) (today) (since your last application) (since the last session)?”
The medically qualified investigator should review adverse events in a timely 
manner; this review should be documented in writing in the source document or in the 
CRF. 
After the study is completed at a given site, and the site has received their study data 
on Compact Discs (CDs), the electronic data collection tool will be removed from the 
internet to prevent the entry of new data or changes to existing data.
SAE Reporting to GSKCH:
A paper copy of the SAE form provided in the investigator study master file should 
be completed as fully as possible. 
It is essential to enter the following information: 
1. Protocol and subject identifiers
2. Subject’s demography
 
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3. Description of events, with diagnosis if available
4. Investigator opinion of relationship to study product 
5. Criterion for seriousness.
The following are desirable and are of particular relevance for investigator and 
GSKCH assessment of the SAE report:
1. Date of onset of AE 
2. Date AE stopped, if relevant
3. Study product start date
4. Study product end date if relevant
5. Action taken on study product
6. Outcome if known
The SAE form, completed as fully as possible, and SAE fax cover sheet must be 
faxed or e-mailed to the appropriate GSKCH Study Manager as soon as possible, but 
not later than 24 hoursafter study site personnel learn of the event. The GSKCH 
Study Manager shouldbe notified of the situation by telephone or email.
Serious Adverse Events to:
Brazil Clinical Study Manager (
):
Tel: 
E-mail: 
Pharmacovigilance (Brazil)Fax Number: 
The GSKCH Study Manager will be responsible for forwarding the SAE form to the 
Case Management Group, Global Clinical Safety and Pharmacovigilance, the 
Medical Director responsible for the study and other GSKCH personnel as 
appropriate via email.
The initial report will be followed up with more information as relevant, or as 
requested by the GSKCH study manager.
7.5. Follow-up of Adverse Eventsand Serious Adverse Events
Follow-up of AEs and SAEs:
After the initial report, the investigator is required to proactively follow up with each 
subject and provide further information on the subject’s condition.
All AEs/SAEs will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the subject is lost to follow-up.  
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
 
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PPD
PPD
PPD
PPD

elucidate as fully as possible the nature and/or causality of the AE or SAE.
Investigators are not obliged to actively seek AEs or SAEs in former subjects.  
However, if the investigator learns of any SAE, including the death, at any time after 
a subject has been discharged from the study, and considers the event reasonably 
related to the investigational product or study participation, the investigator will 
promptly notify GSKCH.
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
Regulatory and ethics reporting requirements for SAEs:
The investigator will promptly report all SAEs to GSKCH within the designated 
reporting timeframes (within 24 hours of learning of the event).  GSKCH has a legal 
responsibility to notify, as appropriate, the local regulatory authority and other 
regulatory authorities about the safety of a product under clinical investigation.  
Prompt notification of SAEs by the investigator to GSKCH is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSKCH will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBand investigators.
Investigator safety reports are prepared according to GSKCH policy and are 
forwarded to investigators as necessary.  An investigator safety report is prepared for 
a SAE(s) that is both attributable to investigational product and unexpected.  The 
purpose of the report is to fulfill specific regulatory and GCP requirements, regarding 
the product under investigation.
An investigator who receives an investigator safety report describing a SAE(s) or 
other specific safety information (e.g., summary of listing of SAEs) from GSKCH 
will file it with the Investigator Brochure (or safety statement) and will notify the 
IRB, if appropriate according to local requirements.
 
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7.6. Collection of Pregnancy Information
7.6.1. Time Period for Collectingof Pregnancy Information
Collection of Pregnancy Information:
Pregnancy information will be collected on all pregnancies reported following 
administration of any test product.Information on a pregnancy identified during the 
screening phase and prior to test product administration does not need to be collected.
7.6.2. Action to be Taken ifPregnancy Occurs
Action to be Taken:
The investigator will collect pregnancy information on any subject who becomes 
pregnant while participating in the study after administration of the test product. The 
investigator will record pregnancy information on the appropriate form and submit it 
to GSKCH within 2 weeks of learning of the subject becoming pregnant. The subject 
will be followed to determine the outcome of the pregnancy. Information on the status 
of the mother and infant / neonate (including concomitant medications taken by the 
mother during the pregnancy) will be forwarded to GSKCH. Generally, follow-up 
will be no longer than 6 to 8 weeks following the estimated delivery date. Any 
termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE, any pregnancy complication or 
elective termination for medical reasons will be recorded as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. An SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject completed the study and considered by the investigator as 
possibly related to the investigational product, must be promptly forwarded to GSK.
While the investigator is not obliged toactively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting.
If the subject becomes pregnant during the study they should be withdrawn from the 
study and this should be recorded in the appropriate section of the CRF.
8. DATA MANAGEMENT
For this study subject data will be entered into an electronic case report form, using a 
GSKCH validated data system.
 
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8.1. Source Documents/ Data
The source documents (e.g. hospital records, clinical and office charts, laboratory 
notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files and records kept at the 
pharmacy, at the laboratory and at the medico-technical departments involved in the 
clinical study) which contain the source of data recorded in the CRF should be 
specified in the Source DocumentDesignation Form.  In some cases the CRF can be 
used as a source document.
Each subject will be assigned and identified by a unique Screening Number. Any 
reference made to an individual subject within the study must be done using the 
unique Screening Number.
8.2. Electronic Case Report Form
A CRF is a printed, optical, or electronic document designed to record all of the 
protocol required information to be reported to the sponsor on each trial subject.
For each subject who has given informed consent/assent and has been screened, CRF 
must be completed and signed by the Principal Investigator (or authorized designee) 
to certify that the data are complete and correct.  
Management of clinical data will be performed in accordance with applicable 
GSKCH standards and data cleaning procedures to ensure the integrity of the data e.g. 
removing errors and inconsistencies in the data. 
In order to protect the privacy of subjects, no Personally Identifiable Information 
(PII) (including the subject
's name or initials or birth date) is to be recorded in the 
CRF or as part of the query text.
Adverse events and concomitant medications terms (if applicable) will be coded 
using MedDRA (Medical Dictionary for Regulatory Activities) and an internal 
validated medication dictionary, GSKDrug.  
Subject data will be entered into GSKCH defined CRFs and transmitted electronically 
to GSKCH in a validated (21 CFR Part 11 compliant) web-based electronic data 
capture system (InForm
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All CRF pages should be completed during a subject assessment when the CRF has 
been designated as the source.  Data that is sourced elsewhere should be entered into 
the CRF in an agreed upon timeframe between the Investigator and Sponsor.  
The CRFs (including queries, query responses and audit trails) willbe retained by 
GSKCH. Site data archived compact discs (CD(s)) prepared by a third party will be 
sent to the investigator to maintain as the investigator copy following the 
decommissioning of the study.
8.3. Data Handling
Documentation of all data management activities should allow step-by-step 
retrospective assessment of data quality and study performance. Any changes or 
corrections to data will be performed in the Electronic Data Capture (EDC) System, 
and it will include rationale for changes. The EDC system has an audit trail, which 
will provide a complete record of the changes and corrections endorsed by the 
Investigator.
8.3.1. Data Queries
Programmed edit checks will be generated automatically, as the data is being entered 
into the system. Data Management will also run reports and listings on the CRF data, 
in addition to the queries already programmed and generated by the system, to raise 
manual queries as needed for site clarification or correction. The Clinical Dictionary 
Development and Management Group will raise queriesas needed on safety data to 
ensure the code terms (Adverse Events and Drugs) are reported appropriately. 
The study monitor at the study site will review the CRFs in accordance with the 
monitoring plan, and any queries will be generated in the EDC System to the 
Investigator or designee, enabling the errors to be addressed in parallel with Data 
Management review. Monitor can also run reports and listings on the CRFs, to raise 
manual queries as needed for site clarification or correction
9. STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1 Sample Size Determination
Approximately 280 healthy subjects will be screened to randomize at least 240 
subjects to ensure 200 evaluablesubjects complete the entire study. If no reaction is 
 
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observed in 200 subjects, there is a 95% certainty that the actual rateof reactionsin 
the wider population is <1.8%.
9.2. General Considerations
9.2.1. Definition of Analysis Populations
The ‘Intent to treat’(ITT) population includes all subjects who are randomised into 
the study and have skin irritation scores from at least one of the test sites available.
Aseparate Per Protocol (PP) analysis will not be performed. Protocol deviations will 
however be listed for review.
The Safety population includes all subjects who received any application of the study 
products. All safety analyses will be performed using the Safety population.
9.2.2. Exclusion of Data from Analysis
No data will be excluded from any analysis.
9.2.3. Criteria for Evaluation
The primary evaluation will be to assess the cutaneous irritation and sensitisation 
potentialof the test and control product, based on the irritation (dermal response) and 
superficial irritation (other effects) score/grade after patch removal during the 
induction and challenge phase using the ITT population. 
Safety and tolerability will be evaluated by adverse events assessments using the 
Safety population.
9.2.4. Handling of Dropouts and Missing Data
Missing data will not be replaced or imputed. Dropouts will be included in analyses 
up to the point of discontinuation.
9.3. Statistical Methods and Analytical Plan
Additional details of the proposed statistical analysis will be documented in the 
statistical analysis plan (SAP), which will be written following finalization of the 
protocol and prior to study unblinding.
 
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9.3.1. Demographic and Baseline Characteristics
Age will be summarized using descriptive statistics such as means, medians and 
standard deviations. Gender, race and Fitzpatrick skin type will be summarized using 
frequency countsand percentages.
9.3.2. Primary Analysis(es)
The primary analysis will be based on the irritation (dermal response) and superficial 
irritation (other effects) scores/grades assessed using the scales described in Tables 1 
and 2 of Appendix 2. Individual observations will be assessed based on these scales 
and a narrative description of all skin responses, both in the induction and challenge 
phases, will be provided.  
No formal statistical inference will be performed. 
The number and percentage of subjects recording each category of score/grade, as 
well as any skin response versus those without any skin response will be presented by 
treatment group at each assessment time point and over the induction and challenge 
phases using the maximum grade/score. If there are subjects with non-zero dermal 
response or other effects scores, then the dermal response, other effects and a 
combined dermal and others effects score will be summarised using descriptive 
statistics at each assessment time point and over the induction and challenges phases 
using a total score across time points.
9.3.3. Safety Analysis(es)
Adverse Events (AE) will be tabulated according to the current version of the 
MedDRA. Frequencies and percentages will be presented overall, for each system 
organ class, and for each preferred term. Summaries of treatment-emergent AEs, 
treatment-related AEs, AEs leading to discontinuation, and serious AEs will be 
completed. For treatment-related or treatment skin site related AEs, these will also be 
presented by product/test site.
10. STUDY GOVERNANCE CONSIDERATIONS
10.1.Posting of Information on Publicly Available Clinical Trials 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
 
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10.2.Regulatory and Ethical Considerations, Including the Informed 
Consent
The study will be conducted in accordance with all applicable regulatory 
requirements, and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice 
(GCP), all applicable subject privacy requirements, and the guiding principles of the 
current version of the Declaration of Helsinki.  This includes, but is not limited to, the 
following:
1. Before initiating a trial, the investigator/institution should have written and 
dated approval/favorable opinion from the IRBfor the trial protocol 
(including amendments), written informed consent form, consent form 
updates, subject recruitment procedures (e.g., advertisements), investigator 
brochure/ safety statement (including any updates) and any other written 
information to be provided to subjects. A letter or certificate of approval 
will be sent by theinvestigator to the sponsor prior to initiation of the 
study, and also when subsequent amendments to the protocol are made.
2. Signed informed consent tobe obtained for each subject before 
participation in the study (and for amendments as applicable).
3. Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB).
4. GSK will provide full details of the above procedures, either verbally, in 
writing, or both.
10.3.Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK 
or designee (i.e. thirdparty vendor) monitors will contact the site prior to the start of 
the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.
When reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the CRF will serve as the 
source document.
 
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GSK or designee will monitor the study and site activity to verify that the:
1. Data are authentic, accurate, and complete.
2. Safety and rights of subjects are being protected.
3. Study is conducted in accordance with the currently approved protocol and 
any other study agreements, GCP, and all applicable regulatory 
requirements.
The extent and nature of monitoring will be described in a written monitoring plan on 
file at GSKCH. The investigator (or designee) agrees to allow the monitor direct 
access to all relevant documents and agrees to co-operate with the monitor to ensure 
that any problems detected in the course ofthese monitoring visits are resolved.
10.4.Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
The sponsor will be available to help investigators prepare for an inspection.
10.5.Conditions for Terminating the Study
Upon completion or premature discontinuation of the study, the GSKCH monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSKCH Standard 
Operating Procedures.
Both GSKCH and the Investigator reserve the right to temporarily suspend or 
prematurely discontinue this study at any time for reasons including, but not limited 
to, safety or ethical issues or severe non-compliance. For multicenter studies (if 
applicable), this can occur at one or more or at all sites.  
 
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If the trial is prematurely terminated or suspended for any reason, the investigator site 
should promptly inform the trial subjects and should assure appropriate therapy/ 
follow-up for the subjects. Where required by the applicable regulatory requirements, 
GSKCH should inform the regulatory authority (ies). 
In addition: 
1. If the investigatorterminates or suspends a trial without prior agreement of 
GSKCH, the investigator site should promptly inform the sponsor and the 
IRB, and should provide the sponsor and the IRB a detailed written 
explanation of the termination or suspension.
2. If the GSKCHterminates or suspends a trial, the investigator should promptly 
inform the IRB and provide the IRB a detailed written explanation of the 
termination or suspension. 
3. If the IRB terminates or suspends its approval/favorable opinion of a trial, the 
investigator should promptly notify the GSKCH and provide GSKCH with a 
detailed written explanation of the termination or suspension.
10.6.Records Retention
Following closure of the study, the investigator must maintain all site study records 
(except for those required by local regulations to be maintained elsewhere), in a safe 
and secure location.  
The records (study/ site master file) must be maintained to allow easy and timely 
retrieval, when needed (e.g., for a GSK audit or regulatory inspection) and must be 
available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken. 
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.
The investigator must assure that the subject’s anonymity will be maintained.  On 
CRFs or other documents submitted to GSKCH, subjects should not be identified by 
their names or initials, but by an identification code. The investigator should keep a 
 
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separate log of subjects’ codes, names and addresses.  Documents not for submission 
to GSKCH, e.g. subjects’ written consent forms, should be maintained by the 
investigator in strict confidence.
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements (GSKCH recommends that 
documents be kept for 10 years). The investigator is also required to keep subject 
identification codes on file for at least 15 years after completion or discontinuation of 
thestudy. The minimum retention time will meet the strictest standard applicable to 
that site for the study, as dictated by any institutional requirements or local laws or 
regulations, GSK standards/procedures, and/or institutional requirements.  
No study document should be destroyed without a prior written agreement between 
GSKCH and the investigator. The investigator must notify GSK of any changes in the 
archival arrangements, including, but not limited to, archival at an off-site facility or 
transfer of ownership of the records in the event the investigator is no longer 
associated with the site.
10.7.Provision of Study Results to Investigators, posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report.  The investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location.
GSK will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, 
as appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will bein accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
11. REFERENCES
ANVISA, Guideline for the Safety Evaluation of Cosmetics Products, 2012
 
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ANVISA;Resolution 79/00, Annex XXI and its updates
Basketter, D. A., York, M., McFadden, J. P. and Robinson, M. K. (2004), 
Determination of skin irritation potential in the human 4-h patch test. Contact 
Dermatitis, 51:1–4
Birmingham, J. Clinical Aspects of Cutaneous Irritation and Sensitization, Toxicology 
and Applied Pharmacology 7:(54-59)
Bruze, M Recommendation of appropriate amounts of petrolatum preparation to be 
applied at patch testing* Contact Dermatitis 2007 0105-1873, 56(5):281
Dooms-GoossensA. Cosmetics as causes of allergic contact dermatitis. Cutis 1993; 
52: 316-320.
Dooms-Goossens, A, Corticosteroid contact allergy: an EECDRG Multicenter study
Contact Dermatitis, 1996, 0105-1873, 35(1):40
Draize JH, Methods for the study of irritation and toxicity of substances applied 
topically to the skin and mucous membranes Journal of Pharmacology and 
Experimental Therapeutics, 1944, 0022-3565, 82(3):377
Edward, M. Jackson, and FMT Robillard Norman. "The controlled use test in a 
cosmetic product safety substantiation program." Journal of Toxicology: Cutaneous 
and Ocular Toxicology 1.2 (1982): 117-132.
European Commission (EC) Regulation No 1223/2009of the European Parliament 
and of the Council of 30 November 2009on cosmetic products
Fitzpatrick TB, Pathak M, Parrish JA. Protection of human skin against the effects of 
the sunburn ultraviolet (290-320 nm). In: Fitzpatrick TB et al. (eds). Sunlight and 
man, normal and abnormal photobiological responses. Tokyo, p. 751-755.
Fitzpatrick, T.B., The validity and practicability of sun-reactive skin types I through 
VI.Arch. Dermatol.124, pp. 869-871, 1988
Food and Drug Administration. ICH Topic E6: Guideline for Good Clinical Practice.  
Fed Reg1997; 62(90):25691-709.
Guidance for Industry; Skin Irritation and Sensitisation Testing of Generic 
Transdermal Drug Products, U.S. Department of Health and Human Services
Food and Drug Administration Center for DrugEvaluation and Research (CDER) 
Federal Register. 1999;64(38):9516. 
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.
ICH Topic 6 Guideline for Good Clinical PracticeCPMP/ICH/135/95 17th July 1996.
Isaksson, M., Gruvberger, B., Frick-Engfeldt, M. and Bruze, M. (2007), Which test 
chambers should be used for acetone, ethanol, and water solutions when patch testing? 
Contact Dermatitis, 57:134–136. doi:10.1111/j.1600-0536.2007.01094.x
LachapelleJ.-M., Maibach H. I, Patch Testing and Prick Testing, A practical Guide 
Official Publication of the ICDRG, 3rdEdition, 2012
Lee E, An S, Choi D, Moon S, Chang I. Comparison of objective and sensory skin 
irritations of several cosmetic preservatives. Contact Derm2007; 56: 131-6.
McNamee PM, Api AM, BasketterDA, et al.A review of critical factors in the 
conduct and interpretation of the human repeat insult patch test. Regul Toxicol 
 
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Pharmacol2008; 52: 24-34.
NationalHealthSurveillance AgencyBrazil (ANVISA). Guideline for the Safety 
Evaluation of CosmeticProducts.Brasília; 2012.
Spiewak R. Patch testing for contact allergy and allergic contact dermatitits. Open 
Allergy J2008; 1: 42-51.
Walberg JE, Magnus L. Patch testing. In:Frosch PJ, Mene T, Lepoittevin J-P, eds. 
Contact Dermatitis. 4
thedition.Berlin: Springer. 2006; 365-90. 
Wilkinson, D. S., et al. "Terminology of contact dermatitis." Acta Derm Venereol 
50.4 (1970): 287-292.
World Medical Association Declaration of Helsinki, 59thGeneral Assembly, Seoul 
2008.
Zatz JL. Skin Permeation: fundamentals and application. Wheathon, Allured 
Publishing Corporation, 1993.
12. APPENDICES
12.1. Appendix 1 -Abbreviations and Trademarks
Abbreviations
AE 
Adverse Event
aq
Aqueous 
AUC
Area under Curve
CD
Compact Disc
cm
2
Centimetre squared
CRF
Case Report Form
DVD
Digital Versatile Disc
EDC
Electronic Data Capture
EEMCO
European Group for Efficacy Measurements on Cosmetics and Other 
Topical Products
FSFV
First Subject First Visit
g
Gram
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
GSKCH
GlaxoSmithKline Consumer Healthcare
hr
Hour(s)
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
Intention to Treat
 
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LSLV
Last Subject Last Visit
m2
Square metre
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
min
Minute
ml
Milliliters
nm
Nanometers
PII
Personally Identifiable Information
PP
Per Protocol
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
12.2. Appendix 2 –Dermal Response Score
Any skin response at a patched site will be clinically assessed using the criteria 
recommended by the US Department of Health and Human Services Food and Drug 
Administration (FDA), 1999.
Any localised response to the patch application and removal that’s typical to the 
procedure, won’t be captured as an AE, unless more severe thanexpected in which 
case will be captured as an AE.
The following gradesand their respective numerical equivalentscoreswill be used to 
express the response observed at the time of examination:
Table1.
Skin Irritation Scoring System
 
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CII

Table2.
Superficial IrritationScore (Symbols and Numerical Equivalents)
The results willbe presented as individual responses to each test product and the 
negative control (saline solution) at each assessment time point. All responses will be 
reviewed in context of the grading scale.
Each of the scores represents an effect that is localised in a representative portion of 
the patch area, defined as 25% or more of the patch test site. Individual observations 
will be recorded in tables and a narrative description of all skin responses (any score
>0) will be provided. Superficial irritation scoresare only provided if there is a 
dermal response score >0.
Each Superficial Irritation Score should be reported as a letter. The combined score 
will equal the sum of the dermal response score plus the numerical equivalent of the 
superficial irritation score (e.g.  dermal response score=3 and superficial irritation 
letter =”C” implies a combined score of 3 + 2 = 5).
If a subject develops a combined score of 3 or greaterat any pointduring the 
Induction phase, the patch will be applied to an adjacent naïve site for the next 
application. If a combined score of 3 or greater occurs at the naïve site, no further 
patch applications will be made. Such reactive subjects will, however, receive patches 
on naïve test sites during the challenge phase of the study unless, in the opinion of the 
Investigator, it would be unwise to do so.  
Dermal irritation or sensitisation reactionswithinthe patch area (i.e., irritation 
reactions outlined inTable 1andTable 2above) will not be recorded as AEs during
 
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the study. Reactions to the patch itself will also not be recorded as AEs.Unexpected 
reactions (e.g., rash, hives) will be recorded as AEs. 
12.3. Appendix 3-Fitzpatrick Skin Type Grading
The Fitzpatrick scale is a numerical classification that is widely used by 
dermatologists to classify a person’s skin type by their response to sun exposure 
(Fitzpatrick, 1988). 
 
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