Clinical trial NCT02974114
Conditions: Pain
Sponsor: GlaxoSmithKline
Start date: 2016-10-31; Completion date: 2017-02-06
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This parallel, assessor blind, placebo-controlled, stratified, randomized study will investigate the effects of everyday pain on cognition and mobility in otherwise healthy individuals.

Detailed description:
This study consisted of 3 visits. Visit 1 (Day1, Screening), minimum (min) of 7 days and maximum (max) of 28 days gap followed by Visit 2 (Day 2, pain-state assessment), a recovery period of min of 2 days and max of 30 days followed by Visit 3 (Day 3, pain-free assessment). Participants received treatment once only on Visit 2.

Arms: arm 1: Participants will be administered test product (containing 500 mg paracetamol and 65 mg caffeine). Two tablets will be taken orally once with 200 mL (milliliters) of water. arm 2: Participants will be administered test product (containing 500 mg paracetamol). Two tablets will be taken orally once with 200 mL of water. arm 3: Participants will be administered reference product (placebo to match Paracetamol 665mg sustained release tablets). Two tablets will be taken orally once with 200 mL of water.
Interventions: intervention 1: Paracetamol and caffeine intervention 2: Paracetamol intervention 3: Placebo
Intervention descriptions: intervention 1: Test product containing 500 mg paracetamol and 65 mg caffeine intervention 2: Test product containing 500 mg paracetamol intervention 3: Placebo to match paracetamol 665mg sustained release tablets

Protocol documents:
Prot_000.pdf: 
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  An unpublished work subject to trade secret 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
204503
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CONFIDENTIAL
SUMMARY INFORMATION
Title:
Assessment of cognitive function and mobility in 
individuals with pain 
Protocol Number:
204503
Sponsor:
GlaxoSmithKline Consumer Healthcare (UK) Trading 
Limited
St. George’s Avenue, 
Weybridge, 
Surrey, 
KT13 0DE, UK
Tel: 
Product Name:
Paracetamol and Caffeine combination tablet
Paracetamol tablet
Development Phase:
IV
Expert Advice Outside of Normal 
Working Hours:
Tel: 
Key Protocol Authors:
PRIMARY CONTACT
Clinical Study Manager:
, PHD
GSKCH, ST. GEORGE’S AVENUE
WEYBRIDGE, SURREY KT13 0DE -
UK
Tel:
Fax: 
Biostatistician:
Clinical Research Lead:
New Product Research Lead:
Other Protocol Authors:
Clinical Supplies:
Data Manager:
Medically Qualified Person:
Dr 
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Chief Investigator
Dr.
DANI HRISTOVA
Principal Investigator:
Dr.
DANI HRISTOVA
Study Coordinator
, PhD
Study Site Name & Address:
GSK Human Performance Lab
Unit 2 Brentside Executive Park
Great West Road
Brentford
Middlesex
United Kingdom
TW8 9DA
Study Site Telephone Number:
EudraCT Number:
2015-002330-42
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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 and the Declaration of 
Helsinki.  
Investigator Name:
Dr
Dani Hristova
Investigator Qualifications:
MBBS, PhD, MRCP
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...............10
PROTOCOL AMENDMENT PAGE ....................................11
SCHEDULE OF EVENTS .....................................................14
PROTOCOL SYNOPSIS FOR STUDY 204503 ...................15
1. INTRODUCTION...............................................................21
2. OBJECTIVES AND ENDPOINTS....................................24
3. STUDY PLAN .....................................................................25
3.1. Study Design.......................................................................25
3.2. Subject Restrictions ...........................................................27
3.3. Type and Planned Number of Subjects ............................28
3.4. Study Design and Dose Justification.................................28
4. SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA........................................30
4.1. Inclusion Criteria...............................................................30
4.2. Exclusion Criteria..............................................................32
4.3. Screening/ Baseline Failures..............................................34
4.4 Women of Childbearing Potential Definition....................34
4.5. Withdrawal/ Stopping Criteria .........................................35
4.6. Subject Replacement..........................................................35
4.7. Subject and Study Completion..........................................35
5. PRODUCT INFORMATION.............................................36
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5.1. Study Product.....................................................................36
5.2. Dose Schedule.....................................................................36
5.3. Dose Modification ..............................................................36
5.4. Product Compliance ..........................................................37
5.5. Precautions.........................................................................37
5.6. Overdose.............................................................................37
5.7. Rescue Therapy..................................................................37
5.8. Product Assignment...........................................................37
5.8.1 Randomization ...................................................................37
5.8.2 Blinding...............................................................................38
5.8.3 Code Breaks........................................................................38
5.9. Packaging and Labelling ...................................................39
5.9.1. Accountability of Product.................................................39
5.9.2. Storage of Product ............................................................40
6. STUDY ASSESSMENTS AND PROCEDURES ..............41
6.1. Visit 1 - Screening Visit......................................................41
6.1.1 Email/Telephone Screening ...............................................41
6.1.2. Informed Consent .............................................................41
6.1.3. Demographics....................................................................41
6.1.4. Medical History and Concomitant Medication ...............42
6.1.5. Brief Pain Inventory – Short Form Questionnaire..........42
6.1.6. Pain State Question...........................................................42
6.1.7. Physical Exam/Vital Signs ................................................42
6.1.8. Anthropometric Measurements .......................................43
6.1.9. Pregnancy Test..................................................................43
6.2. Visit 2 (Pain State) and Visit 3 (Pain-free)........................43
6.2.1. Drug and Alcohol Assessment ..........................................43
6.2.2. Pregnancy Test..................................................................43
6.2.3. Cognitive Function Assessments ......................................44
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6.2.4. Mobility Assessments ........................................................46
6.2.5 Physical Exam / Vital Signs (Visit 2 only pre- and post-
treatment)..........................................................................47
6.2.6. Medical History and Concomitant Medication ...............48
6.2.7. Brief Pain Inventory – Short Form Questionnaire..........48
6.2.8. Pain State Question...........................................................48
6.3. Study Conclusion ...............................................................48
7. SAFETY ASSESSMENTS ...................................................48
7.1. Definitions of an Adverse Event and Serious Adverse 
Event.................................................................................48
7.1.1. Adverse Events..................................................................49
7.1.2. Serious Adverse Events.....................................................50
7.2. Recording Adverse Events and Serious Adverse Events.51
7.3. Evaluating Adverse Events and Serious Adverse Events 51
7.4. Reporting Adverse Events and Serious Adverse Events..52
7.5. Follow-up of Adverse Events and Serious Adverse Events
..........................................................................................54
7.6. Collection of Pregnancy Information................................55
7.6.1. Time Period for Collecting of Pregnancy Information ...55
7.6.2. Action to be Taken if Pregnancy Occurs .........................55
8. DATA MANAGEMENT ....................................................56
8.1. Source Documents/ Data....................................................56
8.2. Case Report Form..............................................................56
8.3. Data Handling ....................................................................57
8.3.1. Data Queries......................................................................57
8.4. Processing Patient Reported Outcomes............................57
8.5. External Data .....................................................................58
9. STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES ....................................................................59
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9.1 Sample Size Determination.................................................59
9.2. General Considerations .....................................................59
9.2.1. Definition of Analysis Populations ...................................59
9.2.2. Exclusion of Data from Analysis ......................................59
9.2.3. Criteria for Evaluation .....................................................59
9.2.4. Criteria for Assessing Efficacy .........................................59
9.2.5. Criteria for Assessing Tolerability ...................................60
9.2.6. Criteria for Assessing Bioequivalence..............................60
9.2.7. Handling of Dropouts and Missing Data .........................60
9.2.8. Other Issues.......................................................................60
9.3. Statistical Methods and Analytical Plan...........................60
9.3.1. Demographic and Baseline Characteristics.....................60
9.3.2. Primary Analysis...............................................................60
9.3.3. Secondary and Exploratory Analysis...............................61
9.3.4. Safety Analysis ..................................................................62
9.3.5. Other Analysis...................................................................62
10. STUDY GOVERNANCE CONSIDERATIONS.............63
10.1. Posting of Information on Publicly Available Clinical 
Trials Registers................................................................63
10.2. Regulatory and Ethical Considerations, Including the 
Informed Consent............................................................63
10.3. Quality Control (Study Monitoring)...............................63
10.4. Quality Assurance............................................................64
10.5. Conditions for Terminating the Study............................64
10.6. Records Retention............................................................65
10.7. Provision of Study Results to Investigators, posting of 
Information on Publicly Available Clinical Trials 
Registers and Publication................................................66
11. REFERENCES..................................................................67
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12. APPENDICES...................................................................69
12.1. Appendix 1 - Abbreviations and Trademarks................69
12.2. Appendix 2 - Brief Pain Inventory - Short Form...........70
12.3. Appendix 3 – Pain Recurrence Questionnaire ...............72
12.4. Appendix 4 – Pain State Question...................................73
12.5. Appendix 5 – Recruitment Tracking Log.......................74
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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 IEC in accordance with local requirements, before the revised edition can 
be implemented. 
All non-substantial/ minor/ administrative amendments should be submitted to the 
IEC as 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 add text: 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.:1
Non-Substantial/Minor    The primary purpose of this 
amendment is to update the 
SAE reporting information.  
Other clarification and 
consistency changes have 
also been made.
Informed 
Consent      
Yes 
No
Safety 
Statement     
Yes 
No
CRF                   
Yes 
No
!
Summary 
Information –
Key Protocol 
Authors
!
Schedule of 
Events
!
Protocol 
Synopsis
!
Section 6.1.6 
Pain State 
Question
!
Section 6.2.5 
Physical Exam / 
Vital Signs
!
Section 7.4 
Reporting 
Adverse Events 
Signature:
Protocol 
Version 
No.:5.0
Substantial/ Major           
Date:
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and Serious 
Adverse Events
!
Section 12.3 
Appendix 3
!
Section 12.4 
Appendix 4
!
Section 12.5
!
Appendix 5
Amendment 
No.:2
Non-Substantial/Minor    The purpose of this 
amendment is to update a 
change in Chief and Principal 
Investigator.
Two other updates were 
made to ensure consistency 
between protocol sections 
with regard to time frame of 
collection of adverse events 
and to ensure consistency 
between protocol sections 
with respect to time frame of 
restriction of prohibited 
medications.
Informed 
Consent   
Yes 
No
Safety 
Statement     
Yes 
No
CRF                   
Yes 
No
!
Summary 
Information –
Key Protocol 
Authors
!
Principal 
Investigator 
Protocol 
Agreement Page
!
Schedule of 
Events
!
Protocol 
Synopsis
!
Section 3.1 
Study Design
!
Section 3.2 
Subject 
Restrictions
!
Section 4.2 
Exclusion 
Criteria
Signature:
Protocol 
Version 
No.:6.0
Substantial/ Major           
Date:
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SCHEDULE OF EVENTS
Procedure
Visit 1
Screening
Min of 7-days and max. of 28-days
Visit 2
Pain-state assessment
Recovery Period (min of 2-days and max. 30-days)
Visit 3
Pre-
treatment 
Assessment
Post-treatment 
assessment
(1 hr ± 15 mins 
post dosing)
Pain-free 
assessment
Informed Consent
X
Demographics
X
GP name and contact details 
collected
X
GP Letter response 
reviewed if received1
X
Brief Pain Inventory – Short 
Form
X
X
X
X
Pain Recurrence 
Questionnaire
X
Pain State Question
X
X
General Medical History2
X
X
Current / Concomitant 
medication
X
X
X
X
Height and Weight 
measurements
X
Inclusion / Exclusion 
Criteria
X
X
Subject Eligibility
X
X
Physical Examination/ Vital 
Signs3
X
X
X
For women of child bearing 
potential: Pregnancy test
X
X
Urine drug screen and 
alcohol breath test
X
X
Cognitive testing (Axon 
Sports & CANTAB  Cog 
Assessment)4
X (Practice)5
X
X
X
Mobility assessments (Gait, 
Time to standing, Grip 
Force)
X (Practice)5
X
X
X
Stratification and 
Randomization to OTC 
medication
X
Supervised OTC medication 
given 
X
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1. Proceed with completion of visit 2 unless GP letter response received advising against participation.
2. General Medical history and GP letter response if received.
3. The physical exam post-treatment assessment will be a brief physical exam 
4. The cognitive tests will be conducted in the following order at visit 2 and visit 3: Axon Sports Priming Application, 
CANTAB battery (RTI, OTS, AST, SWM, RVP)
5. COGNITIVE TESTING AND MOBILITY ASSESSMENTS AT VISIT 1 ARE PART OF FAMILIARIZATION 
TASKS
6. AES WILL BE COLLECTED FROM TIME OF SIGNATURE OF CONSENT FORM FOR ALL SUBJECTS WHO 
ARE ELIGIBLE AT ASSESSMENT FAMILIARIZATION STAGE (AFTER CONFIRMED ELIGIBILITY BUT 
PRIOR TO FAMILIARIZATION TASKS)
PROTOCOL SYNOPSIS FOR STUDY 204503
Brief Summary
Pain is a multidimensional, subjective experience, which can have an effect both 
physically and psychologically.  Individuals with chronic pain often report deficits in 
their mobility and cognitive function is also thought to be affected.  Whilst a vast 
amount of research has been conducted on individuals with chronic or disease 
specific pain there is very little known about the cognitive and mobility deficit 
experienced by individuals with everyday pain (pain treatable with Over-the-Counter 
(OTC) medicine).
The primary focus of this exploratory study will be to investigate the effects of 
everyday pain on cognition and mobility in otherwise healthy individuals. This study 
will also evaluate the relationship between specific types and intensity of everyday 
pain with cognitive function and mobility. Finally, the potential effect of an 
intervention with paracetamol or paracetamol with caffeine on cognitive function and 
mobility will be studied on an exploratory basis. 
Objectives and Endpoints
Objectives
Endpoints
Primary
!
To investigate within-subject 
cognitive changes in individuals 
with everyday pain compared to 
!
Subject level change from pain-
free state in cognition as 
measured by cognitive function 
assessment (CANTAB and Axon 
Adverse Events
X6
X
X
X
Study conclusion
X
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pain-free performance.
Sports) in the pain state.
Secondary
!
To investigate within-subject 
mobility changes in individuals 
with everyday pain compared to 
pain-free performance.
!
Subject level change from pain-
free state in mobility as measured 
by gait, time to standing and grip 
force score in the pain state.
Exploratory
!
Investigate the relationship 
between pain type and intensity 
with cognitive function and 
mobility.
!
Correlation between pain intensity 
and each cognitive assessment for 
each pain type at Visit 2 Pre and 
Visit 2 Post.
!
Correlation between pain 
intensity and each mobility
assessment for each pain type at 
Visit 2 Pre and Visit 2 Post.
!
To investigate the effects of OTC 
treatment (paracetamol +/-
caffeine and placebo) on 
cognitive function and mobility in 
individuals with everyday pain.
!
Effect of intervention on change 
from pain-state assessment in 
cognition as measured by 
cognitive function assessment 
(CANTAB and Axon Sports) to 
post-treatment assessment period.
!
Effect of intervention on change 
from pain-state assessment in 
mobility as measured by gait 
score, time to standing score and 
change of muscle score to post-
treatment assessment period.
Study Design
Overall Design
This parallel, assessor blind, placebo-controlled, stratified, randomized study will 
recruit approximately 65 male and female participants with everyday pain (as 
assessed by the Brief Pain Inventory – Short Form questionnaire). They will be 
recruited from GSK employees or a Clinical Research Organisation, screened for 
eligibility and assessed at The Human Performance Lab (HPL).
Visit 1 - Screening Visit
After initial screening via email/telephone subjects will be invited for a screening 
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visit at the HPL at a suitable time.  
The below activities will be conducted during the screening visit in the following 
order:
1. Informed Consent
2. Subject Eligibility assessments (in any order)
- Demographics
- Brief Pain Inventory - short form (See Appendix 2)
- Pain Recurrence Question (see Appendix 3)
- General Medical History
- GP name and contact details collected
- Current/concomitant medication
- Height, Weight and BMI measurements
- Physical exam and vital signs
- Pregnancy Test (Women of childbearing potential only)
- Subject eligibility (Confirm subject satisfies all entry criteria relevant 
to screening Visit 1 prior to progression to familiarization activities)
3. Familiarization activities (in any order)
- Cognitive testing practice session (CANTAB and Priming 
Application)
- Mobility assessments practice session (Gait, Time to standing, Grip 
Force
- Inclusion/Exclusion criteria
      4. ADVERSE EVENTS
            - TO BE COLLECTED FROM THE TIME OF SIGNATURE
             OF THE CONSENT FORM FOR ALL SUBJECTS WHO ARE
             ELIGIBLE AT ASSESSMENT FAMILIARIZATION STAGE
             (AFTER CONFIRMED SUBJECT ELIGIBILITY BUT PRIOR
            TO FAMILIARIZATION TASKS).
             
Letter to GP sent via email or next day delivery post on same day as screening visit. 
GP letter to include summary of the study and request that GP contact the site if any 
reason known that the subject should not participate.
Visit 2 - Pain state assessment 
A minimum of 7-days and a maximum of 28-days later, a pain-state assessment will 
be performed.  The following assessments will be conducted in the order written:
!
Brief Pain Inventory - short form (See Appendix 2)
!
Pregnancy test (females of child bearing potential only)
!
Urine drug screen and alcohol breath test 
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!
General medical history
!
GP letter response reviewed if received
!
Current/concomitant medication
!
Physical exam and vital signs 
!
Pain State Question (see Appendix 4)
!
Subject Eligibility
!
Inclusion/Exclusion criteria
!
Pre-treatment Cognitive testing (Axon Sports and CANTAB 
cognitive assessment)
!
Pre-treatment Mobility assessments (Gait, Time to standing, Grip 
Force)
!
Stratification and randomization to OTC medication
!
Subject will be stratified to one of four strata according to their pain 
type and then randomized accordingly to one of the three treatment 
groups.
!
Supervised OTC medication given on site (subjects wear eye mask)
!
Post-treatment (1hr ± 15 mins) Brief Pain Inventory - short form
(See Appendix 2)
!
Post-treatment Cognitive testing (Axon Sports and CANTAB
cognitive assessment)
!
Post-treatment Mobility assessments (Gait, Time to standing, Grip 
Force)
!
Physical exam and vital signs 
!
Adverse Events
Visit 3 - Pain-free state assessment
Subjects will be requested to return a minimum of 2-days and a maximum of 30-days
post Visit 2 once they are pain-free for another assessment (visit 3). In order to be 
pain-free participants must rate their pain as zero in response to Question 6 on Brief 
Pain Inventory – Short Form.  If after 30 days their score is still >0 in response to 
Question 6 on Brief Pain Inventory – Short Form then only their pain state and post-
intervention data will be used in analysis and will not be required for further follow-
up.  The following assessments will be conducted in the order written:
!
Urine drug screen and alcohol breath test 
!
Brief Pain Inventory - short form (See Appendix 2)
!
Current/concomitant medication
!
Cognitive testing (Axon Sports and CANTAB cognitive assessment)
!
Mobility assessments (Gait, Time to standing, Grip Force)
!
Adverse events
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!
Study conclusion/Medical sign-off
Type and Planned Number of Subjects
A sufficient number of subjects will be screened to randomize approximately 65
subjects to ensure approximately 60 evaluable subjects complete the entire study. 
This will ensure approximately 20 evaluable subjects per treatment arm.
Diagnosis and Main Criteria for Inclusion
Subjects with everyday pain (treatable with an OTC medicine) will be required for 
entry to this study. Inclusion criteria for this study includes: consent from the 
volunteer; aged at least 18 years and in good general health; understands the study 
and is willing to participate; has a pain rating of ≥5 on question 6 of the brief pain 
inventory - short form (at Visit 2 only).
Product Information
Test Product 1
Test Product 2
Reference Product 1
Product Name 
Panadol® Extra 
Advance (500mg 
paracetamol 
+65mg caffeine) 
tablets
Panadol®
Advance 
(500mg 
paracetamol) 
tablets
Placebo to match 
Paracetamol 665mg 
Sustained Release Tablets 
Panadol Extend Placebo 
Tablets
Product 
Formulation 
Code (MFC)
UK Marketed 
Product
UK Marketed 
Product
Placebo 
Extend Tablet
Dose
2 tablets taken 
once
2 tablets taken 
once
2 tablets taken once
Route of 
Administration
Oral
Oral
Oral
Dosing 
Instructions
Take medication 
with 200 mL of 
water. Eye mask
worn by subject.
Take medication 
with 200 mL of 
water. Eye mask
worn by subject.
Take medication with 200 
mL of water. Eye mask
worn by subject.
Criteria for Evaluation
!
Statistically significant deficit in cognitive performance (as measured by 
individual scores from the Axon Sports Priming Application and each of the 
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CANTAB tasks – RTI, OST, AST, SWM and RVP) observed between an 
individual in pain vs. their pain-free performance.
!
Statistically significant deficit in mobility (as measured by individual scores 
from gait, time to standing and grip force assessments) observed between an 
individual in pain vs. their pain-free performance.
Statistical Methods
Efficacy
Primary:
!  Change from pain-free state in cognition as measured by cognitive function
assessment (CANTAB and Axon Sports) in the pain state (pre-treated).
Secondary:
!
Change from pain-free state in mobility as measured by gait, time to standing
and grip force score in the pain state (pre-treated).
Exploratory:
!
Correlate pain type and intensity to cognitive and mobility assessments. 
!
Effect of intervention on change from pain-state assessment (pretreated) in 
cognition as measured by cognitive function assessment (CANTAB and Axon 
Sports) to post-treatment assessment period.
!  Effect of intervention on change from pain-state assessment (pretreated) in 
mobility as measured by gait score, time to standing score and
change of muscle function score, to post-treatment assessment period.
A two-sided paired t-test will be used to analyze the primary and secondary efficacy 
endpoints for all subjects with a significance level ∀=0.05. For the exploratory 
efficacy analysis with between treatment comparisons, the mixed effect model with 
treatment group and pain type as the fixed effect and the baseline value as a covariate 
will be employed on the change-from-baseline type of variables at Visit 2, 1 hour (± 
15 min) post-treatment and at visit 3 for variables other than ‘time’ related type. For 
the ‘time’ related variables (e.g., Reaction Time (RTI), time to standing, etc.) the non-
parametric method using Van Elteren’s test with stratification factor pain type will be 
employed at 1 hour post treatment. For the exploratory analysis a Pearson correlation 
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analysis will be employed. All tests will be two-sided with an alpha level of 0.05. The 
95% CI and the p-value will also be presented.
Safety
AEs will be listed and reviewed. Only treatment emergent AEs (i.e., those occurring
after first use of the study treatment) will be tabulated. AEs occurring prior to
randomization will be included in the AE listing. AE tables will be presented using
the safety population.
1. INTRODUCTION
Pain is a multidimensional, subjective experience, which can have an effect both 
physically and psychologically. While there is very little known about the cognitive 
and mobility deficit experienced by individuals with everyday pain (pain treatable 
with OTC medicine) – the purpose of this study - there is, however, a vast amount of 
research on individuals with chronic or disease specific pain. Therefore, this 
introduction will review and reference the previous work on individuals with chronic 
pain as a background to the study proposed.
Individuals with chronic pain often report deficits in their mobility and movement. 
For example, patients with chronic neck pain have significantly decreased range of 
movement in all anatomical values during repeated cervical spine movements 
compared to age-matched, healthy control subjects (Vogt et al., 2007). Furthermore, 
individuals with hip or knee pain, due to osteoarthritis, have reported limitations in 
physical activities and this has been shown to be associated with the level of pain and 
range of motion of hip flexion (van Dijk et al., 2009). This study also showed that the 
level of pain was associated with performance-based limitations (timed walking test) 
and range of motion.
Mobility and movement are not the only deficits experienced by individuals with 
chronic pain, but cognition is also thought to be affected. Clinical data supporting this 
includes observed deficit in attention, executive and general cognitive functioning in
individuals suffering chronic pain (reviewed in Moriaty and Finn, 2011). 
Furthermore, recent research has investigated the effect of pain on cognitive function 
and showed that generalized and neuropathic pain, in comparison to localized pain, 
has a greater effect on cognition (Landrø et al., 2013). 
The effect of pain on cognitive attention has been well studied in chronic pain 
patients and it is hypothesized that pain competes for cognitive resources against 
daily tasks which act as attention demanding stimuli (Eccelston, 1994). In one study, 
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those with chronic pain had significantly higher error rates in an attention capacity 
probe task compared to healthy individuals (Veldhuijzen et al., 2006). The authors of 
this study concluded that allocation of attention resources was impaired in chronic 
pain sufferers rather than their capacity. Chronic pain patients, compared to matched 
controls also seem to have slower reaction times in a variety of cognitive tests 
(reviewed in Moriaty and Finn, 2011). 
Memory studies in chronic pain patients have predominantly tested explicit/working 
memory. For example, fibromyalgia (FM) patients had a significant cognitive deficit 
compared to age matched healthy controls and control subjects who were 20 years 
older than each of the FM patient. The cognitive performance of the FM patients was 
similar to the older control group, which in turn performed poorly compared to the 
younger control group. In particular, memory and vocabulary deficits were most 
prevalent (Park et al, 2001). A recent systematic review further supports this evidence 
by suggesting that people with chronic pain perform worse on working memory tests 
in comparison to healthy control subjects (Berryman et al., 2013).
Chronic pain has also been shown to affect executive function, which includes higher 
order tasks such as planning, organization and control of conflicting thoughts. 
Chronic pain patients perform poorly on executive function tests, including 
interference or attention switching tasks, for example, one study showed that those 
experiencing intense pain had performance decrements in an attention demanding 
numerical interference task, but only at the most complex level (Eccelston, 1994). 
This study is interesting as it sheds light on the correlation between intensity of pain 
and cognitive deficit which is infrequently explored.
Although previous research has advanced our knowledge in the interaction between 
individuals with chronic pain, cognition and mobility, very little is known about the 
effects of everyday pain on cognition and mobility. Therefore further work is needed 
to fully understand the effects of everyday pain (i.e., individuals with pain suitable for 
OTC medication) on cognition and mobility. Furthermore, a better understanding of 
the effects of analgesic medications on cognition is required in individuals with 
everyday pain. While some have investigated the effects of Ibuprofen (Allen et al., 
2003), little is known about the effects of paracetamol on cognition in individuals 
with everyday pain. Caffeine has been demonstrated to increase the absorption and 
efficacy in formulation with paracetamol (Renner et al., 2007). Therefore the effects 
of paracetamol with and without caffeine will be investigated. 
This study will investigate the effects of everyday pain on cognition and mobility in 
otherwise healthy individuals. The effects of one dose of paracetamol with and 
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without caffeine on cognitive function and mobility will also be investigated. This 
study will also explore the relationship between type and intensity of everyday pain 
with cognitive function and mobility.
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2. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
!
To investigate within-subject 
cognitive changes in individuals 
with everyday pain compared to 
pain-free performance.
!
Subject level change from pain-
free state in cognition as 
measured by cognitive function 
assessment (CANTAB and Axon 
Sports) in the pain state.
Secondary
!
To investigate within-subject 
mobility changes in individuals 
with everyday pain compared to 
pain-free performance.
!
Subject level change from pain-
free state in mobility as measured 
by gait, time to standing and grip 
force score in the pain state.
Exploratory
!
Investigate the relationship 
between pain type and intensity 
with cognitive function and 
mobility.
!
Correlation between pain 
intensity and each cognitive 
assessment for each pain type at 
Visit 2 Pre and Visit 2 Post.
!
Correlation between pain 
intensity and each mobility
assessment for each pain type at 
Visit 2 Pre and Visit 2 Post.
!
To investigate the effects of OTC
treatment (paracetamol +/-
caffeine and placebo) on 
cognitive function and mobility in 
individuals with everyday pain.
!
Effect of intervention on change 
from pain-state assessment in 
cognition as measured by 
cognitive function assessment 
(CANTAB and Axon Sports) to 
post-treatment assessment period.
!
Effect of intervention on change 
from pain-state assessment in 
mobility as measured by gait 
score, time to standing score and 
change of muscle score to post-
treatment assessment period.
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3. STUDY PLAN
3.1. Study Design
Overall Design
This parallel, assessor blind, placebo-controlled, stratified, randomised study will 
recruit approximately 65 male and female participants with everyday pain (as 
assessed by the Brief Pain Inventory – Short Form questionnaire). They will be 
recruited from GSK employees or by a Clinical Research Organisation, screened for 
eligibility and the assessment will be at The Human Performance Lab (HPL).
Visit 1 - Screening Visit
After initial screening via email/telephone subjects will be invited for a screening 
visit at the HPL at a suitable time.  
The below activities will be conducted during the screening visit in the following 
order:
1. Informed Consent
2. Subject Eligibility assessments (in any order)
- Demographics
- Brief Pain Inventory - short form (see Appendix 2)
- Pain Recurrence Question (see Appendix 3)
- General Medical History 
- GP name and contact details collected
- Current/concomitant medication
- Height, Weight and BMI measurements
- Physical exam and vital signs
- Pregnancy test (women of childbearing potential only)
- Subject eligibility (Confirm subject satisfies all entry criteria relevant 
to screening Visit 1 prior to progression to familiarization activities) 
3. - Familiarization activities (in any order)
- Cognitive testing practice session (Axon Sports and CANTAB 
cognitive assessment)
- Mobility assessments practice session (Gait, Time to standing, Grip 
Force)
- Inclusion/Exclusion criteria
      4. ADVERSE EVENTS
            - TO BE COLLECTED FROM THE TIME OF SIGNATURE
             OF THE CONSENT FORM FOR ALL SUBJECTS WHO ARE
             ELIGIBLE AT ASSESSMENT FAMILIARIZATION STAGE
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             (AFTER CONFIRMED SUBJECT ELIGIBILITY BUT PRIOR
            TO FAMILIARIZATION TASKS).
Letter to GP sent via email or next day delivery post on same day as screening visit. 
GP letter to include summary of the study and request that GP contact the site if any 
reason known that the subject should not participate.
Visit 2 - Pain state assessment 
A minimum of 7-days and a maximum of 28-days later, a pain-state assessment will 
be performed.  The following assessments will be conducted in the order written:
!
Brief Pain Inventory - short form (See Appendix 2)
!
Pregnancy test (females of child bearing potential only)
!
Urine drug screen and alcohol breath test 
!
General Medical History
!
GP letter response reviewed if received
!
Current/concomitant medication
!
Physical exam and vital signs
!
Pain State Question (see appendix 4)
!
Subject Eligibility
!
Inclusion/Exclusion criteria
!
Pre-treatment Cognitive testing (Axon Sports and CANTAB 
cognitive assessment)
!
Pre-treatment Mobility assessments (Gait, Time to standing, Grip 
Force)
!
Stratification and Randomization to OTC medication
!
Subject will be stratified to one of four strata according to their pain 
type and then randomized accordingly to one of the three treatment 
groups.
!
Supervised OTC medication given on site
!
Post-treatment (1hr ± 15 mins) Brief Pain Inventory - short form
(See Appendix 2)
!
Post-treatment Cognitive testing (Axon Sports and CANTAB 
cognitive assessment)
!
Post-treatment Mobility assessments (Gait, Time to standing, Grip 
Force)
!
Physical exam and vital signs 
!
Adverse Events
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Visit 3 - Pain-free state assessment
Subjects will be requested to return a minimum of 2-days and a maximum of 30-days 
post Visit 2 once they are pain-free for another assessment (visit 3). In order to be 
pain-free participants must rate their pain as 0 in response to Question 6 on Brief Pain 
Inventory – Short Form (See Appendix 2).  If after 30 days their score is still >0 in 
response to Question 6 on Brief Pain Inventory – Short Form then only their pain 
state and post-intervention data will be used in analysis and will not be required for 
further follow-up.
The following assessments will be conducted in the order written:
!
Urine drug screen and alcohol breath test 
!
Brief Pain Inventory - short form (See Appendix 2)
!
Current/concomitant medication
!
Cognitive testing (Axon Sports and CANTAB cognitive assessment)
!
Mobility assessments (Gait, Time to standing, Grip Force)
!
Adverse events
!
Study conclusion/Medical sign-off
3.2. Subject Restrictions
Lifestyle/ Dietary
Assessment visits (visits 2 and 3):
!
Subjects will be requested to refrain from excessive alcohol consumption for 
24 hours prior to assessment visits 2 and 3.  Excessive alcohol consumption is 
an amount that would result in a positive alcohol breath test at the start of each 
assessment visit.  If, the subject has a positive alcohol breath test at visit 2 or 3
then the visit may be rescheduled.
!
Subjects should abstain from any caffeine products for 4 hours prior to the 
visit on assessment days.
!
While on site subjects are asked to adhere to the following restrictions; no 
smoking, food, fluids or medication other than study medication and water
provided.
!
Subjects should stay at the site until all assessments are completed on 
assessment days and during their time on site will be required not to work 
during any breaks.
Medications and Treatments
No analgesics, other pain/inflammation therapy, OR VITAMIN SUPPLEMENTS
are allowed to be taken 48 hours prior to the day of the pain-state and pain-free state 
assessment days (visit 2 and 3).  No other medication or product which could 
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counteract paracetamol and/or caffeine is permitted on assessment days.  No anti-
depressants may be taken for the study duration.
3.3. Type and Planned Number of Subjects
A sufficient number of subjects will be screened to randomize approximately 65
subjects to ensure approximately 60 evaluable subjects complete the entire study. 
This will ensure approximately 20 evaluable subjects per treatment arm.
Subjects will be recruited from GSK employees or a local Clinical Research 
Organization via advertisement.  Subjects may also be recruited from a panel of pain 
sufferers held by the HPL.  
3.4. Study Design and Dose Justification
The Brief Pain Inventory (BPI) (Cleeland CS., 2009; Appendix 2) is a common 
measurement tool for assessing clinical pain.  The BPI allows patients to rate the 
severity of their pain and the degree to which their pain interferes with common 
dimensions of feeling and function.  It has been validated in studies in cancer patients 
and fibromyalgia sufferers (Klepsted et al, 2002; Arnold LM et al, 2007) and these 
studies have shown subjects to indicate a baseline pain level of 4-6 to question 4.  A 
score of ≥5 to Q6 has been chosen for the current study of subjects with everyday 
pain as they will be subjects with everyday pain as they will be primarily be recruited 
from the general population experiencing a transient pain episode; cognitive 
impairment has been correlated with pain intensity.
A recovery period of up to 30 days ensures participants are pain free (0 in response to 
Question 6 on Brief Pain Inventory – Short Form) upon their return for pain-free 
measurement. This is a simpler design than a prospective study and prevents 
habituation effects in cognitive and mobility assessments. 
Two independent batteries of cognitive tests will be used to assess cognition.  
CANTAB and Axon Sports are validated and widely used tests of cognition.  Three 
mobility measures (Gait, Time to Standing, Grip Force [Roberts HC et al, 2011]) 
have been selected as a range of movements that may be affected by pain.
Subjects will take two tablets of their allocated treatment once.  This dosage is based 
on the recommended dosing as per the product label.
In line with ICH guidelines, for a study to be classed as truly double blind, not only 
does the subject and the assessor (and any appropriate member of staff who may be 
involved in treatment dispensing, analysis of data etc.) need to be blinded as to the 
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treatment the subject receives, but the treatments under investigation must be 
identical in every way (e.g. colour, flavour, appearance, packaging).  The products 
tested in this study will differ in visual appearance (colours/packaging).  This study 
will therefore be described as assessor blind.  Every effort will be made to ensure that 
subjects (wearing eye masks) and other staff members remain blind to the treatment 
received by the subject.  Dispensing and supervised product usage will be performed 
in a separate area.  Subjects will be instructed not to discuss their treatment with team 
members supervising the assessments. 
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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 Summary of 
Product Characteristics for Panadol® Extra Advance and Panadol® Advance, and the 
Investigator Brochure for the Placebo.
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 copy of the informed consent form. 
2. AGE
Aged between 18-65 years. 
3. GENDER
Subject is male or female.
If female of childbearing potential, the subject is practicing a reliable method of
contraception in the opinion of the investigator. For the purposes of this study,
reliable contraception is defined as abstinence, oral contraceptive, either combined or 
progestogen alone OR injectable progestogen OR implants of levonorgestrel OR 
estrogenic vaginal ring OR percutaneous contraceptive patches OR intrauterine 
device or intrauterine system OR double barrier method (condom or occlusive cap 
[diaphragm or cervical vault caps] plus spermicidal agent [foam, gel, film, cream, 
suppository]) OR male partner sterilization prior to the female subject's entry into the 
study, and this male is the sole partner for that subject
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4. COMPLIANCE 
Understands and is willing, able and likely to comply with all study procedures and 
restrictions.
5. COMPLETION OF FAMILIARISATION TASKS
Adequately completes cognition and mobility familiarisation tasks in the opinion of 
the investigator.
6. GENERAL HEALTH
Good general and mental health with, in the opinion of the investigator or medically 
qualified designee: 
A. No clinically significant and relevant abnormalities in medical history or upon 
physical examination.
B. Absence of any condition that might impact on the subject’s safety or 
wellbeing or affect the individual’s ability to understand and follow study 
procedures and requirements.
C. BMI >18.5 and <30 kg/m2
7. PAIN TYPE AND INTENSITY
A. VISIT 1 ONLY – Has experienced a minimum of two recurrent, acute pain 
episodes within the past 3 months OR is currently suffering from a flare up
episode of recurrent, acute pain (see appendix 3).
B. VISIT 2 ONLY – A score ≥5 to question 6 (rated on scale 0-10) on the Brief
Pain Inventory – Short Form. 
C. Subjects presenting with only one of the following pain types:  Joint (Knee,
Hip); Back; Headache; Period; (see appendix 4).
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4.2. Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. PREGNANCY
A. Women who are pregnant (Visit 1)
B. Women of child bearing potential who test positive on a urine pregnancy test
(Visit 1 or Visit 2)
1. Females of non-child bearing potential will not be required to 
complete urinary pregnancy test.  Post-menopausal females not 
requiring a pregnancy test will be defined as:
• Age ≥ 50 years with spontaneous cessation of menses for 12 or more 
months
• Age < 55 years and spontaneous menses within the past 1 year, but
currently amenorrheic
2. BREAST-FEEDING
Women who are currently breast-feeding
3. GENERAL HEALTH
In the opinion of the medical designee, subject suffers from medical condition(s) that 
may be aggravated due to testing procedures or may impact the interpretation or
integrity of data. Conditions related to renal, hepatic, respiratory, blood, immune 
systems or heart dysfunction will be considered.
4. COLOUR BLIND
Subject is colour blind.
5. CONCURRENT MEDICATION/ MEDICAL HISTORY
A. Current (within 14 days of the start of the study) or regular use of any 
prescription, over-the-counter (OTC), herbal medicine unless the medication 
has been approved by the study physician. FOR STUDY VISITS 2 and 3, 
OTC analgesics for pain relief and vitamin supplements are permitted only 
until 48 hours prior to START OF study visits. 
B. Current or in the 30 days prior to dosing use of any drug, food, herbal product, 
or dietary supplement known to induce or inhibit hepatic drug metabolism 
(e.g. barbiturates, theophylline, cimetidine, or erythromycin).
C. Use of analgesics and anti-inflammatory drugs 48 hours prior to dosing at 
Visit 2 AND VISIT 3.
D. Known to be taking any other medication which could counteract with 
paracetamol and/or caffeine.
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E. Current or past use of anti-depressants or psychoactive drugs within the 
previous 2-years.
6. ALLERGY/ INTOLERANCE
A. Known or suspected intolerance or hypersensitivity to the study materials (or 
closely related compounds) or any of their stated ingredients.
7. SUBSTANCE ABUSE
A. Positive breath alcohol test at Visit 2.
B. Positive urine drugs of abuse test at Visit 2.
8. CLINICAL STUDY/ EXPERMENTAL PRODUCT
A. Participation in another clinical study (including cosmetic studies) or receipt 
of an investigational product within 7 days of the screening visit.
B. Previous participation and randomization in this study.
9. LIFESTYLE
A. Subject has excessive frequent caffeine intake equivalent to 6 cups of brewed 
coffee or 12 cups of tea per day.
B. Unwilling to abstain from any caffeine products from 4 hours prior to the visit 
on assessment days (Visit 2 and 3).
C. Current Smoker (or regular nicotine consumption): Subject smokes more than
3 cigarettes per day (or equivalent for e-cigarettes, chewing tobacco or pipes). 
Investigator to ensure there is no impact of withdrawal effect from those with 
nicotine dependence.
D. Current Alcohol Consumer: Subject consumes greater than 21 units of alcohol
per week (male) and 14 units per week (female) (e.g. Spirit 25ml = 1 unit / 
AlcoPop 275ml = 1.5 unit / Bottle of beer 330 ml = 1.7 unit / Glass of wine 
175ml = 2.1 unit / Pint of beer 568 ml = 3 unit).
10. PERSONNEL
Members of the study site staff or members of their immediate family.
11. INVESTIGATOR’S OPINION
Any subject who in the opinion of the investigator should not take part in this study.
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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 and re-evaluation of subjects will be allowed in this study per 
the following rules:
1. It is allowable for subjects to be re-scheduled for Visit 2 if they do not 
meet the inclusion criteria related to pain intensity (Score of ≥5 on BPI 
question 6), as long as the re-scheduled date falls within the period of 
7-28 days post Visit 1.
2. If the subject fails alcohol breath test at Visit 2 or 3, re-scheduling is 
permitted as long as the re-scheduled date falls within the period of 7-
28 days post-Visit 1 [for Visit 2] or 2-30 days post-Visit 2 [for Visit 
3].
3. If the subject fulfills one of the aforementioned criteria and a
subsequent date cannot be scheduled within allowable time frames 
detailed, subjects may be re-screened, effectively rendering them as a 
‘new subject’. 
4. Rescheduling and re-screening rules may be applied to other
inclusion/exclusion criteria where the timing of the assessment affects 
evaluation of the subject. It may not be applied to criteria that in the 
opinion of the medical designee will impact the integrity and 
interpretation of study data or subject safety. All such instances not 
explicitly detailed in the protocol must be checked with the sponsor.
4.4 Women of Childbearing Potential Definition
Female subjects of non-childbearing potential must meet at least one of the following
criteria:
1. Have undergone a documented hysterectomy and/or bilateral oophorectomy.
2. Have medically confirmed ovarian failure.
All other female subjects (including females with tubal ligations and females that do 
NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian 
failure) will be considered to be of childbearing potential.
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4.5. 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.
The following actions must be taken in relation to a subject who fails to attend the 
clinic for a required study visit:
!
The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 
!
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. 
!
In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, at least 2 telephone calls). The contact attempt should be 
documented in the subject’s record. 
!
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”.
4.6. Subject Replacement
Subjects who withdraw from the study post-randomization will not be replaced.
4.7. Subject and Study Completion
A completed subject is one who has completed all study visits (Visits 1, 2 and 3).  
There will be no follow-up post Visit-3 with the exception of subjects with ongoing 
AEs which will be followed until resolved, the condition stabilizes, is otherwise 
explained, or the subject is lost to follow-up.
The end of the study is defined as the date of the last subject’s last visit.
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5. PRODUCT INFORMATION
5.1. Study Product
The following study products will be supplied by the Clinical Supplies Department, 
GSKCH:
Product Name 
Panadol® Extra 
Advance (500mg 
paracetamol 
+65mg caffeine) 
tablets
Panadol® Advance 
(500mg 
paracetamol) 
tablets
Placebo to match 
Paracetamol 665mg 
Sustained Release 
Tablets Panadol Extend 
Placebo Tablets
Product 
Formulation 
Code (MFC)
UK Marketed 
Product
UK Marketed 
Product
Placebo 
Extend Tablet
Dose
2 tablets taken 
once
2 tablets taken 
once
2 tablets taken once
Route of 
Administration
Oral
Oral
Oral
Dosing 
Instructions
Take medication 
with 200 mL of 
water. Eye mask 
worn by subject.
Take medication 
with 200 mL of 
water. Eye mask 
worn by subject.
Take medication with 
200 mL of water. Eye 
mask worn by subject.
Other items to be supplied by the Clinical Supplies Department, GSKCH and the 
GSK HPL:
Name of Item
Purpose
Pregnancy tests
Pregnancy
Urine drug test
Drug abuse
Breathalyser
Alcohol abuse
Dosing Cups
Dosing
Eye Masks
Dosing (GSK HPL)
5.2. Dose Schedule
At Visit 2 each subject will receive 2 tablets of the product that they have been 
randomized to within each stratum
5.3. Dose Modification
No dose modification is permitted in this study.
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5.4. Product Compliance
A record of the administration of study products will be kept using the Dosing 
Accountability Log and the CRF - Any comments on the performance of this 
procedure should be recorded on the CRF. Any violation of compliance will require 
evaluation by the investigator and sponsor to determine if the subject will continue in 
the study.
5.5. Precautions
No special precautions are necessary provided the study is carried out in accordance 
with this protocol.
5.6. Overdose
An overdose is a deliberate or inadvertent administration of a product at a dose higher 
than specified in the protocol.
Overdose is not likely to occur in this study.  Limited quantities of the product will be 
supplied, and closely monitored by the site for each subject.
Overdose per se is not an AE.  However, any clinical sequelae of an overdose should 
be reported as an AE (and serious adverse event (SAE), if appropriate).  For 
reporting, follow the AE and SAE reporting instructions.
5.7. Rescue Therapy
No rescue therapy is required in this study.
5.8. Product Assignment
Subjects will be assigned to study product in accordance with the randomization 
schedule generated by the Biostatistics Department, GSKCH, prior to the start of the 
study, using validated internal software.
5.8.1 Randomization
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 stratified and randomized according to the randomization schedule.
Within each stratum, randomization numbers will be assigned in ascending numerical 
order as each subject is determined to be fully eligible and completes the pre-
treatment cognitive function and mobility assessments.
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Subject will be stratified according to the Pain Type (I.e. Joint, Back, Headache and 
Period). Recruitment into each of the 4 stratum will be controlled as follows: 
Stratum 1: Person feels the pain in the knee or hip joint at baseline
Stratum 2: Person feels the pain in the upper or lower back at baseline 
Stratum 3: Person has headache at baseline
Stratum 4: Person (Female only) having menstrual period related pain at baseline
Study site team will ensure that there are minimum 8 subjects in each stratum (≥8)
using the recruitment tracking log (see appendix 5). 
The randomization schedule will be provided by the Biostatistics Department, 
GSKCH. 
5.8.2 Blinding
The study statistician and other employees of the Sponsor who may influence study 
outcomes are blinded to the product allocation of subjects.
The assessor will be blinded to the treatment received.  The assessor is not permitted 
in the room where and when the product is dispensed.  In order to maintain the blind 
as much as possible the dispensing staff will not be involved in any 
cognitive/mobility assessments during the study.
Subjects will wear eye masks at dosing to ensure those familiar with the appearance 
of Panadol® Advance and Panadol® Extra Advance tablets are not unblinded.
5.8.3 Code 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 site will receive two versions of the randomization schedule, each in a 
sealed envelope and clearly marked as either “For Dispensing” or “Emergency Use 
Only”.  The dispensing schedule will be used by the site for subject randomization
purposes and will not identify the treatments by name (treatments will be identified as 
A, B etc corresponding to the labelled study supplies).  The other randomization
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schedule will only be removed from the sealed envelope in an emergency situation.  
This schedule will be footnoted with a key identifying the content of treatments A, B 
etc.  However, to maintain the blinding of the study as far as possible, all treatment 
allocations for all randomization numbers (and the key) on this randomization
schedule will be masked with scratch-off panels.  Only the panels required for the 
subject unblinding should be removed.
The study blind must be returned to GSKCH at the end of the study.
5.9. 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.
Each study label will contain, but not be limited to, protocol number, product code 
letter, directions for storage, emergency contact telephone number and the statements 
“For Clinical Trial Use Only” and “Keep out of the reach and sight of children”. 
The Panadol® Advance and Panadol® Extra Advance tablets will be sourced from the 
UK market place and supplied in commercial packaging with a study label applied to 
each sample. 
The Placebo to match Paracetamol 665mg Sustained Release Tablets (Panadol Extend 
Placebo Tablets) will be supplied in cartons containing blister cards. Both the carton 
and blister card will have a study label affixed.
All sundry items will be provided in their commercial packaging.
Care should be taken with the supplied products and their labels so that they are 
maintained in good condition.  It is important that all labels remain intact and legible 
for the duration of the study. Subjects should be instructed to not remove or deface 
any part of the study label.
5.9.1. Accountability of Product
All products supplied are for 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 and will contain the 
following information:
!
The identification of the subject to whom the study product was dispensed.
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!
The date(s) and quantity of the study product dispensed to the subject.
!
The date(s) and quantity of the study product returned by the subject (if 
applicable).
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.
5.9.2. Storage of Product
Study product supplies must be stored in compliance with the label requirements in a 
secure place with limited or controlled access.
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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 Email/Telephone Screening
Prior to the screening visit, email/telephone screening will be conducted for
individuals who have responded to advertisement using a standard email/telephone 
script. This will be conducted by the site recruitment staff or designee.
6.1.2. Informed Consent
The investigator, or designee, must obtain written (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 
consent form will include a statement of consent permitting the investigator, or 
designee, to notify the subject’s general practitioner of their participation in the study. 
If no response is received from the general practitioner in relation to the subject’s 
participation before the subject returns for visit 2 then the subject will be considered 
eligible to proceed providing all other inclusion/exclusion criteria are met.
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 written consent 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.  The 
subject, will be provided with a copy of their signed and dated consent form and any 
other written information which they should be instructed to retain.
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 of the signed and dated 
amended consent form. The date of consent will be recorded on the CRF.
6.1.3. Demographics
The following demographic parameters will be captured by the Investigator or 
designee and recorded on the CRF: year of birth, gender and race.
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6.1.4. Medical History and Concomitant Medication
Medical history for each subject 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, 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.
6.1.5. Brief Pain Inventory – Short Form Questionnaire
The BPI-Short Form questionnaire (Cleeland CS, 2009) allows the user to rate the 
severity of their pain and the degree to which their pain interferes with common 
dimensions of feeling and function. Initially developed to assess pain related to 
cancer (Cleeland et al., 1994), the BPI has been shown to be an appropriate measure 
for pain caused by a wide range of clinical conditions. See Appendix 2.
6.1.6. Pain Recurrence Questionnaire And Pain State Question
The Pain Recurrence Questionnaire (see Appendix 3) will be administered to confirm 
the eligibility for the study per Inclusion 7A.
The pain state question (See Appendix 4) will be administered to confirm eligibility 
for the study as per Inclusion 7C.
6.1.7. Physical Exam/Vital Signs
The investigator or designee will perform a physical exam that includes central
nervous system, neck, head, ears, eyes, nose and throat, respiratory, cardiovascular,
gastrointestinal, abdomen, musculoskeletal, neurological, endocrine/metabolic,
hematopoietic/lymphatic and dermatological assessments. 
The investigator or designee will measure vital signs while the subject is seated 
(Blood Pressure measured after 5 minutes seated at rest). The following normal 
ranges are given as a guide:
! Systolic Blood Pressure > 100 and  <140 mm Hg
! Diastolic Blood Pressure >60 and <90 mm Hg
! Heart Rate >50 and <100 beats per minute
! Respiratory Rate >8 and <20 respirations per minute
! Tympanic Body Temperature >35.5ºC and  <37.8ºC (95.9-100 ºF)
The outcome of these assessments will be documented in the CRF, including details
of any abnormalities. A subject with vital signs marginally outside the normal range
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may be included in the study if (in the investigator’s opinion) they are not clinically
significant.
6.1.8. Anthropometric Measurements
Height will be measured using a wall mounted stadio-meter, with the subject standing 
without shoes, to the nearest 0.1 cm. Weight will be measured in standard clothing on 
calibrated weighing scale to the nearest 0.1 kg. BMI will then be calculated as 
follows:
BMI = Weight (kg) / [Height]2 (m2)
6.1.9. Pregnancy Test
Urine pregnancy testing will be performed on females of child bearing potential
according to the test kit manufacturer’s instructions.  Any urine collected will be 
disposed of as soon as the test is complete and will be tracked as detailed in section 
6.2.1.
6.2. Visit 2 (Pain State) and Visit 3 (Pain-free)
Subjects advised to eat before dosing with no food less than 1 hour before dosing. All 
pre-treatment assessments will be performed prior to randomization. 
6.2.1. Drug and Alcohol Assessment
A urine sample will be collected and analyzed for cannabinoids, amphetamine, 
cocaine, ecstasy, methamphetamine and morphine before the subject undergoes 
assessment at Visit 2 and Visit 3 to check eligibility.  The urine will be labeled with 
the subject’s number and date to ensure traceability and will be disposed of as soon as 
the test is complete by flushing down the toilet at the HPL.  A tracking log will be 
used to document collection and destruction of the urine samples.  The subject will 
also breathe into an alcohol breathalyzer at Visit 2 and Visit 3.  The results of this 
analysis must be negative for all such substances in order for the subject to continue 
in the study.
6.2.2. Pregnancy Test
Urine pregnancy testing will be performed on females of child bearing potential (only 
Visit 2) according to the test kit manufacturer’s instructions.  Any urine collected will 
be disposed of as soon as the test is complete and will be tracked as detailed in 
section 6.2.1.
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6.2.3. Cognitive Function Assessments
Familiarization cognitive function assessments will have been performed at Visit 1. A 
member of the site team will instruct the subjects to complete the cognitive 
assessments in the following order:
For the Axon Sports Priming Application the site team will follow administration 
instructions as outlined in WA-525.
1. Axon Sports Priming Application (approximately 5 minutes)
The Axon Sports Priming Application is a computerized test performed on a tablet 
device that measures cognitive performance, namely psychomotor speed. The main 
outcome measure is simple reaction time (SRT) (msec), error (msec) and error 
adjusted SRT (msec).
For the CANTAB tasks (2-6 listed below) the site team will supervise testing which is 
delivered automatically via tablet devices as provided by Cambridge Cognition.
2. Reaction Time, RTI (approximately 5 minutes)
In this five-choice reaction time task the participant holds down a button at the 
bottom of the screen until a yellow spot appears in one of the five circles at the top of 
the screen. They must then release the button and touch inside the circle where the 
yellow spot appeared as quickly as they can. The key outcome measure for this task is 
median five-choice reaction time (the median duration between the onset of the 
stimulus and the release of the button. Calculated for correct, assessed trials where 
the stimulus could appear in any one of five locations). This task takes approximately 
5 minutes to complete.
3. One Touch Stockings of Cambridge, OTS (approximately 10 minutes)
This task is a measure of executive function and takes approximately 10 minutes to 
complete. The participant is shown two displays containing three coloured balls. The 
displays are presented in such a way that they can easily be perceived as stacks of 
coloured balls held in stockings or socks suspended from a beam. This arrangement 
makes the 3-D concepts involved apparent to the participant, and fits with the verbal 
instructions. There is a row of numbered boxes along the bottom of the screen. The 
test administrator first demonstrates to the participant how to use the balls in the 
lower display to copy the pattern in the upper display, and completes one 
demonstration problem, where the solution requires one move. The participant must 
then complete three further problems, one each of two moves, three moves and four 
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moves. Next the participant is shown further problems, and must work out in their 
head how many moves the solutions to these problems require, and then touch the 
appropriate box at the bottom of the screen to indicate their response. The main 
outcome variable is the OTS problems solved on first choice which is the number of 
assessment problems on which the first box choice made was correct.
4. Attention Switching Task, AST (approximately 8 minutes)
This task is a measure of executive attention and takes approximately 8 minutes to 
complete. The test displays an arrow which can appear on either side of the screen 
(right or left) and can point in either direction (to the right or to the left). Each trial 
displays a cue at the top of the screen that indicates to the participant whether they 
have to press the right or left button according to the “side on which the arrow 
appeared” or the “direction in which the arrow was pointing”. Some trials display 
congruent stimuli (e.g. arrow on the right side of the screen pointing to the right) 
whereas other trials display incongruent stimuli which require a higher cognitive 
demand (e.g. arrow on the right side of the screen pointing to the left). The main 
outcome is the AST congruency cost (median; msec) which is the difference between 
the median latency of response (from stimulus appearance to button press) on the 
trials that were congruent versus the trials that were incongruent. It is calculated by 
subtracting the median congruent latency (in msec) from the median incongruent 
latency. This measure is complex in sense in that close to zero indicates less variation 
in latencies across congruent and incongruent trials.  A positive score indicates that 
the subject is faster on congruent trials and a negative score indicates that the subject 
is faster on incongruent trials.
5. Spatial Working Memory, SWM (approximately 6-7 minutes)
This task is a measure of working memory and takes approximately 6-7 minutes to 
complete. The task involves a number of coloured squares (boxes) being shown on 
the screen. The aim of this test is to find one blue token in each of a number of boxes 
by process of elimination and use these to fill up an empty column on the right hand 
side of the screen. The number of boxes gradually increases up to a maximum of 
eight boxes to search and the colour and position of the boxes change from trial to 
trial. The main outcome variable is the SWM between errors and is defined as times 
the subject revisits a box in which a token has previously been found. This is 
calculated for trials of four, six and eight tokens.
6. Rapid Visual information Processing, RVP (approximately 7 minutes)
This task measures attention and takes approximately 7 minutes to complete. A white 
box appears in the centre of the computer screen, inside which digits, from 2 to 9, 
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appear in a pseudo-random order, at the rate of 100 digits per minute. Participants are 
requested to detect target sequences of digits (for example, 2-4-6, 3-5-7, 4-6-8) and to 
register responses using the press pad. The main outcome variable is RVPA’ (A 
prime) and it is the signal detection measure of sensitivity to the target, regardless of 
response tendency (the expected range is 0.00 to 1.00; bad to good). In essence, this 
metric is a measure of how good the subject is at detecting target sequences.
6.2.4. Mobility Assessments
Familiarisation mobility assessments will have been performed at Visit 1. A member 
of the site team will instruct the subjects how to complete the mobility assessments 
using the following work aids - Gait - WA-532 (optojump),  Time to standing - WA-
530 (force plate) and grip force - WA-531 (Grip force).  These work aids outline 
procedures for completing the following mobility assessments will be conducted:
1. Gait 
Subjects will perform a walking assessment in comfortable walking shoes (subjects 
own) to measure gait parameters (contact phase, stride length and walking speed over 
5-10m for each foot). An athletic movement analysis system (Optojump, Microgate)
will be utilised. Differences in contact phase (m/s), stride length (cm) and walking 
speed over 5-10m (metres/second) and their within-test variability will be analyzed 
between baseline (pain state), post-intervention and pain-free follow-up assessments. 
The system will be set up over a 15m length of track with only the 5-10m section 
measured and analysed.  Subjects will be instructed to walk the 15m length a 
minimum of 6 times (3 practice and a minimum of 3 test walks) always entering the 
15m length with the same foot first.  The foot (left or right) entering the 5-10m 
section first will be recorded by visual assessment of the Optojump operator for the 
test walks.  Test walks will be repeated until there are 3 walks in which the subject 
has entered the 5-10m section with the same foot first.  Parameters will be averaged 
based on the 3 test walks in which this occurs.
2. Time to Standing
Time to standing provides a simple assessment of physical mobility.  From a seated 
position with arms crossed so that the right hand is placed on the left shoulder and the 
left hand on the right shoulder, participants will stand to a fully erect stature in as 
short a time as possible.  Time to standing will be measured using a stopwatch and 
ground reaction force (GRF) during the movement analyzed using a force plate 
(AMTI) interfaced with a computer.  Subjects will conduct the movement 3-times 
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continuously as a practice effort and 5-times continuously as a test effort at each visit.  
There will be a 1-minute rest between the practice and test effort. Differences in
average time to standing and average peak GRF output between baseline (pain-state), 
post-intervention and pain free follow-up assessments will be analysed for the test 
effort.  
3. Grip Force
This task is a measure of grip strength. The subject holds the dynamometer in their 
dominant hand and the arm is swung from above the head to by the side of the body.  
If the dominant arm or hand is painful then the non-dominant hand will be used. 
Subjects will be instructed to assert maximum effort during the squeezing motion and 
maintain it for about 4 seconds using a metronome.  Subjects will conduct the 
movement 4-times (1 practice effort and 3 test efforts) and there will be a 1-minute 
recovery period between each effort. The handle of the dynamometer is adjusted if 
required - the base should rest on first metacarpal (heel of palm), while the handle 
should rest on middle of four fingers. The result from 3 test efforts will be recorded, 
with the average grip strength being used for data analysis.
6.2.5 Physical Exam / Vital Signs (Visit 2 only pre- and post-treatment)
The investigator or designee will perform a brief physical exam that will be focused 
on general appearance, the respiratory and cardiovascular systems, as well as towards 
subject reported symptoms.
The investigator or designee will measure vital signs while the subject is seated 
(Blood Pressure measured after 5 minutes seated at rest). The following normal 
ranges are given as a guide:
! Systolic Blood Pressure > 100 and <140 mm Hg
! Diastolic Blood Pressure >60 and <90 mm Hg
! Heart Rate >50 and <100 beats per minute
! Respiratory Rate >8 and <20 respirations per minute
! Tympanic Body Temperature >35.5ºC and <37.8ºC (95.9-100 ºF)
The outcome of these assessments will be documented in the CRF, including details
of any abnormalities. A subject with vital signs marginally outside the normal range
may be included in the study if ,in the investigator’s opinion, they are not clinically
significant.
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6.2.6. Medical History and Concomitant Medication
Medical history for each subject 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, 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.
6.2.7. Brief Pain Inventory – Short Form Questionnaire
The BPI-Short Form questionnaire (Cleeland CS, 2009) allows the user to rate the 
severity of their pain and the degree to which their pain interferes with common 
dimensions of feeling and function. Initially developed to assess pain related to 
cancer (Cleeland et al., 1994), the BPI has been shown to be an appropriate measure 
for pain caused by a wide range of clinical conditions. See Appendix 2.
6.2.8. Pain State Question
The pain state question (See Appendix 4) will be administered on Visit 2 to confirm 
eligibility for the study as per Inclusion 7C.
6.3. 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 
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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.
Events meeting AE definition include:
!
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.
!
Exacerbation of a chronic or intermittent pre-existing condition including 
either an increase in frequency and/or intensity of the condition.
!
New condition(s) detected or diagnosed after study product administration 
even though it may have been present prior to the start of the study.
!
Signs, symptoms, or the clinical sequelae of a suspected interaction.
!
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:
!
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. 
!
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.. 
!
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is an AE.
!
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
!
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.
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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 be exercised 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 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, 
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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. Recording Adverse Events and 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 site staff 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 of 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 time of signature of the consent form - for all 
subjects who are eligible at assessment familiarisation stage until Visit 3 or 5 
days following last administration of the study product (whichever is the 
latter).
!
SAEs will be collected over the same time period as stated above for AEs.  
However, any SAEs assessed as related to 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.
7.3. Evaluating Adverse Events and 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:
!
Mild:  An event that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities.
!
Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities
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!
Severe:  An event that prevents normal everyday activities. - an AE 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 Investigator Brochure (IB) and/or 
Product Information, for marketed products, in the determination of his/her 
assessment.
!
For each AE/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.
!
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 Events and 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 
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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 dose) (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: 
!
Protocol and subject identifiers
!
Subject’s demography
!
Description of events, with diagnosis if available
!
Investigator opinion of relationship to study product (see section 8.3)
!
Criterion for seriousness.
The following are desirable and are of particular relevance for investigator and 
GSKCH assessment of the SAE report:
!
Date of onset of AE 
!
Date AE stopped, if relevant
!
Study product start date
!
Study product end date if relevant
!
Action taken on study product
!
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 hours after study site personnel learn of the event. The GSKCH 
Study Manager should be notified of the situation by telephone or email.
Fax Serious Adverse Events to:
UK: 
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.
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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 Events and 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 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, IEC and 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 IEC, if appropriate according to local requirements.
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7.6. Collection of Pregnancy Information
7.6.1. Time Period for Collecting of Pregnancy Information
Collection of Pregnancy Information:
!
Pregnancy information will be collected on all pregnancies reported following 
administration of any investigational product. Information on pregnancy 
identified during the screening phase and prior to investigational product 
administration does not need to be collected.
7.6.2. Action to be Taken if Pregnancy 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 
investigational 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 to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting.
!
There is no requirement for the subject to be withdrawn from the study as a 
result of the pregnancy.  However if they are withdrawn, this should be 
recorded in the appropriate section of the CRF.
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8. DATA MANAGEMENT
For this study subject data will be entered into an electronic case report form, using a 
GSKCH validated data system.
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 Document Designation 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. 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 
.
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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) will be 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 queries as needed on safety data to 
code the 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.
8.4. Processing Patient Reported Outcomes
Patient reported outcome (PRO) data are collected directly from the subject PRO 
measures e.g. diary cards, questionnaires etc, and entered into the sponsor’s clinical 
data management system (DMS) by the study site representative. In instances where 
the PRO data is entered into the DMS by GSKCH, the PROs will be anonymised, and 
forwarded to GSKCH for entry, as agreed and documented ahead of the study 
starting. PROs that are source will be retained by the investigator and certified copies 
will be sent to GSKCH. 
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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 on all 
PRO’s that will be forwarded to GSKCH.
8.5. External Data
External Data are subject data obtained externally to the CRF. These data are 
generated from laboratory instruments, computers or other sources and then 
transcribed into a file and format agreed upon by GSKCH to identify the subject and
time point referenced in the CRF and/or protocol. 
An agreed upon quality control process is performed against the transcribed data to 
the source to ensure the accuracy of the transcription. The transcribed data is 
transmitted in an agreed upon format to GSKCH via secured web portal or CD/DVD 
via mail carrier with tracking capabilities. 
Proper reconciliation will be performed between the transcribed data and the clinical 
database to ensure subject and time point referenced in the Clinical Database match
before Clinical Database Freeze (locking of the database) can occur.
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9. STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1 Sample Size Determination
A sufficient number of subjects will be screened in order to randomise approximately
65 subjects to obtain 20 subjects per treatment group for a 5 week analysis. Since this 
is an exploratory study, the sample size calculation is not based on any formal 
formulations.
9.2. General Considerations
9.2.1. Definition of Analysis Populations
Safety population: All randomized subjects who receive at least one treatment during 
study period will be considered as the safety population.
ITT population: All randomized subjects who receive study treatment and have at 
least one post-baseline efficacy measurement.
PP population: Since this is an exploratory study, no per protocol (PP) population will 
be defined.
9.2.2. Exclusion of Data from Analysis
There is no intention to exclude any data from the planned analysis. 
9.2.3. Criteria for Evaluation
See the following two sub-sections for details.
9.2.4. Criteria for Assessing Efficacy
!
Statistically significant deficit in cognitive performance (as measured by 
individual scores from the Axon Sports Priming Application and each of the 
CANTAB tasks – RTI, OST, AST, SWM and RVP) observed between an 
individual in pain vs. their pain-free performance.
!
Statistically significant deficit in mobility (as measured by individual scores 
from gait, time to standing and grip force assessments) observed between an 
individual in pain vs. their pain-free performance.
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9.2.5. Criteria for Assessing Tolerability
Adverse events (AEs) will be used to evaluate the tolerability for this study.
9.2.6. Criteria for Assessing Bioequivalence
NA.
9.2.7. Handling of Dropouts and Missing Data
Subjects who meet the definition for inclusion in the ITT population and who 
withdraw from the study early will be included in the statistical analysis up to the 
point of when they withdraw. There will be no imputation for missing data (i.e., 
analysis will be conducted on an observed case basis).
9.2.8. Other Issues
Since this is an exploratory study, the multiplicity issue for multiple comparisons in 
primary efficacy endpoints will not be considered. No p-value adjustments will be 
done and all p-values will be reported as is.
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 / analysis (as appropriate).
9.3.1. Demographic and Baseline Characteristics
Descriptive statistics of demographic and baseline characteristics data will be 
tabulated. Continuous variables will be presented using summary statistics: number of 
observation, arithmetic mean, SD, median, minimum and maximum values. 
Categorical variables will be presented using summary statistics: number of 
observations, counts, and percentages.
9.3.2. Primary Analysis
The primary efficacy variables are:
!
Subject level change from pain-free state in cognition as measured by 
cognitive function assessment (CANTAB and Axon Sports) in the pain state.
The cognitive function assessment contains the following measurements:
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1. Reaction Time (RTI)
2. Rapid Visual information Processing (RVP)
3. Attention Switching Task (AST)
4. Spatial Working Memory (SWM)
5. One Touch Stockings of Cambridge (OTS)
6. Axon Sports Priming Application
Detailed descriptions for each assessment are presented in Section 6.2. 
A two-sided paired t-test will be used to analyze the primary efficacy endpoints that 
are not ‘time-related’. For the ‘time-related’ variables, the non-parametric method 
using Wilcoxon Sign Rank test will be employed at visit 2 Pre (Baseline) and visit 
Post (Baseline). All tests will be two-sided with an alpha level of 0.05. The 95% CI 
and the p-value will also be presented.
9.3.3. Secondary and Exploratory Analysis
The secondary variables are:
!
Subject level change from pain-free state in mobility as measured by gait, 
time to standing and grip force score in the pain state.
The exploratory variables are:
!
Correlation between pain type and intensity to cognitive assessments.
!
Correlation between pain type and intensity to mobility assessments
!
Effect of intervention on change from pain-state assessment in cognition as 
measured by cognitive function assessment (CANTAB and Axon Sports) to 
post-treatment assessment period.
!
Effect of intervention on change from pain-state assessment in mobility as 
measured by gait score, time to standing score and percent change of muscle 
score to post-treatment assessment period.
The mobility assessment contains the following assessments:
1. Gait score, which consists of three measurements: (1) Contact phase, (2) 
Stride length, (3) Within test variability. 
2. Time to Standing, which consists of two measurements: (1) Time to standing, 
(2) Ground reaction force (GRF).
3. Grip Force
All the detailed descriptions for these assessments can be found in Section 6.2.3.
A two-sided paired t-test will be used to analyze the secondary efficacy endpoints for 
subject level change from pain free-state in mobility measurements that are not ‘time-
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related’. For the ‘time-related’ mobility variables, the non-parametric method using 
Wilcoxon Sign Rank test will be employed at visit 2 Pre (Baseline) and visit 2 Post
(Baseline). For the between treatment comparisons, the mixed effect model with 
treatment and pain type as the fixed effect and the baseline value as a covariate will 
be employed for the change from baseline type of analysis at Visit 2, 1 hour post-
treatment and at visit 3 (follow-up visit) for variables other than ‘time’ related type. 
For the ‘time’ related variables, the non-parametric method using Van Elteren’s test
with stratification factor pain type will be employed. The 95% CI and the p-value will 
also be presented.
9.3.4. Safety Analysis                                                                                                                                    
AEs will be listed and reviewed. Only treatment emergent AEs (i.e., those occurring 
after first use of the study treatment) will be tabulated, AEs occurring prior to 
randomization will be included in the AE listing. AE tables will be presented using 
the safety population.
9.3.5. Other Analysis
To investigate the relationship between pain type and intensity to cognitive and 
mobility assessments will be considered as an exploratory analysis and the Pearson 
correlation analysis method will be used for this purpose.
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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.
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:
!
Before initiating a trial, the investigator/institution should have written and 
dated approval/favorable opinion from the IEC/Competent Authority for 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 the investigator to the sponsor prior to initiation of 
the study, and also when subsequent amendments to the protocol are made.
!
Signed informed consent  to be obtained for each subject before participation 
in the study (and for amendments as applicable)
!
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IEC)
!
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. third party 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.
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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.
GSK or designee will monitor the study and site activity to verify that the:
!
Data are authentic, accurate, and complete.
!
Safety and rights of subjects are being protected.
!
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 of these 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.  
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/ 
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follow-up for the subjects. Where required by the applicable regulatory requirements, 
GSKCH should inform the regulatory authority (ies). 
In addition: 
!
If the investigator terminates or suspends a trial without prior agreement of 
GSKCH, the investigator site should promptly inform the sponsor and the 
IEC, and should provide the sponsor and the IEC a detailed written 
explanation of the termination or suspension.
!
If the GSKCH terminates or suspends a trial, the investigator should promptly 
inform the IEC and provide the IEC a detailed written explanation of the 
termination or suspension. 
!
If the IEC 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 
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.
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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 
the study. 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 be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
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11. REFERENCES
Allen GJ, Hartl TL, Duffany S, Smith SF, VanHeest JL, Anderson JM, Hoffman 
JR, Kraemer WJ, Maresh CM. Cognitive and motor function after administration of 
hydrocodone bitartrate plus ibuprofen, ibuprofen alone, or placebo in healthy subjects 
with exercise-induced muscle damage: a randomized, repeated-dose, placebo-
controlled study. Psychopharmacology (Berl), 2003; 166(3): 228-33. 
Arnold LM, Goldenberg DL, Stanford SB, Lalonde JK, Sandhu HS, Keck PE Jr.,
Welge JA, Bishop F, Stanford KE, Hess EV, and Hudson JI.  Gabapentin in the 
Treatment of Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Trial. Arthritis & Rheumatism, 2007; 56(4): 1336–1344.
Berryman, C, Stanton T, Bowering, J, Tabor, A, McFarlane, A, Moseley, L. Evidence 
for working memory deficits in chronic pain: A systematic review and meta-analysis. 
Pain, 2013; 154: 1181-1196.
Cleeland CS, Gonin R, Hatfield AK, Edmonson JH, Blum RH, Stewart JA, Pandya 
KJ. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med, 1994; 
330(9): 592-596.
Cleeland CS.  The Brief Pain Inventory User Guide; 2009.
Eccleston, C. Chronic pain and attention: A cognitive approach. British Journal of
Clinical Psychology, 1994; 33: 535–547.
ICH Topic 6 Guideline for Good Clinical Practice CPMP/ICH/135/95; 1996.
Klepsted P, Loge JH, Borchgrevink PC, Mendoza TR, Cleeland CS, Kaasa S. The 
Norwegian Brief Pain Inventory Questionnaire: Translation and Validation in Cancer 
Pain Patients. Journal of Pain and Symptom Management, 2002; 24(5): 517–525.
Landrø NI, Fors EA, Våpenstad LL, Holthe Ø, Stiles TC, Borchgrevink PC. The 
extent of neurocognitive dysfunction in a multidisciplinary pain centre population. Is 
there a relation between reported and tested neuropsychological functioning? Pain,
2013; 154(7): 972-7.
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Moriarty O, McGuire BE, Finn DP. The effect of pain on cognitive function: A 
review of clinical and preclinical research. Prog Neurobiol, 2011; 93(3): 385-404. 
Park DC, Glass JM, Minear M, Crofford LJ. Cognitive function in fibromyalgia 
patients.  Arthritis Rheum, 2001; 44(9): 2125-33.
Renner B, Clarke G, Grattan T, Beisel A, Mueller C, Werner U, Kobal G, Brune K. 
Caffeine accelerates absorption and enhances the analgesic effect of acetaminophen. J 
Clin Pharmacol, 2007; 47(6): 715-26. 
Roberts HC, Denison HJ, Martin HJ, Patel HP, Syddall H, Cooper C and Sayer AA, 
A review of the measurement of grip strength in clinical and epidemiological studies: 
towards a standardised approach. Age Ageing, 2011; 40(4): 423-429.
van Dijk GM1, Veenhof C, Lankhorst GJ, Dekker J. Limitations in activities in 
patients with osteoarthritis of the hip or knee: the relationship with body functions, 
comorbidity and cognitive functioning. Disabil Rehabil, 2009; 31(20): 1685-91.
Veldhuijzen DS, Kenemans JL, van Wijck AJ, Olivier B, Kalkman CJ, Volkerts ER. 
Processing capacity in chronic pain patients: a visual event-related potentials study. 
Pain, 2006; 121(1-2): 60-8. 
Vogt L, Segieth C, Banzer W, Himmelreich H. Movement behaviour in patients with 
chronic neck pain. Physiother Res Int, 2007; 12(4): 206-12.
WA-525 – Site staff instructions for conduct of Axon Sports Priming Application, 
2016.
WA-530 - Site staff instructions for conduct of the time to standing (force plate) 
assessment, 2015.
WA-531 - Site staff instructions for conduct of the Grip force assessment, 2015.
WA-532 - Site staff instructions for conduct of the Gait assessment (OptoJump), 
2015.
World Medical Association Declaration of Helsinki, 59th General Assembly, Seoul 
2008.
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12. APPENDICES
12.1. Appendix 1 - Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
AMTI
Advanced Mechanical Technology, Inc
AST
Attention Switching Task
BMI
Body Mass Index
BPI
Brief Pain Inventory
CANTAB
Cambridge Cognition Cognitive Assessments
CD
Compact Disc
CRF
Case Report Form
DVD
Digital Versatile Disc
EDC
Electronic Data Capture
FM
Fibromyalgia
GCP
Good Clinical Practice
GP
General Practitioner
GRF
Ground Reaction Force
GSKCH
GlaxoSmithKline Consumer Healthcare
HPL
Human Performance Lab
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
OTC
Over-the-Counter
OTS
One Touch Stockings of Cambridge
PII
Personally Identifiable Information
PP
Per Protocol
RTI
Reaction time
SAE
Serious Adverse Event
SWM
Spatial Working Memory
SRT
Simple Reaction Time
RVP
Rapid Visual information Processing
RVPA
Rapid Visual information Processing A prime
PRO
Patient Reported Outcome
Trademark Information
Trademarks of the GlaxoSmithKline group of companies:
Panadol
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12.2. Appendix 2 - Brief Pain Inventory - Short Form
Visit number:
Subject ID:
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12.3. Appendix 3 – Pain Recurrence Questionnaire
Visit number:
Subject ID:
Date:
Including today, how many episodes of acute (< 3 months in duration), re-current 
pain have you suffered from in the past 3 months? Please indicate number in relevant 
box:
Pain Recurrence
Joint
Knee
Hip
Muscle
Upper Back
Lower Back
Headache
Period
Other, please provide details below:
If currently within an acute pain episode, please indicate where you are currently 
suffering from pain.
Current Pain
Not currently suffering from acute pain
Joint
Knee
Hip
Muscle
Upper Back
Lower Back
Headache
Period
Other, please provide details below:
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12.4. Appendix 4 – Pain State Question 
Visit number:
Subject ID:
Date:
Please mark an X to indicate where you are currently suffering pain:
Pain State
Joint
Knee
Hip
Muscle
Upper Back
Lower Back
Headache
Period
Other, please provide details below:
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12.5. Appendix 5 – Recruitment Tracking Log
When a subject is randomised the subject number must be tracked in 
the below log to ensure that a minimum of 8 subjects per pain type are 
included in the study:
Minimum subjects per pain type:
Pain type
FRXQW
Joint .QHHRU
+LS
Muscle 8SSHU
RU/RZHUEDFN
Headache
Period








Additional subjects per pain type:
2QFHVXEMHFWVDUHUHFUXLWHGIRUDSDLQW\SHSOHDVHFRPSOHWHWKHURZVEHORZDVSHUWKH
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

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Biostatistics Approval
Clinical Operations Approval
07-Dec-2016 11:32:11
Approved
204503 Clinical Protocol
07-Dec-2016 11:30:35
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PPD
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PPD

SAP_001.pdf: 
CONFIDENTIAL
STATISTICAL ANALYSIS PLAN FOR PROTOCOL 204503
Assessment of cognitive function and mobility in
Individuals with pain
BIOSTATISTICS DEPARTMENT
GLAXOSMITHKLINE CONSUMER HEALTHCARE
INVENTIV HEALTH CLINICAL
(Statistician)
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PPD
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Table of Contents
Glossary.....................................................................................4
1
Introduction .....................................................................5
2
Objectives.........................................................................5
3
Study Design.....................................................................6
4
Sample Size Determination.............................................8
5
Data Considerations ........................................................8
5.1
Analysis Populations...................................................8
5.2
Subgroups/Stratification ............................................10
5.3
Time Windows ............................................................10
6
Demographics and Baseline Characteristics..................10
6.1
Subject Disposition .....................................................10
6.2
Demographics..............................................................10
6.3
Baseline Characteristics .............................................11
7
Treatment Compliance and Concomitant Medications 11
7.1
Treatment Compliance...............................................11
7.2
Concomitant Medications...........................................11
8
Efficacy Analysis..............................................................11
8.1 Determination of Efficacy Measure ..............................11
8.2
Primary Efficacy Analysis..........................................14
8.2
Secondary Efficacy Analysis ......................................15
9
Safety Analysis.................................................................16
10
Interim Analysis...............................................................17
11
Topline Summary ............................................................17
12
Changes to Planned Analysis ..........................................17
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13
References ........................................................................17
Appendix 1 Study Schedule .....................................................19
Appendix 2 List of Tables, Figures & Listings .......................20
Appendix 3 Templates for Tables, Figures & Listings...........24
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Glossary
AE
Adverse Event
ANCOVA
Analysis of Covariance
AST
Attention Switching Task
BMI
Body Mass Index
BPI
Brief Pain Inventory
CRF
Case Report Form
CANTAB
Cambridge Cognition Cognitive Assessments
GCP
Good Clinical Practice
GRF
Ground Reaction Force
GSKCH
GlaxoSmithKline Consumer Healthcare
HPL
Human Performance Lab
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
mITT
Modified Intention to Treat
OTC
Over-the-Counter
OTS
One Touch Stockings of Cambridge
RTI
Reaction time
SAE
Serious Adverse Event
SWM
Spatial Working Memory
SRT
Simple Reaction Time
SAP
Statistical Analysis Plan
RVP
Rapid Visual information Processing
RVPA
Rapid Visual information Processing A prime
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1
Introduction
This document describes the statistical methods and data presentations to be used in the 
summary and analysis of the final data from Protocol 204503.
This statistical analysis plan will be finalized and approved prior to database freeze and 
unblinding.
2
Objectives
Objectives
Endpoints
Primary
!
To investigate within-subject 
cognitive changes in individuals 
with everyday pain compared to 
pain-free performance.
!
Subject level change from pain-
free state in cognition as measured 
by cognitive function assessment 
(CANTAB and Axon Sports) in the 
pain state.
Secondary
!
To investigate within-subject 
mobility changes in individuals 
with everyday pain compared to 
pain-free performance.
!
Subject level change from pain-
free state in mobility as measured 
by gait, time to standing and grip 
force score in the pain state.
Exploratory
!
Investigate the relationship 
between pain type and intensity 
with cognitive function and 
mobility.
!
Correlation between pain intensity 
and each cognitive assessment for 
each pain type at Visit 2 Pre and 
Visit 2 Post.
!
Correlation between pain intensity 
and each mobility assessment for 
each pain type at Visit 2 Pre and 
Visit 2 Post.
!
To investigate the effects of OTC 
treatment (paracetamol +/- caffeine 
and placebo) on cognitive function 
and mobility in individuals with 
everyday pain.
!
Effect of intervention on change 
from pain-state assessment in 
cognition as measured by cognitive 
function assessment (CANTAB 
and Axon Sports) to post-treatment 
assessment period.
!
Effect of intervention on change 
from pain-state assessment in 
mobility as measured by gait score, 
time to standing score and grip 
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strength to post-treatment 
assessment period.
3
Study Design
Overall Design
This parallel, assessor blind, placebo-controlled, stratified, randomised study will recruit 
approximately 65 male and female participants with everyday pain (as assessed by the 
Brief Pain Inventory – Short Form questionnaire). They will be recruited from GSK 
employees or by a Clinical Research Organisation, screened for eligibility and the 
assessment will be at The Human Performance Lab (HPL).
Visit 1 - Screening Visit
After initial screening via email/telephone subjects will be invited for a screening visit 
at the HPL at a suitable time.  
The below activities will be conducted during the screening visit in the following order:
1. Informed Consent
2. Subject Eligibility assessments (in any order)
- Demographics
- Brief Pain Inventory - short form (SEE APPENDIX 2)
- Pain Recurrence Question (see Appendix 3)
- General Medical History 
- GP name and contact details collected 
- Current/concomitant medication
- Height, Weight and BMI measurements
- Physical exam and vital signs
- Pregnancy test (women of childbearing potential only)
- Subject eligibility (Confirm subject satisfies all entry criteria relevant to 
screening Visit 1 prior to progression to familiarization activities) 
3. - Familiarization activities (in any order)
- Cognitive testing practice session (Axon Sports and CANTAB 
cognitive assessment)
- Mobility assessments practice session (Gait, Time to standing, Grip 
Force)
- Inclusion/Exclusion criteria
Letter to GP sent via email or next day delivery post on same day as screening visit. GP 
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letter to include summary of the study and request that GP contact the site if any reason 
known that the subject should not participate.
Visit 2 - Pain state assessment 
A minimum of 7-days and a maximum of 28-days later, a pain-state assessment will be 
performed.  The following assessments will be conducted in the order written:
!
Brief Pain Inventory - short form (SEE APPENDIX 2)
!
Pregnancy test (females of child bearing potential only)
!
Urine drug screen and alcohol breath test 
!
General Medical History
!
GP letter response reviewed if received
!
Current/concomitant medication
!
Physical exam and vital signs 
!
Pain State Question (see appendix 4)
!
Subject Eligibility
!
Inclusion/Exclusion criteria
!
Pre-treatment Cognitive testing (Axon Sports and CANTAB cognitive 
assessment)
!
Pre-treatment Mobility assessments (Gait, Time to standing, Grip 
Force)
!
Stratification and Randomization to OTC medication
!
Subject will be stratified to one of four strata according to their pain type 
and then randomized accordingly to one of the three treatment groups.
!
Supervised OTC medication given on site
!
Post-treatment (1hr ± 15 mins) Brief Pain Inventory - short form (SEE 
APPENDIX 2)
!
Post-treatment Cognitive testing (Axon Sports and CANTAB cognitive 
assessment)
!
Post-treatment Mobility assessments (Gait, Time to standing, Grip 
Force)
!
Physical exam and vital signs 
!
Adverse Events
Visit 3 - Pain-free state assessment
Subjects will be requested to return a minimum of 2-days and a maximum of 30-days 
post Visit 2 once they are pain-free for another assessment (visit 3). In order to be pain-
free participants must rate their pain as 0 in response to Question 6 on Brief Pain 
Inventory – Short Form (SEE APPENDIX 2).  If after 30 days their score is still >0 in 
response to Question 6 on Brief Pain Inventory – Short Form then only their pain state 
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and post-intervention data will be used in analysis and will not be required for further 
follow-up.
The following assessments will be conducted in the order written:
!
Urine drug screen and alcohol breath test 
!
Brief Pain Inventory - short form (SEE APPENDIX 2)
!
Current/concomitant medication
!
Cognitive testing (Axon Sports and CANTAB cognitive assessment)
!
Mobility assessments (Gait, Time to standing, Grip Force)
!
Adverse events
!
Study conclusion/Medical sign-off
4
Sample Size Determination
This is an exploratory study, the sample size calculation is not based on any formal 
formulations. A sufficient number of subjects will be screened in order to randomize 
approximately 65 subjects to obtain 20 subjects per treatment group for a 5 week 
analysis.
5
Data Considerations
5.1
Analysis Populations
All Subject: The population of All Subjects includes all subjects that are screened for 
entry into the study.
Safety Population: Safety population will include subjects who are randomized and 
received at least one dose of study treatment.
Safety population summaries will be presented by actual treatment received.
Intent-to Treat Population (ITT):  ITT population will include subjects who are 
randomized, receive at least one dose of study treatment and provide at least one post-
baseline assessment of efficacy.
Modified Intent-to-Treat (mITT) Population: All the subjects those who are 
randomized, received at least one dose of study treatment and have at least one post-
baseline assessment without any violation of study inclusion-exclusion criteria will be 
included in the mITT population.
Primary population for efficacy assessment will be considered as mITT.
  
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All mITT population summaries and analyses will be presented by treatment 
randomized.
Efficacy analysis will be performed on the cognitive performance (as measured by 
individual scores from the Axon Sports Priming Application and each of the CANTAB 
tasks – RTI, OST, AST, SWM and RVP) and mobility (as measured by individual 
scores from gait, time to standing and grip force assessments) for mITT populations.
A blinded data review will be performed before database lock to identify protocol
violations (Important protocol are listed below). The protocol violations deemed to have 
potential to affect efficacy measures will lead to the exclusion of subjects from mITT
population or the exclusion of the affected data from mITT analysis. The review listings 
will include, but will not be necessarily limited to, the following:
!
Violations of Inclusion or Exclusion Criteria;
!
Current / Concomitant Medications;
!
Treatment Non-Compliance;
!
Protocol Deviations;
!
Visit schedule not followed as required in protocol, i.e.
Visit 2 (Pre-Treatment) (schedule or re-schedule) not within 7-28 days of Visit 1
Visit 2 (Post Treatment) – Same day within 45-75 (1 hr +/- 15 min ) minutes as     
Visit 2 (Pre Treatment), i.e. anything that is not fall within 45-75 (1 hr +/- 15 
min ) minutes should be listed.
Visit 3 (schedule or re-schedule) not within 2 - 30 days of Visit 2 
(NONCOMPLIANCE WITH VISIT SCHEDULE).
!
Subjects deviating from the protocol in any other major way, as determined by
blinded review of the CRF comments pages.
!
Listing of all efficacy variables falling outside Mean +/- 3 SD will be produced 
for each time points.
Details of blinded review listings will be given in the Review Listing Requirement
document. Protocol violations will be identified between the statistician and Clinical
Research Scientist or designee, ahead of study unblinding.
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5.2
Subgroups/Stratification
There will be four strata in this study based on pain type. Subject will be stratified 
according to the Pain Type (I.e. Joint, Back, Headache and Period).
Stratum 1: Person feels the pain in the knee or hip joint at baseline
Stratum 2: Person feels the pain in the upper or lower back at baseline 
Stratum 3: Person has headache at baseline
Stratum 4: Person (Female only) having menstrual period related pain at baseline
5.3
Time Windows
The study schedule should be followed as per protocol. Deviations from the study
schedule with respect to visit timings will be reviewed on a case-by-case basis. Required 
time windows are presented in Section 5.1.
6
Demographics and Baseline Characteristics
6.1
Subject Disposition
The subject disposition summary will present the number of screened subjects, the 
number of screening failures and the number of subjects randomized. The number and 
percentage of subjects, in the Safety and mITT populations will also be presented with 
percentages based upon the total number of subjects randomized.
The number and percentage of subjects completing the study and not completing the 
study, including a breakdown of the reasons for not completing the study, will also be 
presented with percentages based upon the total number of subjects randomized.
A separate summary table of major protocol violations will be produced indicating the
number and percentage of subjects with each violation. Percentages will be based on the 
mITT population
6.2
Demographics
Descriptive statistics (number of subjects, mean, and standard deviation, median, 
minimum and maximum for continuous variables, and frequency and percentage for 
categorical variables) will be provided for demographic data. These data include age, 
gender, race and BMI, and will be presented for the Safety and mITT population.
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6.3
Baseline Characteristics
Number and percentage of subjects in each stratum (stratified by pain type) will be 
summarized by treatment group and will be presented for the Safety and mITT 
population. 
7
Treatment Compliance and Concomitant Medications
7.1
Treatment Compliance
Assessment of treatment compliance will be based on comments reported on the CRF 
comments page. Treatment compliance will be reviewed during blinded review and a 
listing will be produced for evaluation of protocol violations only. Treatment 
compliance will be neither tabulated nor listed. However Treatment compliance will be 
checked during blinded review.
7.2
Concomitant Medications
A listing of concomitant medications will be produced.
8
Efficacy Analysis
8.1 Determination of Efficacy Measure
8.1.1 Determination Cognitive Function Assessments:
!
Axon Sports: The Axon Sports Priming Application is a computerized test 
performed on a tablet device that measures cognitive performance, namely
psychomotor speed. The main outcome measure is simple reaction time (SRT)
(msec), error (msec) and error adjusted SRT (msec). Subject level change from 
pain-free state (Visit 3) in error adjusted SRT at pain state (Visit 2 [Pre-
treatment & Post treatment) will be used as efficacy variable.
!
Reaction Time (RTI): In this five-choice reaction time task the participant 
holds down a button at the bottom of the screen until a yellow spot appears in 
one of the five circles at the top of the screen. They must then release the button 
and touch inside the circle where the yellow spot appeared as quickly as they 
can. The key outcome measure for this task is median five-choice reaction time 
(the median duration between the onset of the stimulus and the release of the 
button. Calculated for correct, assessed trials where the stimulus could appear in 
any one of five locations). Subject level change from pain-free state (Visit 3) in 
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median five choice reaction time at pain state (Visit 2 [Pre-treatment & Post 
treatment) will be used as efficacy variable. 
!
One Touch Stockings (OTS): This task is a measure of executive function and 
takes approximately 10 minutes to complete. The participant is shown two 
displays containing three colored balls. The displays are presented in such a way 
that they can easily be perceived as stacks of colored balls held in stockings or 
socks suspended from a beam. This arrangement makes the 3-D concepts 
involved apparent to the participant, and fits with the verbal instructions. There 
is a row of numbered boxes along the bottom of the screen. The test 
administrator first demonstrates to the participant how to use the balls in the
lower display to copy the pattern in the upper display, and completes one
demonstration problem, where the solution requires one move. The participant 
must then complete three further problems, one each of two moves, three moves 
and four moves. Next the participant is shown further problems, and must work 
out in their head how many moves the solutions to these problems require, and 
then touch the appropriate box at the bottom of the screen to indicate their 
response. The main outcome variable is the OTS problems solved on first choice 
which is the number of assessment problems on which the first box choice made 
was correct. Subject level change from pain-free state (Visit 3) in number of 
assessment problems on which the first box choice made was correct at pain 
state (Visit 2 [Pre-treatment & Post treatment) will be used as efficacy variable.
!
Attention Switching Task (AST): This task is a measure of executive attention 
and takes approximately 8 minutes to complete. The test displays an arrow 
which can appear on either side of the screen (right or left) and can point in 
either direction (to the right or to the left). Each trial displays a cue at the top of 
the screen that indicates to the participant whether they have to press the right or 
left button according to the “side on which the arrow appeared” or the “direction 
in which the arrow was pointing”. Some trials display congruent stimuli (e.g. 
arrow on the right side of the screen pointing to the right) whereas other trials 
display incongruent stimuli which require a higher cognitive demand (e.g. arrow 
on the right side of the screen pointing to the left). The main outcome is the AST 
congruency cost (median; msec) which is the difference between the median 
latency of response (from stimulus appearance to button press) on the trials that 
were congruent versus the trials that were incongruent. It is calculated by 
subtracting the median congruent latency (in msec) from the median incongruent 
latency. This measure is complex in sense in that close to zero indicates less 
variation in latencies across congruent and incongruent trials. A positive score
indicates that the subject is faster on congruent trials and a negative score 
indicates that the subject is faster on incongruent trials.
!
Spatial Working Memory (SWM): This task is a measure of working memory 
and takes approximately 6-7 minutes to complete. The task involves a number of 
colored squares (boxes) being shown on the screen. The aim of this test is to find 
one blue token in each of a number of boxes by process of elimination and use 
these to fill up an empty column on the right hand side of the screen. The 
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number of boxes gradually increases up to a maximum of eight boxes to search 
and the color and position of the boxes change from trial to trial. The main 
outcome variable is the SWM between errors and is defined as times the subject 
revisits a box in which a token has previously been found. This is calculated for 
12 tokens.
!
Rapid Visual information Processing: This task measures attention and takes 
approximately 7 minutes to complete. A white box appears in the center of the 
computer screen, inside which digits, from 2 to 9, appear in a pseudo-random 
order, at the rate of 100 digits per minute. Participants are requested to detect 
target sequences of digits (for example, 2-4-6, 3-5-7, 4-6-8) and to register 
responses using the press pad. The main outcome variable is RVPA’ (Aprime) 
and it is the signal detection measure of sensitivity to the target, regardless of
response tendency (the expected range is 0.00 to 1.00; bad to good). In essence, 
this metric is a measure of how good the subject is at detecting target sequences.
8.1.2 Determination Mobility Function Assessments:
!
Gait: Subjects will perform a walking assessment in comfortable walking shoes 
(subjects own) to measure gait parameters (contact phase, stride length and 
walking speed over 5-10m for each foot). An athletic movement analysis system 
(Optojump, Microgate) will be utilized. Differences in contact phase (s), stride 
length (cm) and walking speed over 5-10m (meters/second) and their within-test 
variability will be analyzed between baseline (pain state), post-intervention and 
pain-free follow-up assessments. 
The system will be set up over a 15m length of track with only the 5-10m 
section measured and analyzed. Subjects will be instructed to walk the 15m 
length a minimum of 6 times (3 practice and a minimum of 3 test walks) always 
entering the 15m length with the same foot first. The foot (left or right) entering 
the 5-10m section first will be recorded by visual assessment of the Opto jump 
operator for the test walks. Test walks will be repeated until there are 3 walks in 
which the subject has entered the 5-10m section with the same foot first. 
Parameters will be averaged based on the 3 test walks in which this occurs.
!
Time to Standing: Time to standing provides a simple assessment of physical 
mobility. From a seated position with arms crossed so that the right hand is 
placed on the left shoulder and the left hand on the right shoulder, participants 
will stand to a fully erect stature in as short a time as possible. Time to standing 
will be derived from the force plate data and ground reaction force (GRF) during 
the movement analyzed using a force plate (AMTI) interfaced with a computer. 
Subjects will conduct the movement 3-times.
!
Grip Force: This task is a measure of grip strength. The subject holds the 
dynamometer in their dominant hand and the arm is swung from above the head 
to by the side of the body. If the dominant arm or hand is painful then the non-
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dominant hand will be used. Subjects will be instructed to assert maximum effort 
during the squeezing motion and maintain it for about 4 seconds using a 
metronome. Subjects will conduct the movement 4-times (1 practice effort and 3 
test efforts) and there will be a 1-minute recovery period between each effort. 
The handle of the dynamometer is adjusted if required - the base should rest on 
first metacarpal (heel of palm), while the handle should rest on middle of four 
fingers. The results from 3 test efforts will be recorded, with the average grip 
strength being used for data analysis.
8.2
Primary Efficacy Analysis
Subject level change from pain-free state (Visit 3) in cognition as measured by cognitive 
function assessment (CANTAB and Axon Sports) in the pain state (Visit 2 Pre-
treatment & Visit 2 Post treatment) will be considered as the primary efficacy variable.
Efficacy variable corresponding to the each cognitive function assessment and are as 
follow,
Reaction Time (RTI) – Subject level change from pain-free state in median five-choice
reaction time (RTIFMDRT) will be used as efficacy variable
Rapid Visual information Processing (RVP) – Subject level change from pain-free 
state in signal detection sensitivity to the target (RVPA) will be used as efficacy variable
Attention Switching Task (AST) – Subject level change from pain-free state in the 
AST congruency cost (median) (ASTCCMD) will be used as efficacy variable
Spatial Working Memory (SWM) – Subject level change from pain-free state in the 
SWM Between errors (SWMBE) will be used as efficacy variable
One Touch Stockings of Cambridge (OTS) – Subject level change from pain-free 
state in the number of assesments problems on which the first box choice made was 
correct (OTSPSFC) will be used as efficacy variable
Axon Sports Priming Application– Subject level change from pain-free state in error 
adjusted SRT will be used as efficacy variable.
Detailed descriptions for each assessment are presented in Section 8.1.1 of SAP.
A two-sided paired t-test will be used to analyse the primary efficacy endpoints that are 
not ‘time-related’ (RVP, SWM and OTS) For the ‘time-related’ variables (RTI, AST 
and Axon Sports), the non-parametric method using Wilcoxon Sign Rank test will be 
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employed at visit 2 Pre-treatment and visit 2 Post treatment. All tests will be two-sided 
with an alpha level of 0.05. The 95% CI and the p-value will also be presented.
The assumption of normality of residuals will be investigated and if violated, an 
appropriate data transformation or non-parametric method will be used. If there is the 
presence of an outlier influencing the residuals then this may be examined through a 
sensitivity analysis.
8.2
Secondary Efficacy Analysis
Gait:
For gait analysis, subject level change from pain-free state (Visit 3) in contact phase (s), 
stride length (cm) and walking speed assessments at pain state (Visit 2 pre-treatment & 
Visit 2 Post treatment) will be used as secondary efficacy variables. For each of these 
parameters the average of the 3 recorded test walks will be used to compute subject 
level assessment. If a subject is missing any test assessments, then data from the 
available assessments will be used to compute the average.
A two-sided paired t-test will be used to analyse the secondary efficacy endpoints stride 
length and Wilcoxon sign rank test will be used to analyse the secondary efficacy 
endpoints Contact phase (s) and walking speed at Visit 2 Pre-treatment and Visit 2 Post-
treatment.
For the parametric analysis, assumption of normality of residuals will be investigated 
and if violated, an appropriate data transformation or non-parametric method will be 
used. If there is the presence of an outlier influencing the residuals then this may be 
examined through a sensitivity analysis.
Time to standing:
For time to standing analysis, subject level change from pain-free state (Visit 3 -
Baseline) in time to standing (s) and ground reaction force (GRF) at pain state (Visit 2 
pre-treatment & Visit 2 Post treatment) will be used as secondary efficacy variables. For 
both of these parameters the average of the 3 recorded sit to stand tests will be used to 
compute subject level assessment. If a subject is missing any test assessments, then data 
from the available assessments will be used to compute the average.
A two-sided paired t-test will be used to analyse the secondary efficacy endpoints 
ground reaction force and Wilcoxon sign rank test will be used to analyse the secondary 
efficacy endpoints time to standing at Visit 2 Pre-treatment and Visit 2 Post-treatment.
For the parametric analysis, assumption of normality of residuals will be investigated 
and if violated, an appropriate data transformation or non-parametric method will be 
used. If there is the presence of an outlier influencing the residuals then this may be 
examined through a sensitivity analysis.
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Grip Force: 
For the grip force analysis, subject level change from pain-free state (Visit 3 -Baseline)
in grip force at pain state (Visit 2 pre-treatment & Visit 2 Post treatment) will be used as
secondary efficacy variables. For this parameter the mean of the three recorded grip 
force tests will be used to compute subject level assessment. If a subject is missing any
test assessments, then data from the available assessments will be used to compute the 
average.
A two-sided paired t-test will be used to analyse the secondary efficacy endpoints grip 
force at Visit 2 Pre-treatment and Visit 2 Post-treatment.
Assumption of normality of residuals will be investigated and if violated, an appropriate
data transformation or non-parametric method will be used. If there is the presence of an
outlier influencing the residuals then this may be examined through a sensitivity 
analysis.
9
Safety Analysis
The safety profile of the study treatments will be assessed with respect to adverse events 
(AEs). All safety data will be reported for the All Subject.
Non treatment-emergent adverse events (TEAEs) are defined as AEs occurring after 
providing written informed consent but prior to administration of study medication. 
Treatment emergent adverse events are defined as AEs that start during the treatment 
period after the first administration of the study medication.
The causality of TEAEs will be classified as related or unrelated. The intensity of 
TEAEs will be rated as mild, moderate, or severe.
All AEs will be reviewed by the Clinical Research Scientist or Designee prior to 
database freeze and will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
The following summary tables and listings will be presented by treatment group.
!
Listing of all AEs (including Non-treatment emergent)
!
Listing of Non Treatment-Emergent Adverse Events
!
Table of treatment emergent AEs by SOC and Preferred Term
!
Treatment emergent treatment related AEs by SOC and Preferred
Term
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!
Listing of serious AEs. (if there are none a null listing will be produced; If there 
are more than 5 treatment emergent serious AEs (SAEs) a table will be produced 
instead by SOC and PT)
!
Non-serious treatment emergent AEs by SOC and PT (only produced if there are 
more than 5 SAEs).
!
Listing of incidents (if there are none a null listing will be produced)
No inferential analyses will be performed to compare treatments with respect to safety.
All subjects screened will be included in the listing of AEs
10
Interim Analysis
No interim analyses are planned for this study.
11
Topline Summary
No topline summary is planned for this study.
12
Changes to Planned Analysis
This study is terminated early due to serious breaches of GCP guidelines observed 
during a GSKCH internal audit. The minimum requirement of 8 subject per strata was 
not met because of early termination so following exploratory analyses will not 
conducted as specified in the protocol.
1) Compare treatment effect for post treatment visit.
2) Correlation analysis between pain intensity with cognitive and mobility 
assessments for each pain type
13
References
Allen GJ, Hartl TL, Duffany S, Smith SF, VanHeest JL, Anderson JM, Hoffman 
JR, Kraemer WJ, Maresh CM. Cognitive and motor function after administration of 
hydrocodone bitartrate plus ibuprofen, ibuprofen alone, or placebo in healthy subjects 
with exercise-induced muscle damage: a randomized, repeated-dose, placebo-controlled 
study. Psychopharmacology (Berl), 2003; 166(3): 228-33. 
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Arnold LM, Goldenberg DL, Stanford SB, Lalonde JK, Sandhu HS, Keck PE Jr., Welge 
JA, Bishop F, Stanford KE, Hess EV, and Hudson JI.  Gabapentin in the Treatment of 
Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. 
Arthritis & Rheumatism, 2007; 56(4): 1336–1344.
Cleeland CS.  The Brief Pain Inventory User Guide; 2009.
For more references related to this study please refer section 11 of the protocol.
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Appendix 1 Study Schedule
Procedure
Visit 1
Screening
Min of 7-days and max. of 28-days
Visit 2
Pain-state assessment
Recovery Period (min of 2-days and max. 30-days)
Visit 3
Pre-
treatment 
Assessment
Post-treatment 
assessment
(1 hr ± 15 mins 
post dosing)
Pain-free 
assessment
Informed Consent
X
Demographics
X
GP name and contact details 
collected
X
GP Letter response 
reviewed if received1
X
Brief Pain Inventory – Short 
Form
X
X
X
X
Pain Recurrence 
Questionnaire
X
Pain State Question
X
X
General Medical History2
X
X
Current / Concomitant 
medication
X
X
X
X
Height and Weight 
measurements
X
Inclusion / Exclusion 
Criteria
X
X
Subject Eligibility
X
X
Physical Examination/ Vital 
Signs3
X
X
X
For women of child bearing 
potential: Pregnancy test
X
X
Urine drug screen and 
alcohol breath test
X
X
Cognitive testing (Axon 
Sports & CANTAB  Cog 
Assessment)4
X (Practice)5
X
X
X
Mobility assessments (Gait, 
Time to standing, Grip 
Force)
X (Practice)5
X
X
X
Stratification and 
Randomization to OTC 
medication
X
Supervised OTC medication 
given 
X
Adverse Events
X6
X
X
X
Study conclusion
X
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Proceed with completion of visit 2 unless GP letter response received advising against participation.
2. General Medical history and GP letter response if received.
3. The physical exam post-treatment assessment will be a brief physical exam 
4. The cognitive tests will be conducted in the following order at visit 2 and visit 3:  Axon Sports Priming Application, 
CANTAB battery (RTI, OTS, AST, SWM, and RVP)
5. COGNITIVE TESTING AND MOBILITY ASSESSMENTS AT VISIT 1 ARE PART OF FAMILIARIZATION 
TASKS
6. AES WILL BE COLLECTED FROM TIME OF SIGNATURE OF CONSENT FORM FOR ALL SUBJECTS WHO 
ARE ELIGIBLE AT ASSESSMENT FAMILIARIZATION STAGE (AFTER CONFIRMED ELIGIBILITY BUT 
PRIOR TO FAMILIARIZATION TASKS)
Appendix 2 List of Tables, Figures & Listings
Use following footnotes for treatment labels in all the TLFs wherever corresponding 
treatments are appearing:
Treatment 1: Panadol Extra Advance (500mg paracetamol +65mg caffeine)
Treatment 2: Panadol Advance (500mg paracetamol)
Placebo: Placebo to match Paracetamol 665mg- MFC51220B
Table No.
Table Title (including population)
Standard
Template
9.1.1
Subject Disposition ─ All Screened Subjects
X
9.1.2
Protocol Violations Deemed to Affect Efficacy 
─ ITT Population
X
9.2.1.1
Demographic Characteristics ─ Safety 
Population
X
9.2.1.2
Demographic Characteristics ─ mITT 
P
l ti
9.2.1.1
9.2.2.1
Baseline Stratification ─ Safety Population
App 3
9.2.2.2
Baseline Stratification ─ mITT Population
9.2.2.1
9.3.1.1
Summary Statistics of Pain intensity ─ mITT 
Population
App 3
9.3.1.2
Summary Statistics of  Pain intensity for each 
Pain Type ─ mITT Population
9.3.1.1
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9.3.1.3
Summary Statistics of Cognitive function 
assessment ─ mITT Population
App 3
9.3.1.4
Summary Statistics of Cognitive function 
assessment for each Pain Type ─ mITT
Population
9.3.1.5
Statistical Analysis of Cognitive function from 
Pain free assessment ─ mITT Population
App 3
9.3.1.6
Statistical Analysis of Cognitive function from 
Pain state (V2 Pre-treatment) assessment ─
mITT Population.
9.3.1.5
9.3.1.7
Summary Statistics of  Pain intensity ─ mITT
Population
9.3.1.1
9.3.1.8
Summary Statistics of  Pain intensity for each 
Pain Type ─ mITT Population
9.3.1.1
9.3.2.1
Summary Statistics of  Mobility function 
assessment ─ mITT Population
9.3.1.3
9.3.2.2
Summary Statistics of  Mobility function 
assessment for each Pain Type ─ mITT
9.3.1.3
9.3.2.3
Statistical Analysis of Mobility function from 
Pain free assessment ─ mITT Population
9.3.1.5
9.3.2.4
Statistical Analysis of Mobility function from 
Pain state (V2 Pre-treatment) assessment ─ 
mITT Population
9.3.1.2
9.4.1
Listing of Adverse Events ─ Safety Population
X
9.4.2
Listing of Non Treatment-Emergent Adverse 
Events ─ Safety Population
X
9.4.3
Treatment Emergent Adverse Events by SOC 
and PT ─ Safety Population
X
9.4.4
Treatment Emergent Treatment Related 
Adverse Events by SOC and PT ─ Safety 
Population
X
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9.4.5
Listing of incidents (Note-if there are none a 
null listing will be produced) ─ Safety 
Population
X
9.4.6
Listing of Adverse Events ─All Subjects 
X
9.4.7**
Listing of Serious Adverse Events ─ Safety 
Population
X
9.4.8**
Listing of Serious Adverse Events ─All 
Subjects 
X
9.4.9***
Table of non-serious AEs by SOC and PT ─ 
Safety Population
X
**If there are none, a null listing will be produced.  If there are more than 5 SAEs a 
table will be produced by SOC and Preferred Term. 
*** Only produced if there are > 5 Non SAE’s
Figure 
Number
Figure Title
Template
9.1.1
Axon Sports (error Adjusted Simple reaction time) by Time 
and Treatment – mITT Population
App 3
9.1.2
Reaction Time by Time and Treatment – mITT Population
9.1.1
9.1.3
Rapid Visual information Processing (RVP) by Time and 
Treatment – mITT Population
9.1.1
9.1.4
Attention Switching Task (AST) by Time and Treatment –
mITT Population
9.1.1
9.1.5
Spatial Working Memory (SWM) by Time and Treatment –
mITT Population
9.1.1
9.1.6
One Touch Stockings of Cambridge (OTS) by Time and 
Treatment – mITT Population
9.1.1
9.1.7
Gait score [contact phase] by Time and Treatment  – mITT
Population
9.1.1
9.1.8
Gait score [Stride phase] by Time and Treatment  – mITT
Population
9.1.1
9.1.9
Gait score [Walking Speed] by Time and Treatment  – mITT
Population
9.1.1
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9.1.10
Time to Standing [Time to standing] by Time and Treatment  
– mITT Population
9.1.1
9.1.11
Time to standing [Ground reaction force] by Time and 
Treatment  – mITT Population
9.1.1
9.1.12
Grip Force [Walking Speed] by Time and Treatment  –
mITT Population
9.1.1
9.2.1
Scatter plot of pain intensity Vs Axon Sports (error Adjusted 
Simple reaction time) by Visit– mITT Population
App 3
9.2.2
Scatter plot of pain intensity Vs Reaction Time by Visit –
mITT Population
9.2.1
9.2.3
Scatter plot of pain intensity Vs Rapid Visual information 
Processing by Visit – mITT Population
9.2.1
9.2.4
Scatter plot of pain intensity Vs Attention Switching Task by 
Visit – mITT Population
9.2.1
9.2.5
Scatter plot of pain intensity Vs Spatial Working Memory by 
Visit – mITT Population
9.2.1
9.2.6
Scatter plot of pain intensity Vs One Touch Stockings of 
Cambridge by Visit – mITT Population
9.2.1
Listing 
No.
Listing Title
Standard
Template
2.1
Randomization Details – All Randomized
Subjects
X
2.2
Previous and Concomitant Medication ─
Safety Population
X
2.3
Subject Disposition – All Randomized 
Subjects
App 3
2.4
Data listing Cantab Assessments –All 
randomized subjects
App 3
2.5
Data listing Mobility Assessments – All 
randomized subjects
2.4
2.6 
Brief pain inventory (BPI) listings- All 
randomized subjects
App 3
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Appendix 3 Templates for Tables, Figures & Listings
Protocol: 204503                                                                                                    Program Run Date: DDMMMYYYY
Table 9.2.2.1
Visit 2 (Pre-treatment) pain state Stratification
Safety Population
Study Population: Safety Population (N=XXX)
_________________________________________________________________________________________________________________________________________________
                                               Treatment 1           Treatment 2           Placebo 
Overall 
                                                 (N = XXX)           (N = XXX)             (N = XXX)         
(N=XXX)   
                                                  N (%)                N (%)               N (%)            
N (%)
     Mean (SD)
  Mean (SD)
      Mean (SD)
Mean (SD)
_________________________________________________________________________________________________________________________________________________
VISIT 2 (PRE-TREATMENT) PAIN TYPE
KNEE OR HIP JOINT                                 XX (XX.X)           XX (XX.X)         XX (XX.X)          XX (XX.X)
    XX.XX (XX.XXX)        XX.XX (XX.XXX)      XX.XX (XX.XXX)     XX.XX (XX.XXX)
UPPER OR LOWER BACK                              XX (XX.X)           XX (XX.X)         XX (XX.X)          XX (XX.X)   
    
     XX.XX (XX.XXX)        XX.XX (XX.XXX)      XX.XX (XX.XXX)     XX.XX (XX.XXX)
                                                 
HEADACHE                                         XX (XX.X)           XX (XX.X)         XX (XX.X)          XX (XX.X)
     XX.XX (XX.XXX)        XX.XX (XX.XXX)      XX.XX (XX.XXX)     XX.XX (XX.XXX)
PERIOD
        XX (XX.X)           XX (XX.X)         XX (XX.X)          XX (XX.X)
   XX.XX (XX.XXX)        XX.XX (XX.XXX)      XX.XX (XX.XXX)     XX.XX (XX.XXX)
_________________________________________________________________________________________________________________________________________________
                                                                                                                                    (Page X of Y)
1] Mean and standard deviation were computed on pain intensity based on Visit 2 pre-treatment.
                                                            
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Protocol: 204503                                                                                                     Program Run Date: DDMMMYYYY
Table 9.3.1.1
Summary Statistics of Pain intensity
Modified Intent to Treat Population
Study Population: Intent to Treat (N=XXX)
________________________________________________________________________________________________________________________________________________
  Treatment 1                Treatment 2                 Placebo                  Overall
     (N=XX)                    (N=XX)                  (N=XX)                     (N=XX)                                                
_______________________________________________________________________________________________________________________________
VISIT 2 (PRE TREATMENT)
  N (NON-MISSING)           XXX                       XXX          
          XXX                       XXX
  MEAN                       X.XX                      X.XX                     X.XX                      X.XX
  SD                         X.XXX                     X.XXX                   X.XXX                     X.XXX
  SE                         X.XXX                     X.XXX                   X.XXX                     X.XXX
  MEDIAN                     X.XX                      X.XX                     X.XX                     X.XX
  MINIMUM                    X.X                       X.X                      X.X                       X.X
  MAXIMUM                    X.X                       X.X                      X.X                       X.X   
....
VISIT 2 (POST TREATMENT) 
  
  N (NON-MISSING)            XXX                       XXX                      XXX
  MEAN                       X.XX                      X.XX                     X.XX
  SD                         X.XXX                     X.XX                     X.XXX
  SE                         X.XXX                     X.XXX                    X.XXX 
  MEDIAN                     X.XX                      X.XX                     X.XX  
  MINIMUM                    X.X                       X.XX                     X.X     
  MAXIMUM                    X.X                       X.XX                      X.X 
  
VISIT 3 (PAIN FREE STATE) (SAME AS POST TREATMENT)
_________________________________________________________________________________________________________________________________________________
                                                                                                                         (Page X of Y)
(NOTE TO PROGRAMMER: 1. OVERALL IS ONLY POPULATED FOR VISIT 2 (PRE TREATMENT) 2. FOR TABLE 9.3.1.2 AND 9.3.1.8 SIMILAR SUMMARY NEED TO BE PRODCUED FOR EACH 
PAIN TYPE)
                                                            
   
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Protocol: 204503                                                                                                     Program Run Date: DDMMMYYYY
Table 9.3.1.3
Summary Statistics of Cognitive function assessment
Modified Intent to Treat Population
Study Population: Intent to Treat (N=XXX)
________________________________________________________________________________________________________________________________________________
  Treatment 1                Treatment 2                 Placebo                  Overall
     (N=XX)                    (N=XX)                  (N=XX)                     (N=XX)                                                
_______________________________________________________________________________________________________________________________
AXON SPORTS
VISIT 2 (PRE TREATMENT)
  N (NON-MISSING)           XXX                       XXX          
          XXX                       XXX
  MEAN                       X.XX                      X.XX                     X.XX                      X.XX
  SD                         X.XXX                     X.XXX                   X.XXX                     X.XXX
  SE                         X.XXX                    X.XXX                   X.XXX                     X.XXX
  MEDIAN                     X.XX                      X.XX                     X.XX                     X.XX
  MINIMUM                    X.X                       X.X                      X.X                       X.X
  MAXIMUM                    X.X                       X.X                      X.X                       X.X   
....
VISIT 2 (POST TREATMENT)
  
  N (NON-MISSING)            XXX                       XXX                      XXX
  MEAN                       X.XX                      X.XX                     X.XX
  SD                         X.XXX                     X.XX                     X.XXX
  SE                         X.XXX                     X.XXX                    X.XXX 
  MEDIAN                     X.XX                      X.XX                     X.XX  
  MINIMUM                    X.X                       X.XX                     X.X     
  MAXIMUM                    X.X                       X.XX                      X.X 
  
VISIT 3 (PAIN FREE STATE) (SAME AS POST TREATMENT)
REACTION TIME
(SAME LAYOUT AS AXON SPORTS)
....
ONE TOUCH STOCKINGS
(SAME LAYOUT AS AXON SPORTS)
....
ATTENTION SWITCHING TASK
(SAME LAYOUT AS AXON SPORTS)
  ....
SPATIAL WORKING MEMORY
(SAME LAYOUT AS AXON SPORTS)
....
RAPID VISUAL INFORMATION PROCESSING
(SAME LAYOUT AS AXON SPORTS)
    
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....
_________________________________________________________________________________________________________________________________________________
                                                                                                                        (Page X of Y)
(NOTE TO PROGRAMMER: 1. OVERALL IS ONLY POPULATED FOR VISIT 2 (PRE TREATMENT) 2. FOR TABLE 9.3.1.4, 9.3.1.10, 9.3.2.2 AND 9.3.2.6 SIMILAR TABLES NEED TO BE 
PRODCUED FOR EACH PAIN TYPE)
                                                            
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Protocol: 204403                                                                                                Program Run Date: DDMMMYYYY
Table 9.3.1.5
Statistical Analysis of Cognitive function from Pain free assessment
Modified Intent to Treat Population
Study Population: Intent to Treat (N=XXX)                      
Treatment 1
(N=XX)
Change from Baseline
Treatment 2                        
  (N=XX)
Change from Baseline
   Placebo
   (N=XX)
Change from Baseline
AXON SPORT
VISIT 2 (PRE TREATMENT)
N
XX
XX
XX
MISSING
XX
XX
XX
MEAN
X.XX
X.XX
X.XX
SD
X.XXX
X.XXX
X.XXX
SE
X.XXX
X.XXX
X.XXX
MEDIAN
X.XX
X.XX
X.XX
MINIMUM
XX
XX
XX
MAXIMUM
XX
XX
XX
Test statistics [1]
XX.XX
    XX.XX
XX.XX
95% CIs [1]
(X.XX,X.XX)
(X.XX,X.XX)
(X.XX, X.XX)
P-VALUE [1]
0.XXXX
0.XXXX
0.XXXX
VISIT 2(POST TREATMENT) 
(SAME AS PRE-TREATMENT) 
.....
REACTION TIME
(SAME LAYOUT AS AXON
SPORTS)
....
ONE TOUCH STOCKINGS
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(SAME LAYOUT AS AXON
SPORTS)
....
ATTENTION SWITCHING TASK
(SAME LAYOUT AS AXON 
SPORTS)
  ....
SPATIAL WORKING MEMORY
(SAME LAYOUT AS AXON
SPORTS)
....
RAPID VISUAL INFORMATION 
PROCESSING
(SAME LAYOUT AS AXON
SPORTS)
....
[1] From two sided paired t test for changes from baseline (Visit 3 Pain Free State).
                                                            
Programming note: 
[1] For time related cognitive (AST, RTI & Axon Sports) and mobility assessments (Gait [contact phase and walking Speed], Time to standing) footnote 1 will be 
changed to:
       From two sided signed rank test for changes from baseline (Visit 3 Pain Free State).
[2] Table 9.3.2.3– include statistical analysis of mobility parameter Gait [Stride length, Contact phase and walking speed], Time to Standing [Time to standing 
and Ground reaction force] and Grip Force for mITT population.
[3] For Table 9.3.1.6, 9.3.1.10, 9.3.2.4:
a) Please use the same format of the able. These tables will have output for only Visit 2(Post treatment). 
b) Footnote non time related assessments will changed to 
[1] From two sided paired t test for changes from baseline (Visit 2 Pre-treatment Pain state)
For time related assessments it will be 
[1] From two sided signed rank test for changes from baseline (Visit 2 Pre-treatment Pain state)
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Protocol: 204503                                                                                                    Program Run Date: DDMMMYYYY
Figure 9.1.1
Axon Sports (error Adjusted Simple reaction time) by Time and Treatment (Raw Mean ± SE)
Modified Intent to Treat Population
________________________________________________________________________________________________________________________________________________
0
1
2
3
4
5
6
0
1
2
3
Axon Sport eSRT(ms)
Study Visit
Treatment 1
Treatment 2
Placebo
Pain state (V2 Pre)            Pain state (V2 Post)                                                                              Pain Free 
________________________________________________________________________________________________________________________________________________
Values are Raw mean ± SE
V2 Pre - Visit 2 Pre Treatment   V2 Post - Visit 2 Pre Treatment   V3 - Visit 3 
(Note to programmer: (1) Use different symbols and line-styles for three treatments. (2) (1) Add ‘Pain state (V2 Pre)’, ‘Pain state (V2 Post)’ and                                     
‘Pain Free (V3)’ to X-axis.
                                                            
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Protocol: 204503                                                                                                    Program Run Date: DDMMMYYYY
Figure 9.2.1
Scatter plot of pain intensity Vs Axon Sports (error Adjusted Simple reaction time) by Time 
Modified Intent to Treat Population
________________________________________________________________________________________________________________________________________________
0
0.5
1
1.5
2
2.5
3
0
2
4
6
8
10
Axon Sport  eSRT (ms)
Pain Intensity
Pre treatment
Treatment 1
Treatment 2
Placebo
0
0.5
1
1.5
2
2.5
3
0
2
4
6
8
10
Axon Sport  eSRT (ms)
Pain Intensity
Post treatment
Treatment 1
Treatment 2
Placebo
________________________________________________________________________________________________________________________________________________
(Note to programmer: (1) Create similar scatter plot for remaining cognitive assessments. (2) Use different symbols and colour for three treatments.
                                                            
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Protocol: 204503
Program Run Date: DDMMMYYYY
Data Listing 2.3
Subject Disposition
All Randomized Subjects
Center/
Subject
Age/
Sex/
Race
Screening
date
Randomization
Date
     Treatment
Start/End of
treatment
Completion/
discontinuation
date
Treatment
completer? #
Subject
completed? $
If applicable,
reason for
discontinuation
Sex: F= Female; M= Male.
Race: AMI=American Indian or Alaska Native; ASN= Asian; BLK= Black or African American; HAW= Native Hawaiian or other Pacific Islander; MUR= Multi-racial; 
OTH= Other; WHT= White.
# A subject is considered 'treatment completer' after completion of the Visit 2 pre-treatment dosing.
$ A subject is considered completed after completion of the Visit 3 assessments. A subject who withdraws study treatment prematurely and who completes the 
end of study assessments is considered completed but not 'treatment completer'.
          Page 1 of 5
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Protocol: 204503
Program Run Date: DDMMMYYYY
Data Listing 2.4
Cantab Assessments
All Randomized Subjects
Endpoint
Assessment Variable 
     Subject ID 
Visit 
Treatment
Actual Value
Actual values are based on subject level assessment.
                                                                                                                                                Page 1 of 5
Programming note: 1) For Cantab Endpoint – Assesment variable are median five-choice reaction time (RTIFMDRT), Signal detection sensitivity to the target 
(RVPA), AST congruency cost (median) (ASTCCMD), SWM Between errors (SWMBE), The number of assessments problems on which the first box choice made was correct 
(OTSPSFC), Error adjusted SRT for RTI, RVP, AST, SWM, OTS and Axon sports respectively.
2)
Please create a same data listing (2.5) For Mobility Endpoint Gait [Stride length, Contact phase and walking speed], Time to Standing [Time to 
standing and Ground reaction force] and Grip force
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Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
30-Mar-2017 09:00:40
eldo_clinical_doc
1.0; CURRENT; Most-Recent; Effective
SAP 204503
Auto Issue
090032d580d1b8a1
3DJH  RI 



Protocol: 204503
Program Run Date: DDMMMYYYY
Data Listing 2.6
Brief pain inventory (BPI) 
All Randomized Subjects
Subject ID 
Treatment
  Visit 1
(Screening)
  Visit 2
(Pre-Treatment)
  Visit 2
(Pre-Treatment)
Visit 3
(Pain Free)
Actual values are based on subject level assessment.
                                                                                                                                                Page 1 of 5
3DJH  RI 
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
30-Mar-2017 09:00:40
eldo_clinical_doc
1.0; CURRENT; Most-Recent; Effective
SAP 204503
Auto Issue
090032d580d1b8a1
3DJH  RI 



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Biostatistics Approval
clinical research approval
30-Mar-2017 08:58:53
SAP 204503
29-Mar-2017 10:43:01
3DJHRI
Document Name 
 
Type 
Version 
Document Identifier 
Effective Date 
 
 
 
 
Reason For Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

30-Mar-2017 09:00:40
eldo_clinical_doc
1.0; CURRENT; Most-Recent; Effective
SAP 204503
Auto Issue
090032d580d1b8a1
3DJHRI


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