Clinical trial NCT04052620
Conditions: Pain
Keywords: Ankle sprain diclofenac diethylamine
Sponsor: GlaxoSmithKline
Start date: 2019-10-24; Completion date: 2020-11-12
Enrollment: 313 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of diclofenac diethylamine 2.32 percent (%) gel applied twice daily versus diclofenac diethylamine 1.16% gel applied four times daily for 7 days in participants with acute ankle sprain.

Detailed description:
This study is a Phase III, randomized, double blind, multi-center, active controlled, 2-treatment arm, parallel group, non-inferiority study to evaluate the efficacy and safety of diclofenac diethylamine 2.32% gel applied twice daily versus diclofenac diethylamine 1.16% gel applied four times daily for 7 days in participants with acute ankle sprain. The participants who experience an acute Grade I -II ankle sprain within the past 24 hours, and pain on movement of at least 50 millimeter (mm) on a 100 mm visual analogue scale (VAS) and who will meet all inclusion and exclusion criteria will be randomized in a 1:1 ratio, immediately post injury. All participants will receive 4 tubes of study drug, for treatment in morning, noon, late afternoon, and late evening, respectively. The very first dose of study drug will be applied at the study center. The participants will be instructed to apply the gel topically with the finger tips for approximately 1 minute in the morning, at noon, late afternoon, and late evening for 7 days. Each tube will be labeled for use at one of these 4 times. After the randomization visit (Visit 1/baseline visit- Day 1), participants will return to the study site for post baseline visits- Visit 2 (Day 3), Visit 3 (Day 5), and Visit 4 (Day 8 +/- 1 d) to complete efficacy and safety assessments. Baseline safety laboratory test blood samples will be taken at Visit 1. End of study safety laboratory tests will be performed at Visit 4, or in case of early termination on the day of termination. In addition, the participants (ex-clinic) will assess pain intensity and pain relief at frequent intervals on Day 1 and then at each study drug application throughout the rest of the study.

Arms: arm 1: Participants will receive 4 tubes, DDEA 2.32% gel and Placebo gel (2 each) and instructed to apply the gel 5 centimeter (cm) topically with the finger tips (for approximately 1 minute) on both sides of affected ankle on area of approximately 200 square centimeters (cm\^2). DDEA 2.32% gel will be applied in morning and late afternoon and Placebo gel will be applied in noon and late evening for 7 days. arm 2: Participants will receive 4 tubes of DDEA 1.16% gel and instructed to apply the gel 5 centimeter (cm) topically with the finger tips (for approximately 1 minute) on both sides of affected ankle on area of approximately 200 square centimeters (cm\^2) in morning, noon, late afternoon, and late evening for 7 days.
Interventions: intervention 1: Diclofenac diethylamine 2.32% gel intervention 2: Diclofenac diethylamine 1.16% gel intervention 3: Placebo
Intervention descriptions: intervention 1: Participants will apply DDEA 2.32% gel topically with the finger tips (for approximately 1 minute) on both sides of affected ankle 5 cm on 200 cm\^2 two times daily for 7 days. intervention 2: Participants will apply DDEA 1.16 % gel topically with the finger tips (for approximately 1 minute) on both sides of affected ankle 5 cm on 200 cm\^2 four times daily for 7 days. intervention 3: Participants will apply Placebo gel topically with the finger tips (for approximately 1 minute) on both sides of affected ankle 5 cm on 200 cm\^2 two times daily for 7 days.

Protocol documents:
Prot_000.pdf: 
Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial
Ma y n ot be use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of G S K C H
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 1  of 6 4
C LI NI C A L P R O T O C O L
A r a n d o mi z e d, d o u bl e bli n d, m ulti c e nt er, a cti v e- c o ntr oll e d, 2 
tr e at m e nt ar m, p ar all el gr o u p n o n i nf eri orit y st u d y t o e v al u at e t h e 
effi c a c y a n d s af et y of di cl of e n a c di et h yl a mi n e 2. 3 2 % g el a p pli e d 
t wi c e d ail y v er s u s di cl of e n a c di et h yl a mi n e 1. 1 6 % g el a p pli e d f o ur 
ti m e s d ail y f or o n e w e e k i n s u bj e ct s wit h a c ut e a n kl e s pr ai n
Pr ot o c ol N u m b er:
2 1 1 2 0 6
C o m p o u n d/ Pr o d u ct N a m e:
Di cl of e n a c Di et h yl a mi n e 2. 3 2 %
U nit e d St at e s ( U S) I n v e sti g ati o n al 
N e w Dr u g (I N D) N u m b er:
N A
E ur o p e a n Cli ni c al Tri al s D at a b a s e 
( E u dr a C T) N u m b er:
N A
Ot h er R e g ul at or y A g e n c y I d e ntifi e d 
N u m b er:
N ati o n al M e di c al Pr o d u ct s A d mi ni str ati o n 
( N M P A) N u m b er _ 2 0 1 6 L 0 9 8 7 5
P h a s e:
P h a s e III
S p o n s or I nf or m ati o n
S p o n s or N a m e & L e g al 
R e gi st er e d A d dr e s s
G S K C o n s u m er H e alt h c ar e S c h w ei z A G
6 3 4 3 Ri s c h
S wit z erl a n d
S p o n s or C o nt a ct D et ail s
Gl a x o S mit h Kli n e C o n s u m er H e alt h c ar e ( C hi n a) 
C o, Lt d
8 F, T h e H e a d q u art er s b uil di n g, N o. 1 6 8 Ti b et 
R o a d ( M), S h a n g h ai, C hi n a, 2 0 0 0 0 1,
T el: 
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
T his d oc u me nt c o ntai ns c o nfi de ntialit y state me nts t hat are n ot rele va nt f or t his p u blicl y
a vaila ble versi o n
P P D


Diclofenac Diethylamine 2.32%
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Document History
Document
Version
Summary of Changes 
Original protocol
1.0
Not applicable (N/A)
Amendment 1
1.0
Refer to Summary of Changes document
Amendments incorporate all revisions to date, including amendments made at the request of 
country health authorities, institutional review boards/ethics committees (IRBs/ECs), etc.  
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Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 3  of 6 4
Pri n ci p al I n v e sti g at or Pr ot o c ol A gr e e m e nt P a g e

I c o nfir m a gree me nt t o c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a n d a n y 
a me n d me nts acc or di n g t o t he c urre nt I nter nati o nal C o nfere nce o n Har m o nisati o n G o o d 
Cli nical Practice (I C H G C P) g ui deli nes.

I ac k n o wle d ge t hat I a m res p o nsi ble f or o verall st u d y c o n d uct. I a gree t o pers o nall y 
c o n d uct or s u per vise t he descri be d st u d y.

I a gree t o e ns ure t hat all ass ociates, c ollea g ues a n d e m pl o yees assisti n g i n t he c o n d uct of 
t he st u d y are i nf or me d a b o ut t heir o bli gati o ns. Mec ha nis ms are i n place t o e ns ure site staff 
recei ves all a p pr o priate i nf or mati o n t hr o u g h o ut t he st u d y.

I a gree t o c o n d uct t his st u d y i n f ull c o nf or ma nce wit h t he la ws a n d re g ulati o ns of t he 
c o u ntr y i n w hic h t he researc h is c o n d ucte d a n d t he Declarati o n of Helsi n ki.
I n vesti gat or Na me:
I n vesti gat or Q ualificati o ns:
I n vesti gat or Si g nat ure:
Date of Si g nat ure/ A gree me nt:
D D- M m m- Y Y Y Y
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
P P D


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Table of Contents
Sponsor Information ............................................................................................................1
Document History................................................................................................................2
Principal Investigator Protocol Agreement Page.................................................................3
Table of Contents.................................................................................................................4
1
PROTOCOL SUMMARY...................................................................................................9
1.1
Schedule of Activities............................................................................................13
2
INTRODUCTION .............................................................................................................15
2.1
Study Rationale......................................................................................................15
2.2
Background............................................................................................................16
2.3
Mechanism of Action/Indication ...........................................................................17
3
STUDY OBJECTIVES AND ENDPOINTS.....................................................................17
4
STUDY DESIGN ..............................................................................................................18
4.1
Overall Design .......................................................................................................18
4.2
Rationale for Study Design....................................................................................19
4.3
Justification for Dose .............................................................................................20
4.4
End of Study Definition.........................................................................................20
5
STUDY POPULATION....................................................................................................20
5.1
Type and Planned Number of Subjects..................................................................20
5.2
Inclusion Criteria....................................................................................................21
5.3
Exclusion Criteria ..................................................................................................21
5.4
Randomization Criteria..........................................................................................22
5.5
Lifestyle Considerations ........................................................................................23
5.5.1
Meals and Dietary Restrictions .............................................................23
5.5.2
Alcohol, Caffeine and Tobacco.............................................................23
5.5.3
Activity..................................................................................................23
5.5.4
Contraception ........................................................................................23
5.6
Screen Failures.......................................................................................................24
5.7
Sponsor’s Qualified Medical Personnel.................................................................24
6
INVESTIGATIONAL/STUDY PRODUCTS...................................................................24
6.1
Investigational/Study Product Supplies .................................................................25
6.1.1
Dosage Form and Packaging:................................................................26
6.1.2
Preparation and Dispensing...................................................................27
6.2
Administration .......................................................................................................27
6.2.1
Medication/Dosing Errors .....................................................................28
6.3
Investigational/Study Product Storage...................................................................28
6.4
Investigational/Study Product Accountability .......................................................29
6.4.1
Destruction of Investigational/Study Product Supplies.........................29
6.5
Blinding and Allocation/Randomization ...............................................................29
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6.6
Breaking the Blind .................................................................................................30
6.7
Subject Compliance ...............................................................................................31
6.8
Subject Diary..........................................................................................................31
6.9
Concomitant Medication/Treatment(s)..................................................................32
6.10
Rescue Medication.................................................................................................33
7
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .........................................................................33
7.1
Subject Discontinuation/Withdrawal.....................................................................33
7.2
Lost to Follow up...................................................................................................33
8
STUDY PROCEDURES...................................................................................................34
8.1
Visit 1/Screening / Randomization Visit ...............................................................34
8.1.1
Informed Consent..................................................................................34
8.1.2
Demographics........................................................................................35
8.1.3
Inclusion/Exclusion Criteria..................................................................35
8.1.4
Medical History and Prior Medication/Treatment ................................35
8.1.5
Subject Eligibility..................................................................................35
8.1.6
Screening/Randomization Procedures...................................................35
8.2
Study Period...........................................................................................................36
8.2.1
Visit 2/Day 3..........................................................................................36
8.2.2
Visit 3/Day 5..........................................................................................37
8.2.3
Visit 4 /Day 8 ± 1 ..................................................................................37
8.3
Study Conclusion...................................................................................................38
8.4
Follow-up Visit / “Phone Call”..............................................................................38
9
STUDY ASSESSMENTS .................................................................................................38
9.1
Screening Assessments ..........................................................................................38
9.2
Efficacy Assessments.............................................................................................38
9.2.1
Ankle Swelling......................................................................................39
9.2.2
Pain on Movement.................................................................................39
9.2.3
Tenderness.............................................................................................39
9.2.4
Ankle Joint Function .............................................................................40
9.2.5
Diary Pain Intensity and Pain Relief Assessments................................40
9.3
Safety and Other Assessments...............................................................................40
9.3.1
Laboratory Tests....................................................................................41
9.3.2
Pregnancy Testing .................................................................................41
9.3.3
Physical Examinations...........................................................................42
9.3.4
Height and Weight.................................................................................42
9.3.5
Vital Signs (Blood Pressure and Pulse Rate) ........................................42
9.4
Blood Volume........................................................................................................43
10 ADVERSE EVENT AND SERIOUS ADVERSE EVENTS............................................43
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10.1
Definition of an Adverse Event (AE) ....................................................................43
10.2
Definition of a Serious Adverse Event (SAE) .......................................................44
10.3
Reporting of Adverse Events.................................................................................45
10.3.1
Reporting Period....................................................................................45
10.4
Reporting Procedures.............................................................................................45
10.4.1
Reporting of an Adverse Event .............................................................46
10.4.2
Reporting of a Serious Adverse Event ..................................................46
10.5
Evaluating Adverse Events....................................................................................47
10.5.1
Assessment of Intensity.........................................................................47
10.5.2
Assessment of Causality........................................................................47
10.6
Follow-up of Adverse Events ................................................................................48
10.7
Withdrawal Due to an Adverse Event....................................................................48
10.7.1
Sponsor’s Reporting Requirements to Regulatory Authorities and 
Ethics Committees.................................................................................49
10.8
Pregnancy...............................................................................................................49
10.8.1
Time Period for Collecting Pregnancy Information..............................49
10.8.2
Action to be Taken if Pregnancy Occurs...............................................49
11 DATA MANAGEMENT ..................................................................................................49
11.1
Case Report Form ..................................................................................................50
11.2
Data Handling ........................................................................................................50
11.2.1
Data Queries..........................................................................................50
11.3
Processing Subject Reported Outcomes ................................................................51
12 STATISTICAL CONSIDERATIONS AND DATA ANALYSES...................................51
12.1
Sample Size Determination....................................................................................51
12.2
Statistical Methods and Analytical Plan ................................................................52
12.2.1
Definition of Analysis Populations .......................................................52
12.2.2
Exclusion of Data from Analysis ..........................................................52
12.2.3
Demographic and Baseline Characteristics...........................................52
12.2.4
Study Drug/Product Compliance and Use of Other Therapies .............53
12.2.5
Primary Analysis(es) .............................................................................53
12.2.6
Secondary Analysis(es) .........................................................................54
12.2.7
Safety Analysis(es)................................................................................55
12.2.8
Other Analysis(es).................................................................................55
12.2.9
Handling of Dropouts and Missing Data...............................................55
12.2.10
Interim Analysis ....................................................................................56
13 STUDY GOVERNANCE CONSIDERATIONS..............................................................56
13.1
Quality Control ......................................................................................................56
13.2
Quality Assurance..................................................................................................56
13.3
Regulatory and Ethical Considerations..................................................................57
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13.3.1
Institutional Review Board/ Ethics Committee.....................................57
13.3.2
Ethical Conduct of the Study.................................................................57
13.3.3
Subject Information and Consent..........................................................57
13.3.4
Subject Recruitment ..............................................................................57
13.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ...............................................................................................58
13.4
Posting of Information on Publicly Available Clinical Trial Registers.................58
13.5
Provision of Study Results to Investigators...........................................................58
13.6
Records Retention..................................................................................................58
13.7
Conditions for Terminating the Study ...................................................................59
14 REFERENCES ..................................................................................................................60
15 APPENDIX........................................................................................................................61
15.1
ABBREVIATIONS ...............................................................................................61
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List of in text tables
Treatment Schedule
10
Table 1-1
Schedule of Activities............................................................................13
Table 3-1
Study Objectives and Endpoints............................................................17
Table 4-1
Treatment Schedule...............................................................................18
Table 6-1
Investigational/Study Product Supplies.................................................25
Table 6-2
Rescue Medication Information ............................................................26
Table 6-3
Sundry Items..........................................................................................26
Table 9-1
Laboratory Tests....................................................................................41
Table 9-2
Blood Volume .......................................................................................43
Table 15-1
Abbreviation..........................................................................................62
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1
PROTOCOL SUMMARY 
Background and Rationale
Topical diclofenac products are well established globally for the treatment of pain and inflammation 
due to acute trauma as well as for the relief of pain associated with non-serious osteoarthritis (OA) 
of the peripheral joints e.g. knee and fingers. The originator product diclofenac diethylamine 
(DDEA) 1.16% gel (Voltarol Emulgel in the UK, and generic name of DDEA Emulgel was 
registered in China) was first registered in 1985 in Switzerland and Romania for use at a dose of 
2-4 g applied three to four times daily and is currently registered in over 130 countries of which 
over 80 countries market this product as over-the-counter (OTC).
As part of the global expansion for the product, China has been identified as a desirable market for 
registration of DDEA 2.32% gel. The identified registration pathway in China for the DDEA 2.32% 
gel is variation specifying addition of a new strength to the already registered DDEA 1.16% gel 
(License Number H20181225/H20181226, firstly issued on March 12, 2013), with the same 
indications as currently registered for DDEA 1.16% gel, i.e. for the relief of mild to moderate pain 
in muscles, soft tissues, and joints, e.g. muscles or soft tissue pains caused by sprain, pulling injury, 
contusions, strain, waist-back injury and various arthralgia etc, and for symptomatic treatment of 
osteoarthritis.
In support of the proposed registration, the National Medical Products Administration (NMPA) 
approved a clinical trial application (CTA) on November 06, 2016 (CTA No. 2016L09875). The 
approved CTA stipulated that a non-inferiority study assessing the efficacy and safety of the DDEA 
2.32% versus that of the registered DDEA 1.16% should be conducted in a local population.
To this effect, GSKCH intends to conduct a randomized, double blind, multi-center, active 
controlled, parallel group, non-inferiority study to evaluate the efficacy and safety of DDEA 2.32% 
gel applied twice daily versus DDEA 1.16% gel applied four times daily in subjects with ankle 
sprain in China.
Objectives and Endpoints
Objective(s)
Endpoint(s)
Primary
To demonstrate non-inferiority between DDEA 
2.32% and DDEA 1.16% with regard to pain 
relief after acute ankle sprain
Change from baseline in pain on movement 
(POM) on Day 5 of treatment as assessed by a 
100 mm VAS scale
Secondary
To assess safety of DDEA 1.16% and DDEA 
2.32% gels after 1 week of use
Number, incidence, and severity of adverse 
events following dosing with study medication
To assess efficacy of treatments for pain relief 
as measured by POM on Days 3 and 8
Change from baseline of POM on VAS on Day 3 
and Day 8 of treatment assessed by 100 mm 
VAS scale
To assess efficacy of treatments for 
inflammation of the affected ankle as measured 
by pressure algometry on Days 3, 5, and 8
Change from baseline in tenderness as 
measured by pressure algometry on Days 3,5, 
and 8
To assess efficacy of treatments for 
inflammation of the affected ankle as measured 
by pressure algometry on Days 3, 5, and 8
Difference between measurement in affected 
ankle and contralateral ankle on Days 3,5,and 8
To assess efficacy of treatments for ankle joint 
function as measured on the Karlsson Scoring 
Scale
Change from baseline in Ankle Joint Function 
(Karlsson Scoring Scale) on Days 3,5, and 8
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To assess efficacy of treatments for swelling of 
affected ankle as measured by Figure of Eight 
Method
Change from baseline in circumference of 
affected ankle as measured by Figure of Eight 
method on Days 3,5, and 8
To assess efficacy of treatments for swelling of 
affected ankle as measured by Figure of Eight 
method
Difference between circumference of affected 
ankle to unaffected ankle by Figure of Eight 
method on Days 3, 5, and 8
To assess efficacy of treatments for effect on 
pain intensity as measured by Sum of Pain 
Intensity Difference (SPID)
SPID from 0 – 24 hours post first dose (Day 1) 
and from 96 – 120 hours post first dose (Day 5)
To assess effect of treatments for effect on pain 
relief as measured by Total Pain Relief 
(TOTPAR)
TOTPAR from 0 – 24 hours post first dose (Day 
1) and from 96 – 120 hours post first dose (Day 
5)
To assess the use of rescue medication among 
subjects
Number of tablets used to treat ankle pain and 
overall
To assess the use of rescue medication among 
subjects
Number of days on which rescue medication 
was used to treat ankle pain and overall
Study Design
This is a Phase III, randomized, double blind, multi-center, active controlled, 2 treatment arm, 
parallel group, non-inferiority study to evaluate the efficacy and safety of diclofenac 
diethylamine 2.32% gel applied twice daily versus diclofenac diethylamine 1.16% gel applied 
four times daily for 1 week in subjects with acute ankle sprain.
To qualify, subjects must experience an acute Grade I -II sprain of the ankle within the past 24 
hours. Subjects should be randomized as soon as possible after the injury.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1 ratio to one of the following two treatment arms:
Treatment Schedule
Treatment Arms
Morning      
(Upon Rising)
Noon
Late Afternoon 
(evening)
Late Evening 
(bed time)
DDEA 2.32%   
four times daily
DDEA 2.32% gel
Placebo gel
DDEA 2.32% gel
Placebo gel
DDEA 1.16%  
four times daily
DDEA 1.16% gel
DDEA 1.16% gel
DDEA 1.16% gel
DDEA 1.16% gel
Approximately 300 subjects (150 in each group) with acute ankle sprain are to be randomized. 
All subjects will receive four (4) tubes of study drug, for treatment in morning, noon, late 
afternoon, and late evening, respectively. The very first dose of study drug will be applied at 
the study center. The subjects will be instructed to apply the gel topically with the finger tips 
(for approximately 1 minute) in the morning, at noon, late afternoon, and late evening for 7 
days. Each tube will be labeled for use at one of these 4 times.
After the randomization visit (Visit 1/baseline visit), subjects will return to the study site for 
post baseline visits, namely Visit 2, Visit 3, and Visit 4 to complete efficacy and safety 
assessments. Baseline safety laboratory test blood samples will be taken. End of study safety 
laboratory tests will also be taken at Visit 4, or in case of early termination. In addition, subjects 
(ex-clinic) will assess pain intensity and pain relief at frequent intervals on Day 1 and then at 
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Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 1 1  of 6 4
eac h st u d y dr u g a p plicati o n t hr o u g h o ut t he rest of t he st u d y. T he sc he d ule of visits is descri be d 
bel o w.
St u d y ce nter visits per s u bject:
Scree ni n g / Ra n d o mizati o n visit [ Visit 1]  
Da y 1 ( 0 h)
1 st i nteri m visit  [ Visit 2]
Da y 3 ( 4 8 ± 4 h after i nitiati n g treat me nt)
2 n d i nteri m visit [ Visit 3]
Da y 5 ( pri mar y e n d p oi nt meas ure me nt) 
( 9 6 ± 4 h after i nitiati n g treat me nt)
Fi nal visit [ Visit 4]
Da y 8 ± 1 d 
( 7 ± 1 da ys after i nitiati n g treat me nt)
St u d y Pr o d u ct s
T he f oll o wi n g pr o d ucts will be a d mi nistere d i n t his st u d y:
A cti v e Tr e at m e nt a
A cti v e C o m p ar at or b
Pl a c e b o Pr o d u ct f or 
Bli n di n g of A cti v e 
Tr e at m e nt a
Pr o d u ct N a m e
D D E A 2. 3 2 % G el
D D E A 1. 1 6 % G el
Pl a c e b o g el - 0 % 
di cl of e n a c g el
P a c k D e si g n
2 x 5 0 g t u b e s
4 x 5 0 g t u b e s
2 x 5 0 g t u b e s
Di s p e n si n g D et ail s
1 kit p er s u bj e ct at Vi sit 
1 a
1 kit p er s u bj e ct at Vi sit 
1 b
1 kit p er s u bj e ct at Vi sit 
1 a
Pr o d u ct M a st er 
F or m ul ati o n C o d e 
( M F C)
D o s e/ A p pli c ati o n
G el –  5 c m ( 2 g) o n 
2 0 0 c m 2
G el –  5 c m ( 2 g) o n 
2 0 0 c m 2
G el –  5 c m ( 2 g) o n 
2 0 0 c m 2
R o ut e of 
A d mi ni str ati o n
T o pi c al
T o pi c al
T o pi c al
U s a g e I n str u cti o n s
T w o ti m e s d ail y ( BI D) 
( m or ni n g a n d l at e 
aft er n o o n)
F o ur ti m e s d ail y ( QI D)
T w o ti m e s d ail y ( BI D) 
( n o o n a n d l at e e v e ni n g)
a  T he st u d y pr o d ucts f or t he Acti ve Treat me nt a n d Place b o Pr o d uct f or Bli n di n g of Acti ve Treat me nt will be 
pr o vi de d i n a si n gle kit c o ntai ni n g 4 t u bes ( 2 t u bes of eac h st u d y pr o d uct)
b  T he st u d y pr o d uct f or t he Acti ve C o m parat or will be pr o vi de d i n a si n gle kit c o ntai ni n g 4 t u bes ( 4 t u bes of Acti ve 
C o m parat or pr o d uct) 
Resc ue me dicati o n ( paraceta m ol, u p t o 2 0 0 0 m g dail y) will be all o we d d uri n g t he st u d y, e xce pt 
f or t he 6 h o urs pri or t o eac h st u d y visit a n d 1 2 h o urs pri or t o Visit 3.
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
C CI
C C
I
C CI


Diclofenac Diethylamine 2.32%
Study 211206
Protocol Amendment 1
GlaxoSmithKline Consumer Healthcare Confidential 
Template Version Effective: 18-May-18 (CCR #11475)
Page 12 of 64
Type and Planned Number of Subjects
Approximately 300 subjects who present to the study within 24 hours of suffering a Grade I-II 
ankle sprain will be randomized to ensure at least 240 evaluable subjects complete the study for 
the (PP) per protocol analysis population. 
Approximately 120 subjects per treatment arm has been determined to provide 80% power to 
demonstrate non-inferiority of DDEA 2.32% gel b.i.d with DDEA 1.16% gel q.i.d. by 
comparing the two-sided 95% confidence interval (CI) of the difference in mean change from 
baseline of VAS POM score between the two products with the non-inferiority margin of 13 
mm.  This assumes a treatment standard deviation of 22mm and allows for a possible small true 
treatment difference of 5mm in favor of DDEA 1.16%.
The primary efficacy endpoint will be the change from baseline in POM on Day 5 of treatment 
as assessed by a 100 mm VAS scale.
The following primary non-inferiority hypothesis will be tested for DDEA 2.32% vs DDEA 
1.16%:
The null hypothesis is Diclofenac 2.32% DDEA Gel administered BID is inferior to Diclofenac 
1.16% DDEA gel administered QID with the alternative hypothesis being Diclofenac 2.32% 
DDEA Gel administered BID is non-inferior to Diclofenac 1.16% DDEA gel administered QID.
Diclofenac 2.32% DDEA Gel administered BID will be declared non-inferior to Diclofenac 
1.16% DDEA gel administered QID if the upper limit of the two-sided 95% CI of the difference 
between their mean changes from baseline VAS POM responses is less than the established 
margin of 13 mm.
211206 | Protocol Amendment  10 Sep 2019 | TMF-29126 | 1.0


Diclofenac Diethylamine 2.32%
Study 211206
Protocol Amendment 1
GlaxoSmithKline Consumer Healthcare Confidential 
Template Version Effective: 18-May-18 (CCR #11475)
Page 13 of 64
1.1
Schedule of Activities
The schedule of activities table provides an overview of the subject visits and study procedures.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct evaluations or assessments 
required to protect the well-being of the subject.
Table 1-1
Schedule of Activities
Screening/Randomization 
(Baseline)
Study Period
Procedure/Assessment
Visit 1 Day 1
Visit 2
Day 3
Visit 3
Day 5
Visit 4 / Early D/C
Day 8 ± 1
Written Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical History 
X
Demographics 
X
Current/Prior/Concomitant Medication Review
X
X
X
X
Subject Eligibility
X
Physical Exam / Vital Signs (including height 
and weight)
X
Xh
Urine Pregnancy Testa
X
X
Laboratory Safety Tests
Xb,c
Xb,c
Subject Continued Eligibility
X
X
X
Examination of Ankle Sprain
X
Diagnostic Testing for Ankle
Xd
Ankle Swelling, Pain on Movement, 
Tenderness, Ankle Joint Function
X
X
X
X
Randomization
X
211206 | Protocol Amendment  10 Sep 2019 | TMF-29126 | 1.0


Diclofenac Diethylamine 2.32%
Study 211206
Protocol Amendment 1
GlaxoSmithKline Consumer Healthcare Confidential 
Template Version Effective: 18-May-18 (CCR #11475)
Page 14 of 64
Screening/Randomization 
(Baseline)
Study Period
Procedure/Assessment
Visit 1 Day 1
Visit 2
Day 3
Visit 3
Day 5
Visit 4 / Early D/C
Day 8 ± 1
Adverse Events (AEs) Review
Xg
X
X
X
Dispense Subject Diary
X
X
X
Weigh Study Medication
X
X
X
X
Dispense Study Medication and Dosing Card
X
Pain Intensity and Pain Relief (Diary)e
X
X
X
X
Apply Study Medication at Clinic by trained 
professional or nurse
X
Dispense Rescue Medication
X
Xf
Review Diary
X
X
X
Count Rescue Medication
X
X
X
Collect Rescue Medication, Study Medication
X
Collect Diary
X
X
X
Study Conclusion/Subject Exit from Study
X
Footnotes:
a Women of child bearing potential
b Blood samples for chemistry and hematology
c Review results to ensure that there are no clinically significant abnormalities. Local laboratory will report results to center in order to allow the Investigator to review results no later than 24 
hours after blood samples being taken
d As judged necessary by the investigator to exclude fracture of the ankle
e Denotes subject completion of diary components
f  If necessary
g Adverse event collection commences from time of signed informed consent
h Height at Visit 1 only
211206 | Protocol Amendment  10 Sep 2019 | TMF-29126 | 1.0


Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 1 5  of 6 4
2 
I N T R O D U C TI O N
A n kle i nj uries are a m o n g t he m ost c o m m o n s p orts i nj uries [ F o n g 2 0 0 7]. Ei g ht y-fi ve perce nt of 
a n kle i nj uries are s prai ns, a n d of t hese, 8 5 % are i n versi o n s prai ns of t he lateral li ga me nts [ Ri ma n d o 
2 0 0 7] . A meta-a nal ysis b y Mas o n et al. of t o pical n o n-ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds) 
c o nsi dere d s prai ns, strai ns a n d s p ort i nj uries, w hic h i ncl u des a n kle s prai n, a n a p pr o priate m o del f or 
ac ute pai n c o n diti o ns [ Mas o n 2 0 0 4]. C o n ve nti o nal f or ms of t hera p y f or ac ute a n kle s prai n i ncl u de 
use of N S AI Ds, cr y ot hera p y wit h c o ol pac ks, ele vati o n of i nj ure d e xtre mit y, sta bilizati o n i n a s plit 
plaster cast a n d ba n da gi n g [ St öc kle 1 9 9 7].
T he efficac y a n d safet y of t o pical N S AI Ds i n t he treat me nt of ac ute, pai nf ul m usc ul os keletal 
c o n diti o ns is wi del y rec o g nize d [ Vaile 1 9 9 8, He y ne ma n 2 0 0 0, Mas o n 2 0 0 4, Rai nsf or d 2 0 0 8, Zac her 
2 0 0 8] . O ver t he past 2 0 years, a n i ncreasi n g n u m ber of t o pical N S AI D f or m ulati o ns ( dicl ofe nac, 
i b u pr ofe n, i n d o met haci n, ket o pr ofe n, a n d na pr o xe n) ha ve bee n a p pr o ve d. A pri mar y be nefit of 
t o picall y a p plie d N S AI Ds is t hat s yste mic a bs or pti o n is o nl y 3- 8 % of t he t otal s yste mic a bs or pti o n 
ac hie ve d wit h oral a d mi nistrati o n [ He y ne ma n 2 0 0 0 ], li miti n g t he p ote ntial f or s yste mic si de effects 
c haracteristic of N S AI Ds. F urt her a d va nta ges of t o pical deli ver y i ncl u de circ u m ve nti n g t he 
gastr oi ntesti nal tract a n d a v oi di n g first- pass meta b olis m i n t he li ver.
P har mac o ki netic st u dies ha ve s h o w n t hat dicl ofe na mic aci d, w he n a p plie d t o picall y, pe netrates t he 
s ki n barrier t o reac h j oi nts, m uscles a n d s y n o vial fl ui d, i n s ufficie ntl y hi g h c o nce ntrati o n t o e xert 
l ocal t hera pe utic acti vit y [Ra de mac her 1 9 9 1 ]. T he first t o pical V oltare n f or m ulati o n, dicl ofe nac 
diet h yla mi ne ( D D E A) 1. 1 6 % gel ( V oltare n E m ul gel) has bee n mar kete d si nce 1 9 8 5 w orl d wi de f or 
t he relief of pai n a n d i nfla m mati o n ass ociate d wit h s oft-tiss ue i nj uries, s oft-tiss ue r he u matis m a n d 
oste oart hritis as a t hree t o f o ur ti mes dail y a p plicati o n. Se veral cli nical trials ha ve bee n c o n d ucte d 
wit h D D E A 1. 1 6 % gel s u p p orti n g t he efficac y a n d safet y of t he t o pical dicl ofe nac f or m ulati o n i n 
t he s oft-tiss ue i nj uries, s oft-tiss ue r he u matis m, 
 a n d 
oste oart hritis i n dicati o ns [ Niet har d et al 2 0 0 5, Zac her et al 2 0 0 1 ]. Si milarl y, a 2. 3 2 % D D E A 
gel , w hic h is a p plie d t wice dail y, has bee n a p pr o ve d w orl d wi de f or t he sa me i n dicati o ns as t he 1. 1 6 % 
D D E A gel si nce 2 0 1 1. T he t wice a da y t o picall y a d mi nistere d re gi me n has de m o nstrate d efficac y 
i n relief of ac ute pai n res ulti n g fr o m s oft tiss ue i nj uries as o bser ve d i n st u d y [ V O P O- P- 3 0 7][ Pre del 
et al 2 0 1 2] . T he gl o bal cli nical st u d y data i n c o nj u ncti o n wit h t he e xte nsi ve p ost mar keti n g 
e x perie nce, pr o vi de r o b ust e vi de nce of t he safet y a n d efficac y of b ot h t he mar kete d D D E A gel 
f or m ulati o ns.
2. 1 
St u d y R ati o n al e
T o pical dicl ofe nac pr o d ucts are well esta blis he d gl o ball y f or t he treat me nt of pai n a n d i nfla m mati o n 
d ue t o ac ute tra u ma as well as f or t he relief of pai n ass ociate d wit h n o n-seri o us oste oart hritis ( O A) 
of t he peri p heral j oi nts e. g. k nee a n d fi n gers. T he ori gi nat or pr o d uct D D E A 1. 1 6 % gel ( V oltar ol 
E m ul gel i n t he U K, a n d ge neric na me of D D E A E m ul gel was re gistere d i n C hi na ) was first 
re gistere d i n 1 9 8 5 i n S witzerla n d a n d R o ma nia f or use at a d ose of 2- 4 g a p plie d t hree t o f o ur ti mes 
dail y a n d is c urre ntl y re gistere d i n o ver 1 3 0 c o u ntries of w hic h o ver 8 0 c o u ntries mar ket t his pr o d uct 
as o ver-t he-c o u nter ( O T C).  
T o picall y a d mi nistere d 2. 3 2 % D D E A gel f or use at a d ose of 2- 4 g a p plie d t wice dail y ( b.i. d.) was 
first a p pr o ve d i n 2 0 1 1 i n P ort u gal as a li ne e xte nsi o n t o D D E A 1. 1 6 % gel a n d is n o w re gistere d i n 
7 2 c o u ntries a n d is mar kete d i n 4 2 c o u ntries.
As part of t he gl o bal e x pa nsi o n f or t he pr o d uct, C hi na has bee n i de ntifie d as a desira ble mar ket f or 
re gistrati o n of D D E A 2. 3 2 % gel. T he i de ntifie d re gistrati o n pat h wa y f or t he D D E A 2. 3 2 % gel is 
variati o n s pecif yi n g a d diti o n of a ne w stre n gt h t o t he alrea d y re gistere d D D E A 1. 1 6 % gel ( Lice nse 
N u m ber H 2 0 1 8 1 2 2 5/ H 2 0 1 8 1 2 2 6, firstl y iss ue d o n Marc h 1 2, 2 0 1 3 ), wit h t he sa me i n dicati o ns 
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
P P D


Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 1 6  of 6 4
as c urre ntl y re gistere d f or D D E A 1. 1 6 % gel, i.e. f or t he relief of mil d t o m o derate pai n i n m uscles, 
s oft tiss ues, a n d j oi nts, e. g. m uscles or s oft tiss ue pai ns ca use d b y s prai n, p ulli n g i nj ur y, c o nt usi o ns, 
strai n, waist- bac k i nj ur y a n d vari o us art hral gia etc, a n d f or s y m pt o matic treat me nt of oste oart hritis.
I n s u p p ort of t he pr o p ose d re gistrati o n, t he Nati o nal Me dical Pr o d ucts A d mi nistrati o n ( N M P A) 
a p pr o ve d a cli nical trial a p plicati o n ( C T A) o n N o ve m ber 0 6, 2 0 1 6 ( C T A N o. 2 0 1 6 L 0 9 8 7 5). T he 
a p pr o ve d C T A sti p ulate d t hat a n o n-i nferi orit y st u d y assessi n g t he efficac y a n d safet y of t he D D E A 
2. 3 2 % vers us t hat of t he re gistere d D D E A 1. 1 6 % s h o ul d be c o n d ucte d i n a l ocal p o p ulati o n.
T o t his effect, G S K C H i nte n ds t o c o n d uct a ra n d o mize d, d o u ble bli n d, m ulti-ce nter, acti ve 
c o ntr olle d, parallel gr o u p, n o n-i nferi orit y st u d y t o e val uate t he efficac y a n d safet y of D D E A 2. 3 2 % 
gel a p plie d t wice dail y vers us D D E A 1. 1 6 % gel a p plie d f o ur ti mes dail y i n s u bjects wit h a n kle 
s prai n i n C hi na.
A n kle s prai n is a c o m m o n a n d well defi ne d j oi nt i nj ur y i n v ol vi n g t he s oft tiss ues. A si g nifica nt 
pr o p orti o n of s u bjects e x perie nce str o n g pai n a n d f u ncti o nal i m pair me nt wit h o ut a p pr o priate 
treat me nt o pti o ns. T he D D E A 2. 3 2 % gel offers t he o p p ort u nit y t o pr o vi de a safe a n d effecti ve 
treat me nt w hile i m pr o vi n g s u bject treat me nt c o m plia nce a n d c o n ve nie nce.
C o m plete i nf or mati o n f or t his c o m p o u n d ma y be f o u n d i n t he si n gle refere nce safet y d oc u me nt 
( S R S D), w hic h f or t his st u d y is t he I n vesti gat or’s Br oc h ure. 
2. 2  
B a c k gr o u n d
D D E A 2. 3 2 % gel c orres p o n ds t o 2 0 m g of dicl ofe nac s o di u m i n 1 g of gel. D D E A 2. 3 2 % gel has 
bee n de vel o pe d as a hi g her-stre n gt h f or m ulati o n of t he well k n o w n gl o ball y mar kete d V oltare n 
E m ul gel ( D D E A 1. 1 6 % gel) a n d is a p pr o ve d f or t he sa me i n dicati o ns as D D E A 1. 1 6 % gel, i.e.: f or 
t he relief of pai n, i nfla m mati o n, a n d s welli n g i n:

S oft tiss ue i nj uries: tra u ma of t he te n d o ns, li ga me nts, m uscles a n d j oi nts, e. g. d ue t o s prai ns, 
strai ns, br uises, a n d bac kac he (s p orts i nj uries);

L ocalize d f or ms of s oft tiss ue r he u matis m: te n d o nitis (e. g. te n nis el b o w), b ursitis, s h o ul der-
ha n d s y n dr o me a n d periart hr o pat h y;
A n d f or t he relief of pai n of n o n-seri o us art hritis of t he k nee or fi n gers.
T he t wice a da y t o picall y a d mi nistere d re gi me n has de m o nstrate d efficac y i n relief of ac ute pai n 
res ulti n g fr o m s oft tiss ue i nj uries as o bser ve d i n st u d y V O P O- P- 3 0 7, w here t he t wice dail y re gi me n 
s h o we d a statisticall y si g nifica nt re d ucti o n i n pai n as c o m pare d t o place b o 5 da ys after i nj ur y. T he 
D D E A 2. 3 2 % gel is desi g ne d t o ac hie ve efficac y wit h less fre q ue nt dail y a p plicati o ns as c o m pare d 
t o t he D D E A 1. 1 6 % gel, t here b y p ote ntiall y i m pr o vi n g treat me nt c o m plia nce a n d c o n ve nie nce f or 
t he s u bject. T o date, t he safet y pr ofile of t he D D E A 2. 3 2 % gel has pr o ve n t o be si milar t o t hat of 
t he D D E A 1. 1 6 % gel (
).
W he n a p plie d t o t he s ki n, D D E A 2. 3 2 % gel ac hie ves pe netrati o n b y t he acti ve i n gre die nt, 
dicl ofe nac, i nt o t he tar get tiss ues wit h l o w s yste mic e x p os ure (
 a n d  
). 
I n a d diti o n t o c o ntai ni n g d o u ble t he c o nce ntrati o n of acti ve i n gre die nt c o m pare d wit h t he ori gi nat or 
pr o d uct D D E A 1. 1 6 % gel, D D E A 2. 3 2 % gel e m pl o ys a per meati o n e n ha ncer, 0. 7 5 % ole yl alc o h ol, 
t o meet t he tar get per meati o n le vel. Ole yl alc o h ol is c o m m o nl y use d i n der mal pr o d ucts a n d is 
k n o w n t o be well t olerate d.
As part of t he de vel o p me nt pr o gra m f or D D E A 2. 3 2 % gel, a series of precli nical st u dies c o m pare d 
t he D D E A 2. 3 2 % gel f or m ulati o n wit h t he mar kete d D D E A 1. 1 6 % gel f or m ulati o n. A n i n vitr o s ki n 
per meati o n st u d y was perf or me d t o e val uate t he deli ver y of dicl ofe nac fr o m D D E A 2. 3 2 % gel. T he 
st u d y s h o we d t hat dicl ofe nac pe netrati o n rates were a p pr o xi matel y t hree ti mes greater f or D D E A 
2. 3 2 % gel t ha n f or D D E A 1. 1 6 % gel. 
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
P P D
P P D
C CI


Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 1 7  of 6 4
2. 3  
M e c h a ni s m of A cti o n/I n di c ati o n
Dicl ofe nac is a p ote nt n o n-ster oi dal a nti-i nfla m mat or y dr u g ( N S AI D) wit h pr o n o u nce d effects 
i n t he relief of pai n, i nfla m mati o n a n d i ncrease d te m perat ure d ue t o fe ver. Dicl ofe nac acts 
t hr o u g h t he i n hi biti o n of pr osta gla n di n s y nt hesis ca use d b y bl oc ki n g t he e nz y me c ycl o-
o x y ge nase 2 ( C O X- 2). I n hi biti o n of pr osta gla n di n ( P G) s y nt hesis is t he pri mar y mec ha nis m of 
acti o n of dicl ofe nac ( Ga n 2 0 1 0 ).
T he gl o bal I n dicati o n (
) f or D D E A 1. 1 6 % a n d 2. 3 2 % 
gel is:
“ F or t he relief of pai n, i nfla m mati o n a n d s welli n g i n:

S oft-tiss ue i nj uries: tra u ma of t he te n d o ns, li ga me nts, m uscles a n d j oi nts, e. g. d ue t o 
s prai ns, strai ns, br uises a n d bac kac he (s p orts i nj uries);

L ocalize d f or ms of s oft tiss ue r he u matis m: te n d o nitis (e. g. te n nis el b o w), b ursitis, 
s h o ul der- ha n d s y n dr o me a n d periart hr o pat h y.
F or t he relief of pai n of n o n-seri o us art hritis of t he k nee or fi n gers.”
Si milarl y, t he a p pr o ve d i n dicati o n i n C hi na f or D D E A 1. 1 6 % is:
F or t he relief of mil d t o m o derate pai n i n m uscles, s oft tiss ues, a n d j oi nts, e. g. m uscles or s oft 
tiss ue pai ns ca use d b y s prai n, p ulli n g i nj ur y, c o nt usi o ns, strai n, waist- bac k i nj ur y a n d vari o us 
art hral gia etc. a n d f or s y m pt o matic treat me nt of oste oart hritis.
3 
S T U D Y O B J E C TI V E S A N D E N D P OI N T S
T he pri mar y o bjecti ve of t his st u d y is t o de m o nstrate n o n-i nferi orit y bet wee n D D E A 2. 3 2 % a n d 
D D E A 1. 1 6 % wit h re gar d t o pai n relief after ac ute a n kle s prai n.
T he pri mar y a n d sec o n dar y e n d p oi nts are detaile d i n Ta ble 3- 1.
T a bl e 3- 1 
St u d y O bj e cti v e s a n d E n d p oi nt s
O bj e cti v e( s)
E n d p oi nt( s)
Pri m ar y
T o d e m o n str at e n o n-i nf eri orit y b et w e e n D D E A 
2. 3 2 % a n d D D E A 1. 1 6 % wit h r e g ar d t o p ai n 
r eli ef aft er a c ut e a n kl e s pr ai n
C h a n g e fr o m b a s eli n e i n p ai n o n m o v e m e nt 
( P O M) o n D a y 5 of tr e at m e nt a s a s s e s s e d b y a 
1 0 0 m m V A S s c al e
S e c o n d ar y
T o a s s e s s s af et y of D D E A 1. 1 6 % a n d D D E A 
2. 3 2 % g el s aft er 1 w e e k of u s e
N u m b er, i n ci d e n c e, a n d s e v erit y of a d v er s e 
e v e nt s f oll o wi n g d o si n g wit h st u d y m e di c ati o n
T o a s s e s s effi c a c y of tr e at m e nt s f or p ai n r eli ef 
a s m e a s ur e d b y P O M o n D a y s 3 a n d 8
C h a n g e fr o m b a s eli n e of P O M o n V A S o n D a y 3 
a n d D a y 8 of tr e at m e nt a s s e s s e d b y 1 0 0 m m 
V A S s c al e
T o a s s e s s effi c a c y of tr e at m e nt s f or 
i nfl a m m ati o n of t h e aff e ct e d a n kl e a s m e a s ur e d 
b y pr e s s ur e al g o m etr y o n D a y s 3, 5, a n d 8
C h a n g e fr o m b a s eli n e i n t e n d er n e s s a s 
m e a s ur e d b y pr e s s ur e al g o m etr y o n D a y s 3, 5 
a n d 8
T o a s s e s s effi c a c y of tr e at m e nt s f or 
i nfl a m m ati o n of t h e aff e ct e d a n kl e a s m e a s ur e d 
b y pr e s s ur e al g o m etr y o n D a y s 3, 5, a n d 8
Diff er e n c e b et w e e n m e a s ur e m e nt i n aff e ct e d 
a n kl e a n d c o ntr al at er al a n kl e o n D a y s 3, 5 a n d 8
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To assess efficacy of treatments for ankle joint 
function as measured on the Karlsson Scoring 
Scale
Change from baseline in Ankle Joint Function 
(Karlsson Scoring Scale) on Days 3,5 and 8
To assess efficacy of treatments for swelling of 
affected ankle as measured Figure of Eight 
Method
Change from baseline in circumference of 
affected ankle as measured by Figure of Eight 
method on Days 3,5 and 8
To assess efficacy of treatments for swelling of 
affected ankle as measured by Figure of Eight 
method
Difference between circumference of affected 
ankle to unaffected ankle by Figure of Eight 
method on Days 3, 5 and 8
To assess efficacy of treatments for effect on 
pain intensity as measured by Sum of Pain 
Intensity Difference (SPID)
SPID from 0 – 24 hours post first dose (Day 1) 
and from 96 – 120 hours post first dose (Day 5)
To assess effect of treatments for effect on pain 
relief as measured by Total Pain Relief 
(TOTPAR)
TOTPAR from 0 – 24 hours post first dose (Day 
1) and from 96 – 120 hours post first dose (Day 
5)
To assess the use of rescue medication among 
subjects
Number of tablets usedto treat ankle pain and 
overall
To assess the use of rescue medication among 
subjects
Number of days on which rescue medication 
was used to treat ankle pain and overall
This study will be considered successful if the primary objective is met; i.e. that DDEA 2.32% 
is non-inferior in terms of change from baseline in pain on movement after acute ankle sprain 
as compared to DDEA 1.16% on Day 5.
.
4
STUDY DESIGN 
4.1
Overall Design
This is a Phase III, randomized, double blind, multi-center, active controlled, 2-treatment arm, 
parallel group, non-inferiority study to evaluate the efficacy and safety of diclofenac 
diethylamine 2.32% gel applied twice daily versus diclofenac diethylamine 1.16% gel applied 
four times daily for 1 week in subjects with acute ankle sprain.
To qualify, subjects must experience an acute Grade I -II sprain of the ankle within the past 24 
hours and experience pain on movement of at least 50 mm on a 100 mm VAS scale. Subjects 
should be randomized as soon as possible after the injury.
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1 ratio to one of the following two treatment arms:
Table 4-1
Treatment Schedule
Treatment Arms
Morning      
(Upon Rising)
Noon
Late Afternoon 
(evening)
Late Evening 
(bed time)
DDEA 2.32%   
four times daily
DDEA 2.32% gel
Placebo gel
DDEA 2.32% gel
Placebo gel
DDEA 1.16%  
four times daily
DDEA 1.16% gel
DDEA 1.16% gel
DDEA 1.16% gel
DDEA 1.16% gel
Approximately 300 subjects (150 in each group) with acute ankle sprain are to be randomized. 
All subjects will receive four (4) tubes of study drug, for treatment in morning, noon, late 
afternoon, and late evening, respectively. The very first dose of study drug will be applied at 
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the study center. The subjects will be instructed to apply the gel topically with the finger tips 
for approximately 1 minute in the morning, at noon, late afternoon, and late evening for 7 days. 
Each tube will be labeled for use at one of these 4 times.
After the randomization visit (Visit 1/baseline visit), subjects will return to the study site for 
post baseline visits, namely Visit 2, Visit 3, and Visit 4 to complete efficacy and safety 
assessments. Baseline safety laboratory test blood samples will be taken at Visit 1. End of study 
safety laboratory tests will also be taken at Visit 4, or in case of early termination. In addition, 
subjects (ex clinic) will assess pain intensity and pain relief at frequent intervals on Day 1 and 
then at each study drug application throughout the rest of the study. The schedule of visits is 
described below.
Study center visits per subject:
Screening / Randomization visit [Visit 1]
Day 1 (0 h)
1st interim visit [Visit 2]
Day 3 (48 ± 4 h after initiating treatment)
2nd interim visit [Visit 3]
Day 5 (primary endpoint measurement) 
(96 ± 4 h after initiating treatment)
Final visit [Visit 4]
Day 8 ± 1 d
(7 ± 1 days after initiating treatment)
Rescue medication (paracetamol, up to 2000 mg daily) will be allowed during the study, except 
for the 6 hours prior to each study visit and 12 hours prior to Visit 3.
4.2
Rationale for Study Design
As discussed in Section 2.2 and Section 2.3, DDEA 1.16% and DDEA 2.32% are registered 
globally for the relief of pain, swelling and inflammation from a variety of musculoskeletal 
conditions. There is an extensive body of clinical study and post marketing experience to 
support the efficacy of both the DDEA 1.16% and 2.32%. Part of the rationale for conducting 
this study is to reproduce the efficacy and safety of the products in a Chinese population.
The DDEA 1.16% gel is currently marketed in China. As described in Section 2.1, in order to 
expand the global footprint of the DDEA 2.32% gel to China, a local study is required. The 
design stipulated in the NMPA approved CTA is a non-inferiority study design versus the 
approved DDEA 1.16% active comparator. This is considered an appropriate design when there 
is extensive evidence of efficacy and safety of the active comparator and the aim is to leverage 
this existing evidence by demonstrating that a new product which can offer advantages, such as 
improved compliance and convenience, would result in no important loss of efficacy versus the 
active comparator. The DDEA 1.16% has demonstrated consistent and reproducible efficacy as 
compared to placebo in both acute and chronic clinical pain models. Moreover, this is especially 
applicable to the current situation as the test product, DDEA 2.32%, has also demonstrated 
efficacy in a placebo-controlled trial. 
Given the extensive global evidence of safety and efficacy in both the active comparator and 
test arms, the important contribution resulting from the conduct of the non-inferiority trial is to 
demonstrate no important loss of efficacy from the approved active comparator in a local 
population.
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4.3
Justification for Dose
The dose for the active comparator DDEA 1.16% will be an application of 5 cm of gel 
(equivalent to approximately 2 g of gel and as determined by a provided dosing card) to both 
sides of the affected ankle four (4) times daily. This is consistent with the approved labeled 
dose for DDEA 1.16% in China.
Globally, the labeled approved dose for DDEA 2.32% is an amount of 2 – 4 g of gel (roughly 
the size of a cherry or walnut) applied twice daily. To produce a more uniform dose for the 
purpose of the trial and to provide recommendations more in line with the approved labeled 
dose of the DDEA 1.16% in China, the dose for the trial for the DDEA 2.32% will be an 
application of 5 cm of gel (equivalent to 2 g of gel and as determined by a provided dosing card) 
to both sides of the affected ankle two (2) times daily. For subjects receiving DDEA 2.32% gel, 
placebo gel will be administered in the same fashion two (2) times daily to maintain blinding.
Based on previous experience it is expected that measurement of pain and disability over 
approximately one week would adequately characterize the profile over time of the analgesic 
effect of both DDEA 1.16% and DDEA 2.32% (Mason, et al 2004, Predel, et al 2004).
To minimize unnecessary risks to subjects during study participation subjects will be screened 
at baseline to ensure absence of the various clinical disorders described in the exclusion criteria. 
This comprehensive process consists of a baseline physical examination, vital signs, medical 
history and drug history. Safety laboratory blood samples for chemistry and hematology will  
also be taken at the baseline visit before subjects are randomized to study treatment, and their 
results will be reviewed as early as possible. 
4.4
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities.
The end of this study is defined as the date of the last visit or the last scheduled procedure of 
the last subject in the study. 
5
STUDY POPULATION
5.1
Type and Planned Number of Subjects
A sufficient number of subjects will be screened to randomize approximately 300 subjects to 
ensure at least 240 evaluable subjects complete the study without any major protocol deviations. 
Healthy adults 18 – 75 years old who present to clinic within 24 hours of sustaining a grade I 
or II lateral ankle sprain (as assessed by the investigator) and experience pain on movement of 
at least 50 mm on a 100 mm VAS scale will be enrolled into the study.
This study can fulfill its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether a subject is suitable for this protocol.  
Subject eligibility to participate in the clinical study should be reviewed by the investigator and 
documented by an appropriate member of the investigator’s study team before subjects are 
included in the study.
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5.2
Inclusion Criteria
An individual must meet all of the following inclusion criteria to be eligible for enrollment into 
the study:
1. Subject provision of a signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study before any assessment is 
performed.
2. Subject is male or female who, at the time of screening, is between the ages of 18 and 75 
years, inclusive.
3. A subject who is willing and able to comply with scheduled visits, treatment plan and 
other study procedures.
4. Acute sprain of the lateral ankle on one side only, Grade I-II [Wolfe 2001] 
5. Pain-on-movement ≥ 50 mm on a 100 mm VAS
6. Injury within the past 24 hours before randomization
7. No pain medication may have been taken within the 24 hours that precedes randomization. 
Treatment by rest, ice, compression, or elevation (RICE) is authorized prior to 
randomization. Stable daily doses of acetylsalicylic acid (≤ 162 mg) taken for at least 30 
days prior to the first dose of study medication for non-analgesic reasons may be continued 
for the duration of the study.
8. A subject in good general and mental health with, in the opinion of the investigator or 
medically qualified designee with no clinically significant/relevant abnormalities in 
medical history or upon physical examination, or condition, that would impact the 
subject’s safety, wellbeing or the outcome of the study, if they were to participate in the 
study, or affect the individual’s ability to understand and follow study procedures and 
requirements.
9. Female subject of childbearing potential and at risk for pregnancy must agree to use a 
highly effective method of contraception throughout the study and for 14 days after the 
last dose of assigned treatment.  A female subject who is of childbearing potential must 
meet requirements in Section 5.5.4.
5.3
Exclusion Criteria
An individual who meets any of the following exclusion criteria will not be eligible for 
enrollment into the study:
1. During the past 3 months: Grade I – III sprain of the affected ankle
2. During the past 6 months: Grade II – III sprain, any other significant injury (such as 
fracture or torn ligament), or surgery (except for skin or nails) of the affected ankle or 
foot.
3. Pain or instability in the affected ankle attributable to previous ankle sprain or any other 
trauma.
4. Ankle sprain attributable to a known disease affecting the ligaments, such as ligament 
hyperlaxity due to connective tissue diseases (e.g. Marfan’s syndrome, Down’s syndrome, 
Ehlers – Danlos syndrome).
5. Any skin lesion or wound in the area to be treated
6. Intent to undergo surgery during time of participation
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7. A subject who is an employee of the investigational site, either directly involved in the 
conduct of the study or a member of their immediate family; or an employee of the 
investigational site otherwise supervised by the investigator; or, a GSK CH employee 
directly involved in the conduct of the study or a member of their immediate family.
8. A subject with, in the opinion of the investigator or medically qualified designee, an acute 
or chronic medical, including other current acute or chronic pain conditions, or psychiatric 
condition or laboratory abnormality that may increase the risk associated with study 
participation or investigational product administration or may interfere with the 
interpretation of study results and, in the judgment of the investigator or medically 
qualified designee, would make the subject inappropriate for entry into this study.
9. A subject who is a pregnant female.
10. A subject who is a breastfeeding female.
11. A subject with known or suspected intolerance or hypersensitivity to the study materials 
(or closely related compounds) or any of their stated ingredients. 
12. A subject who, in the opinion of the investigator or medically qualified designee, should 
not participate in the study. 
13. A subject unwilling or unable to comply with the Lifestyle Considerations (Section 5.5) 
described in this protocol. 
14. A subject who has made use of prescription, non-prescription, or dietary supplements, 
containing NSAIDs, COX-2 inhibitors and other analgesic treatments within 7 days or 5 
half-lives, whichever is longer, prior to the first dose of investigational product and during 
the study.
15. Topical analgesics or anti-inflammatory treatment over the previous 30 days in the area to 
be treated in the study period
16. A subject with evidence of clinically significant laboratory abnormality caused by renal 
disease (Serum creatinine ≥ 1.5 times the upper limit of normal (ULN)), hepatic disease 
(ALT or AST ≥ 2 times the ULN), or subject with allergic disease at screening that may 
increase the risk associated with study participation.
17. A subject with history of regular alcohol consumption exceeding 14 drinks/week 
(1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces 
(45 mL) of hard liquor) within 6 months of Screening. 
18. A subject who has received treatment with an investigational drug within 30 days (or as 
determined by the local requirement) or 5 half-lives preceding the first dose of 
investigational product (whichever is longer). 
19. A subject who has previously been enrolled in this study. 
20. Any physical impairment that would influence the study’s efficacy evaluations, in 
particular POM and the ankle joint function, such as : peripheral or central neurological 
disease, significant back pain, symptomatic osteoarthritis of the hips, knees or feet, or any 
painful conditions of the lower extremities (e.g. painful nail, wound, corn, or wart).
5.4
Randomization Criteria
Subjects will be randomized into the study provided they have satisfied all subject selection 
criteria. 
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5.5
Lifestyle Considerations
5.5.1
Meals and Dietary Restrictions

No special requirement for food and drink prior to safety laboratory evaluations.
5.5.2
Alcohol, Caffeine and Tobacco

Subjects will abstain from caffeine-containing products for 12 hours prior to study 
visit days (except screening/randomization visit). 
5.5.3
Activity

Subjects will abstain from strenuous exercise (e.g. heavy lifting, weight training, 
calisthenics, aerobics) for the duration of the study. Walking at a normal pace will be 
permitted.
5.5.4
Contraception
Female subjects who are of childbearing potential and are sexually active and at risk for 
pregnancy must agree to use at least one highly effective method of contraception consistently 
and correctly for the duration of the active study period and for at least 14 days after the last 
dose of investigational product. 
The investigator or his or her designee will discuss with the subject the need to use highly 
effective contraception consistently and correctly according to the schedule of activities and 
document such conversation.  In addition, the investigator or designee will instruct the subject 
to call immediately if the selected contraception method is discontinued or if pregnancy is 
known or suspected in the subject or the subject’s partner. 
The following is the all-inclusive list of the highly effective methods for avoiding pregnancy 
that meets the GSK definition (i.e., have a failure rate of less than 1% per year when used 
consistently and correctly and, when applicable, in accordance with the product label). 
The list does not apply to females of reproductive potential with same sex partners or for 
subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long 
term and persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
1. Contraceptive subdermal implant
2. Intrauterine device or intrauterine system
3. Combined estrogen and progestogen oral contraceptive [Hatcher 2007])
4. Injectable progestogen [Hatcher 2007]
5. Contraceptive vaginal ring [Hatcher 2007]
6. Percutaneous contraceptive patches [Hatcher 2007]
7. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject [Hatcher 
2007]. The documentation on male sterility can come from site personnel review of 
subject’s medical records, medical examination and/or semen analysis, or medical 
history interview provided by her or her partner.
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These allowed methods of contraception are only effective when used consistently, correctly 
and in accordance with the product label. The investigator is responsible for ensuring that 
subjects understand how to properly use these methods of contraception. Use of hormonal 
contraception will be allowed during the study; however, subjects must have been stabilized on 
this medication for at least 3 months prior to screening.
5.6
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized. To ensure transparent reporting of screen failure subjects, a 
minimal set of screen failure information will include demography, screen failure details (e.g. 
withdrawal of consent), eligibility criteria, and any adverse events or incidents as applicable. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be re-screened.
5.7
Sponsor’s Qualified Medical Personnel
Contact information for the sponsor's appropriately qualified medical personnel for the study is 
documented in the Study Contact List located in the investigator study master file held at the 
study site.
The contact number is only to be used by investigational staff seeking advice on medical 
questions or problems in the event that the established communication pathways between the 
investigational site and the study team are not available.  
The contact number is not intended for direct use by study subjects. To facilitate access to 
appropriately qualified medical/dental personnel on study-related medical/dental questions or 
problems, subjects will be provided with a contact card.  The contact card will provide, as a 
minimum, protocol identifiers, the subject’s study identification number, contact information 
for the investigational site, and contact details in the event that the investigational site cannot 
be reached to provide advice on a medical question or problem identified by a healthcare 
professional other than the investigator.  
6
INVESTIGATIONAL/STUDY PRODUCTS
For the purposes of this study, per International Conference on Harmonization (ICH) guidelines, 
and GSK policy, investigational product is defined as a pharmaceutical form of an active 
ingredient, a non-medicinal product (marketed or investigational), or a placebo, being tested or 
used as a reference (positive or negative control), in a clinical trial. This includes a product with 
a marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use. 
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Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 2 5  of 6 4
6. 1 
I n v e sti g ati o n al/ St u d y Pr o d u ct S u p pli e s
T he f oll o wi n g st u d y pr o d ucts will be s u p plie d b y t he Cli nical S u p plies De part me nt, G S K C H:
T a bl e 6- 1 
I n v e sti g ati o n al/ St u d y Pr o d u ct S u p pli e s
A cti v e Tr e at m e nt a
A cti v e C o m p ar at or b
Pl a c e b o Pr o d u ct f or 
Bli n di n g of A cti v e 
Tr e at m e nt a
Pr o d u ct N a m e
D D E A 2. 3 2 % G el
D D E A 1. 1 6 % G el
Pl a c e b o g el - 0 % 
di cl of e n a c g el
P a c k D e si g n
2 x 5 0 g t u b e s
4 x 5 0 g t u b e s
2 x 5 0 g t u b e s
Di s p e n si n g D et ail s
1 kit p er s u bj e ct at Vi sit 
1 a
1 kit p er s u bj e ct at Vi sit 
1 b
1 kit p er s u bj e ct at Vi sit 
1 a
Pr o d u ct M a st er 
F or m ul ati o n C o d e 
( M F C)
D o s e/ A p pli c ati o n
G el –  5 c m ( 2 g) o n 
2 0 0 c m 2
G el –  5 c m ( 2 g) o n 
2 0 0 c m 2
G el –  5 c m ( 2 g) o n 
2 0 0 c m 2
R o ut e of 
A d mi ni str ati o n
T o pi c al
T o pi c al
T o pi c al
U s a g e I n str u cti o n s
T w o ti m e s d ail y ( BI D) 
( m or ni n g a n d l at e 
aft er n o o n)
F o ur ti m e s d ail y ( QI D)
T w o ti m e s d ail y ( BI D) 
( n o o n a n d l at e e v e ni n g)
R et ur n R e q uir e m e nt s
All u s e d/ u n u s e d 
s a m pl e s t o b e r et ur n e d
All u s e d/ u n u s e d 
s a m pl e s t o b e r et ur n e d
All u s e d/ u n u s e d 
s a m pl e s t o b e r et ur n e d
St or a g e 
R e q uir e m e nt s
St or e b el o w 2 5° C
St or e b el o w 2 5° C
St or e b el o w 2 5° C
a  T he st u d y pr o d ucts f or t he Acti ve Treat me nt a n d Place b o Pr o d uct f or Bli n di n g of Acti ve Treat me nt will be 
pr o vi de d i n a si n gle kit c o ntai ni n g 4 t u bes ( 2 t u bes of eac h st u d y pr o d uct)
b  T he st u d y pr o d uct f or t he Acti ve C o m parat or will be pr o vi de d i n a si n gle kit c o ntai ni n g 4 t u bes ( 4 t u bes of Acti ve 
C o m parat or pr o d uct) 
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Table 6-2
Rescue Medication Information
Rescue Medication
Product Name
500 mg paracetamol tablets
Pack Type
Pack of tablets
Dispensing Details
Dispense at Visit 1. May re-dispense at Visit 3 if 
necessary.
Product Formulation Code
Commercial product
Dose
One 500 mg tablet with water per dose. May be repeated 
after 4 hours. Maximum daily dose 2000 mg.
Route of Administration
Oral
Usage Instructions
As needed for pain
Return Requirements
All used/unused samples to be returned
Storage Requirements
Store sealed.
Table 6-3
Sundry Items
Sundry Items to be supplied:
Return/Disposal Details
Item Name
Supplied By
Pack 
Type
Dispensing Details
Used 
Samples
Unused 
Samples
Urine pregnancy 
test
GSK/CRO/Site* Unit
To be used by site 
staff at visit 1
Dispose at 
site
Return
Dosing Card
GSK
Each
Included in treatment 
kit
Return
Return
Subject Diary
CRO
Each
To be provided to 
subjects
Return
Return
* CRO = Contract Research Organization
Detailed instructions for the return of study product/study supplies for the accountability checks 
and subsequent destruction which will be provided by GSK CH during the course of the study 
in time for study close out visit.
6.1.1
Dosage Form and Packaging: 
DDEA 2.32%, DDEA 1.16%, and placebo gels will be supplied to the clinical site as packaged 
tubes for dispensing by the pharmacy. 
The content of the product labels will be in accordance with all applicable regulatory 
requirements and will be the responsibility of the GSK CH Global Clinical Supplies group. 
Each study label will contain, but not be limited to, protocol number, directions for use and 
storage requirements. 
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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.
All products supplied are for use only in this clinical study and should not be used for any other 
purpose. Subjects must not exchange their designated products with other study subjects.
6.1.2
Preparation and Dispensing 
DDEA 2.32% gel, DDEA 1.16% gel, and placebo will be prepared and/or dispensed by 
qualified site personnel according to the dosage and administration instruction. 
Once the eligibility of a subject has been confirmed, the Investigator (or nominated assistant) 
should contact the IVRS/IWRS Centralized Randomization Centre for allocation of randomized 
therapy.
The actual treatment given to individual subjects will be determined by a randomization scheme 
that has been loaded into the (IVRS/IWRS) database. Subjects will be assigned to products in 
accordance with the randomization schedule generated by an approved GSK CH vendor, using 
validated software.
All subjects will be identified to the Centralized Randomization Centre using an Interactive 
Response Technology (IRT). Before the study is initiated, training, login information and 
directions for the IRT will be provided to each site. 
The IVRS/IWRS Centralized Randomization Centre will inform the investigator of the Kit ID 
number to be allocated to the subject after subjects become eligible for randomization.
6.2
Administration
All subjects will be given 4 tubes of study drug and the same usage instructions. Subjects should 
spread a total of approximately 2 grams of study medication (using the dosing card) on both 
sides of the ankle. The study drug should be applied topically with the fingertips to both sides 
of the affected ankle for approximately 1 minute (corresponds to a region of approximately 200 
cm2). After application, the hands should be washed. On Day 1, to demonstrate proper 
application, the first dose of study drug will be applied at the study center from the morning 
tube (regardless of the time of randomization). Subsequent doses will be applied from the tube 
associated with the corresponding time of day separated by at least 3 hours (i.e. if the first dose 
is applied at 15:00 hr from the morning tube, the next dose will be at approximately 18:00 hr 
from the late afternoon tube and the next dose will be at approximately 21:00 hr from the late 
evening tube).   All 4 doses of study drug should be applied on Day 1, if possible, preferably 
with at least 3 hours between doses. If this is not possible, at a minimum 3 doses should be 
administered with at least 3 hours between doses.
The subjects will be instructed to continue to apply the gel topically with the fingertips four 
times a day for 7 days. Dosing times should be distributed as evenly as possible over the day, 
preferably once upon first arising (i.e., after washing or shower or bath), once at lunch 
(approximately 12:00 hour), once in the late afternoon (approximately 17:00 hour), and once in 
the late evening (i.e., after washing approximately 21:00 hour). There should be a period of at 
least 4 hours between individual applications. The appropriately-labeled tube should be used 
for each application.
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Subjects can take a shower or bathe prior to application. Subjects should not shower, bathe or 
wash the treated area within the first three hours after the application. Subjects should wash 
their hands after use and should wait 10 minutes before covering the treated skin with clothing. 
The investigator will instruct the subject to take the study drug exactly as prescribed and state 
that compliance is necessary for the subject’s safety and the validity of the study. The subject 
will be told to contact the investigator if he/she is unable for any reason to take the gel as 
directed/prescribed. All dosages prescribed and dispensed to the subject and all dose changes 
during the study must be recorded on the Dosage Administration Record CRF. Any missed or 
skipped doses must be recorded in CRF. 
Subjects will be instructed to self-administer their assigned product per the above usage 
instructions which will be explained and provided to the subject. 
6.2.1
Medication/Dosing Errors
Medication/dosing errors may result, in this study, from the administration or consumption of: 

the wrong product,

by the wrong subject, 

at the wrong time, 

or at the wrong dosage. 
Such medication/dosing errors occurring to a study subject are to be captured in the CRF.  In 
the event of medication dosing error, the sponsor should be notified immediately.
Medication/dosing errors are reportable irrespective of the presence of an associated AE, 
including:

Medication/dosing errors involving subject exposure to any of the study products;

Potential medication/dosing errors or uses outside of what is foreseen in the protocol 
that do or do not involve the participating subject.
If a medication/dosing error is accompanied by an AE, as determined by the investigator, the 
medication/dosing error and, any associated adverse event(s) are to be captured in the CRF AE 
form. 
6.3
Investigational/Study Product Storage 
The investigator, or designee, will ensure that all study products are stored in a secured area 
with controlled access under required storage conditions and in accordance with applicable 
regulatory requirements and the product label.  
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should be 
captured from the time of first product receipt throughout the study.  Even for continuous 
monitoring systems, a log or site procedure that ensures active daily evaluation for excursions 
should be available.  The operation of the temperature-monitoring device and storage unit (for 
example, refrigerator), as applicable, should be regularly inspected to ensure it is maintained in 
working order. 
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Any excursions from the product-label storage conditions should be reported to appropriate site 
staff upon discovery and communicated to sponsor as soon as possible.  The site should actively 
pursue options for returning the product to the storage conditions as described in the labeling, 
as soon as possible.  Excursions from the storage requirements, including any actions taken, 
must be documented as a protocol deviation and reported to the Sponsor.  
Once an excursion is identified, the affected product (or products) must be quarantined and not 
used until the sponsor provides documentation of permission to use. Use of any of the affected 
product(s) prior to sponsor approval will be considered a protocol deviation.  
Site staff will instruct subjects on the proper storage requirements for all take-home products. 
6.4
Investigational/Study Product Accountability
All products supplied are for use only in this clinical study and should not be used for any other 
purpose.
All study products must be received by a designated person at the study sites, handled and stored 
safely and properly, and kept in a secured location to which only the study staff have access. 
Upon receipt, all study products should be stored according to the instructions specified on the 
product labels (Table 6-1,Table 6-2) . Study products are to be dispensed only to subjects 
enrolled in the study in accordance with the protocol, by authorized site staff.
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of all the product supplies. All study products will be accounted for using the 
investigational/study product accountability form/record. The investigator is responsible for 
study product accountability, reconciliation, and record maintenance. 
The accountability records must be available for inspection by the study monitor during the 
study. Monitoring of product accountability will be performed by the monitor during site visits 
and at the completion of the study. 
All unused product must be returned at the final Visit 4. The monitoring plan will describe the 
process for investigational product accountability.
The inventory must be available for inspection by the study monitor during the study. 
6.4.1
Destruction of Investigational/Study Product Supplies 
At the conclusion of the study, the Principal Investigator or an appropriate designee, and a 
representative of GSK CH (study monitor) will inventory all used and unused study products 
and sundry items. The investigational/study product accountability record for returned study 
products will then be completed. All study product (used and unused) for this clinical study 
(including emptying containers) will be returned for destruction to the GSK CH Clinical 
Supplies Department or designated vendor using the return instructions provided. 
6.5
Blinding and Allocation/Randomization
At Visit 1, participants who fulfill all the inclusion criteria and none of the exclusion criteria 
will be assigned a unique randomization number in ascending numerical order at each study 
site. The randomization number encodes the participant’s assignment to one of the two arms of 
the study according to the randomization schedule generated prior to the study. These 
randomization numbers are linked to the two treatment arms, which in turn are linked to 
container (kit) numbers. A separate container list will be produced. Subjects will be randomized 
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using an interactive response technology system and container numbers will be provided by the 
system.
Subjects will be randomized in a 1:1 ratio, with equal numbers receiving DDEA 2.32% + 
Placebo gel and DDEA 1.16% gel. Randomization numbers will be assigned to individual 
centers in order to stratify the randomization by center.
Before the study is initiated, training, login information and directions for the IRT will be 
provided to each site. Study products will be dispensed according to the instruction received 
through the IRT at the appropriate study visits.
Returned study products should not be re-dispensed to any subject.
The investigator’s knowledge of the product allocation should not influence the decision to 
enroll a particular subject or affect the order in which subjects are enrolled.
This study is described as double-blind (the subjects and clinical examiner will be blinded to 
the product received). The study statistician, data management staff, other employees of the 
Sponsor and vendors acting on behalf of the sponsor, who may influence study outcomes will 
also be blinded to the product allocation. The placebo gel and active gels will be identical in 
packaging, labeling, odor, schedule of administration, and as identical as possible in appearance.
To ensure the examiner remains blinded throughout the study, staff involved in the preparation, 
dispensing, and application of study products will work in a separate area. The examiner is not 
permitted in any area where study product is stored, dispensed, or in use. 
Subjects will be instructed not to remove study products from the opaque bags provided outside 
of the dispensing room, while at the study site. Dispensing staff and staff supervising 
administration of IP will not be involved in any efficacy/safety assessment procedures during 
the study.  
Randomization data will be kept strictly confidential, accessible only to authorized persons, 
until the time of unblinding. After the study is completed, the data file verified, and protocol 
violations determined, drug codes will be broken and made available for data analysis.
6.6
Breaking the Blind
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  The method will be an electronic process.
The electronic system will be programmed with blind-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unblinding of a 
subject’s product assignment is warranted. Subject safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a subject’s 
product assignment unless this could delay emergency treatment of the subject.
If a subject’s product assignment is unblinded, the sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable.
Any AE associated with breaking the blind must be recorded and reported as specified in this 
protocol. The study site may also be required to inform the IRB/EC if the blind is broken. 
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6.7
Subject Compliance
The first dose of study products will be administered by investigator site personnel in order to 
demonstrate proper application of the treatments. 
The subject will return the trial medication (used or unused) at every visit and the investigator 
will record the number of study drug applications for each tube separately for morning, noon, 
late afternoon and late evening in the CRF. The returned tubes will be weighed with the cap and 
the weight will be recorded in mg on the drug accountability form in the CRF. Applying 2 g per 
use, the weight of each tube will decrease by approximately 2 g each study day.
If it appears that the subject used too little or too much study drug, the subject will be re-
instructed about the correct application technique by the investigator or the study nurse. 
At the last visit, the subject will return the tubes to the investigator who will store them until 
the monitor arranges for their return. The investigator must not destroy any drug.
In addition, a diary will be supplied to promote compliance and to capture details of product 
use throughout the study period. Subjects may also record additional information such as AEs 
or medications used. Any additional details relevant to efficacy or safety should be reviewed 
by the investigator (or suitably qualified designee) with the subjects at each visit and transcribed 
to the CRF as appropriate.
6.8
Subject Diary
A diary will be handed out to the subject at Visit 1,Visit 2, and Visit 3.

Every time gel is applied, the subject must document the time and date of application. 
This includes gel applied at the clinic site

Pain intensity and pain relief will both be assessed by the subjects every 2 hours ± 30 
minutes (after starting study drug) until the subject goes to bed on the evening of Day 
1. The same assessment and recording frequency will also be followed starting with the 
first dose on Day 5. On Day 1 and Day 5 where an assessment time point coincides with 
a dosing time point, the assessment of pain intensity and pain relief should be made prior 
to the dose. For all other time periods, pain intensity and pain relief will be assessed and 
recorded immediately prior to each study drug application.

Every time rescue medication is taken (not allowed within 6 hours of Study Visits and 
within 12 hours of Study Visit 3), the subject must document:
o
Time and date of rescue medication
o
Number of tablets taken
o
Reason for use of rescue medication
o
Pain intensity and pain relief immediately prior to each dose of rescue 
medication
The Investigator or designee will ensure that all diary entries completed by the subject are
legible. The Investigator will review the diary at each clinic visit. The diary handed out to 
subjects on Visit 1, Visit 2, and Visit 3 will be collected by the Investigator or designee at Visit 
2, Visit 3, and Visit 4 (Day 8±1) respectively.
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6.9
Concomitant Medication/Treatment(s)
As a general rule, no concomitant medications should be taken during the study, especially 
those medications prohibited by the exclusion criteria. Special attention should be given to the 
prohibited use of systemic or topical NSAIDs from the time of Screening up to Visit 4– as these 
are the basis for subject exclusion.
Concomitant therapies prohibited during the study: 
• Analgesics since the injury, administered by any route (i.e., topical, oral, rectal, injected,  
or inhaled), except rescue medication as described in Section 6.10, and acetylsalicylic acid 
taken for at least 30 days on a stable daily dose (≤ 162 mg) for non-analgesic reasons. Pain 
medication taken prior to the injury must be washed out for at least 24 hours before 
randomization. The following concomitant medications and/or therapies are prohibited:
•  Systemic or topical NSAIDs;
• Steroids (injected or oral, except inhaled topical asthma and hayfever treatments and 
topical dermal treatments not applied to the sprained ankle); 
• Physiotherapy (including, but not exclusive to, transdermal electro neural stimulation 
(TENS), ultrasound, massage, and spinal manipulation) or any other kind of pain therapy 
throughout the course of the study; 
• Tranquilizers, anxiolytics, hypnotics, or sedatives, unless the subject’s prescribed daily 
dose has been unchanged for a month before the randomization visit; this regimen must 
continue unchanged for the entire study; 
• Amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamines, opiates, 
phencyclidine, and tetrahydrocannabinol; 
• Traditional, herbal or homeopathy treatments (oral and topical); 
• Adhesive and/or immobilizing casts, bandages, Aircast
 splints, treatment by rest, ice, 
compression, or elevation (RICE) are not allowed. 
Subjects will receive paracetamol as rescue medication as described in Section 6.10. Use of a 
crutch and certain physician approved exercises will be allowed. The physician will instruct the 
subject to start Achilles’ tendon stretching on Day 1.
Any medications, treatments or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) taken during the study, from signing the informed consent, 
must be recorded in the CRF with indication, reason for use, unit dose, daily dose, and start and 
stop dates of administration. All subjects will be questioned about concomitant 
medication/treatments at each site visit.
Medication/treatments taken within 90 days of signing the informed consent form will be 
documented as a prior medication/treatment. Medications/treatments taken after signing the 
informed consent form will be documented as concomitant medication/treatments.
Use of hormonal contraception will be allowed during the study; however, subjects must have 
been stabilized on this medication for at least 3 months prior to screening.
Subjects will be allowed to remain on any maintenance medication not excluded by the 
exclusion criteria, provided they have been stabilized on this medication for at least 3 months 
prior to screening.
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6.10
Rescue Medication 
The investigator will provide rescue medication (paracetamol, 500 mg tablets) to the subject at 
the baseline visit. Rescue medication will be re-dispensed on Day 5 (V3), if necessary.
Subjects will be instructed to take only the rescue medication provided for pain in the ankle or 
any other pain (e.g., headache) or fever (e.g., due to common cold) they might experience during 
the trial. One tablet may be taken, repeated after at least 4 hours, if needed, up to a maximum 
of 2000 mg (four tablets) per day. No rescue medication is allowed within 6 hours prior to the 
study visits or within 12 hours of Study Visit 3.
The subject will receive a Subject Diary at Visit 1, Visit 2, and Visit 3 to record the information 
described in Section 6.8. At each visit, the investigator or designee will review the rescue 
medication use recorded in the diary and will transfer the relevant information to the CRF. 
Empty packages and rescue medication not used will be returned to the investigator. The 
investigator or designee will then compare the packages vs. the subject’s rescue medication 
form and any discrepancies will be noted in the CRF. 
The investigator will further investigate any instances in which rescue medication was taken 
for reasons other than ankle sprain and complete the Adverse Event Form, if appropriate.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL
7.1
Subject Discontinuation/Withdrawal 
A subject may withdraw from the study at any time at his or her own request or may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures.  
The following circumstances require discontinuation of study product and/or premature subject 
withdrawal:

Protocol violation that may impact the subject’s safety

Withdrawal of informed consent

Subject lost to follow-up 

Unblinding of the subject 

Pregnancy
If a subject is discontinued or prematurely withdraws from the study, the reason(s) for 
discontinuation or withdrawal and the associated date must be documented in the relevant 
section(s) of the CRF. 
7.2
Lost to Follow up
A subject will be considered lost to follow up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
If a subject fails to return to the site for a required study visit the site must attempt to contact 
the subject and reschedule the missed visit as soon as possible and counsel the subject on the 
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importance of maintaining the assigned visit schedule and ascertain whether or not the subject 
wishes to and/or should continue in the study.
Before a subject is deemed lost to follow up, the investigator or designee must make every effort 
to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a certified 
letter to the subject’s last known mailing address or local equivalent methods). These contact 
attempts should be documented. If contact is made with the subject, the investigator should 
inquire about the reason for withdrawal, request that the subject return all products that they 
had been dispensed and if appropriate request that the subject return for a final visit, and 
follow-up with the subject regarding any unresolved adverse events (AEs).
Final safety assessments may be carried out when the subject returns to the study site, at the 
investigator’s discretion, which could include the following:

Physical examination and vital signs;

Blood and urine specimens for safety laboratory and pregnancy tests (if applicable)
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study and lost to follow up. 
Lack of completion of all or any of the early termination procedures will not be viewed as 
protocol deviations so long as the subject’s safety was preserved.
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
8
STUDY PROCEDURES
This section lists the procedures to be completed at each planned study visit.  The timing of 
each procedure is listed in the Schedule of Activities section.
Adherence to the study design requirements, including all procedures are essential and required 
for study conduct.
8.1
Visit 1/Screening / Randomization Visit
Screening procedures will be conducted by the Investigator, or suitably qualified designee.
As subjects must enter the study and receive treatment within 24 hours of injury, subjects will 
be screened and randomized within 24 hours prior to administration of the investigational 
product to confirm that they meet the subject selection criteria for the study.  
The following procedures will be completed:
8.1.1
Informed Consent
The investigator, or designee, must obtain informed consent from each subject participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study. Two copies of the informed consent form (ICF) will be signed and dated by the 
subject, the subject will retain one copy and the other will be kept at site.
The investigator, or designee, must also explain to the subjects that they are completely free to 
refuse to enter the study or to withdraw from it at any time.  Appropriate forms for documenting 
a signed and dated consent will be provided by either the investigator or by GSK CH.
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The investigator, or designee, should sign and date each copy of the ICF to confirm that the 
consent process was completed correctly after the subject has signed.  
The time the subject signed the informed consent form will also be captured on the Informed 
Consent Form as this is the point at which all Adverse Events will be captured from. The date 
and time of consent will be transcribed to the CRF.
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. Each subject should 
be provided with a copy of the signed and dated amended consent form. The date of re-consent 
will be recorded on the CRF.
After signing the ICF, subjects will undergo the screening assessments to confirm that they 
meet all the inclusion criteria and none of the exclusion criteria. If the subject is confirmed 
eligible by the investigator (or designee) to participate in the study the subject is considered 
enrolled in the study.
8.1.2
Demographics
The following demographic information will be recorded in the CRF: year of birth, gender and 
race.
As an important aspect of the trial is that it be conducted in a local population, race, is an 
important element in establishing a representative population.
8.1.3
Inclusion/Exclusion Criteria
Inclusion and exclusion criteria information will be reviewed and documented in the CRF.
8.1.4
Medical History and Prior Medication/Treatment
Details of relevant medical and surgical history (in the last 5 years), including allergies or drug 
sensitivity, will be documented in the CRF. Of specific interest are diseases of the affected ankle 
or foot in the last 6 months and any concurrent injuries concerning the lower extremities.
Prior medications/treatments, including prescription and non-prescription drugs, dietary 
supplements and herbal remedies, taken in the last 90 days and prior to signing the informed 
consent form, will be documented in the CRF.
8.1.5
Subject Eligibility
The investigator and/or medically qualified designee will review inclusion/exclusion criteria, 
medical history, prior medications to confirm subject eligibility to participate in the clinical trial. 
This will be documented in the CRF.
To prepare for study participation, subjects will be instructed in the Lifestyle Guidelines 
(Section 5.5) and any Concomitant Medication/Treatment(s) (Section 6.9) requirements of the 
protocol.
8.1.6
Screening/Randomization Procedures
The following additional procedures will occur at the Screening/Randomization visit:

Examination of ankle sprain
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
POM, tenderness, ankle swelling, and ankle joint function (total score and subcategories) 
will be assessed

General physical examination including vital signs, weight, and height. Urine pregnancy 
test (women of child bearing potential only)

Safety laboratory blood samples for chemistry and hematology

Eligible subjects receive a randomization number

Baseline Pain Intensity and Pain Relief recorded in CRF

Study medication will be weighed and dispensed to the subject. The weight of each tube 
will be documented in the CRF. The dosing card will also be provided to the subject.

The investigator or a study nurse/doctor’s assistant will apply the first dose of study 
drug at the study site from the morning tube, and the subject will be instructed in 
application amount, method, and time. The subject will also be shown how to utilize the 
dosing card. Four (4) doses of study drug should be applied in total on Day 1, with a 
minimum of 3 hours between each dose.

Dispense Visit 1 subject diary and instruct subject about appropriate use

Spontaneous reporting of adverse events and those elicited by asking subjects to respond 
to a non-leading question such as “How do you feel” will be assessed and any AEs 
recorded in the CRF.

Rescue medication will be dispensed and subjects will be instructed on appropriate use
8.2
Study Period
Remind subject to inform the site if they experience any untoward medical occurrence or use 
any medications in the next 2 days.
8.2.1
Visit 2/Day 3  

Changes in concomitant medication or non-drug treatments/procedures will be 
documented in the CRF. Review safety laboratory tests for chemistry and hematology. 
Having received the results from the samples taken at Visit 1 before the subject attends 
for Visit 2, the Investigator will review the results to ensure that there are no clinically 
significant abnormalities. Any subject with clinically significant abnormalities which in 
the assessment of the investigator are reason for withdrawal will be withdrawn from the 
study at Visit 2 and procedures described for Visit 4 will be completed. Any subject 
with a clinically significant abnormality will be followed until its resolution. 

Subject continued eligibility

Spontaneous reporting of adverse events and those elicited by asking subjects to respond 
to a non-leading question such as “How do you feel?” will be assessed and any AEs 
recorded in the CRF.

The 4 tubes of study medication will be weighed. The weight of each tube will be 
documented in the CRF.

Review Visit 1 Diary
o
Review time and date of each gel application
o
Review scores for Pain Intensity and Pain Relief
o
Review rescued medication use. 
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
POM, tenderness, ankle swelling, and ankle joint function (total score and subcategories) 
will be assessed 

Count and document remaining rescue medication

Collect Visit 1 subject diary

Dispense Visit 2 subject diary and instruct subject about appropriate use
8.2.2
Visit 3/Day 5

Changes in concomitant medication or non-drug treatments/procedures will be 
documented in the CRF. 

Spontaneous reporting of adverse events and those elicited by asking subjects to respond 
to a non-leading question such as “How do you feel?” will be assessed and any AEs 
recorded in the CRF.

Subject continued eligibility 

The 4 tubes of study medication will be weighed. The weight of each tube will be 
documented in the CRF.

Review diary
o
Review time and date of each gel application
o
Review scores for Pain Intensity and Pain Relief
o
Review rescued medication use. 

POM, tenderness, ankle swelling, and ankle joint function (total score and subcategories) 
will be assessed 

Count and document remaining rescue medication.

If insufficient rescued medication remains, additional rescue medication may be 
dispensed

No rescue medication is allowed within 12 hours of this Visit

Collect Visit 2 subject diary

Dispense Visit 3 subject diary and instruct subject about appropriate use
8.2.3
Visit 4 /Day 8 ± 1
Procedures for this visit are also to be completed if the subject terminated the study prematurely.

Changes in concomitant medication or non-drug treatments/procedures will be 
documented in the CRF. 

Spontaneous reporting of adverse events and those elicited by asking subjects to respond 
to a non-leading question such as “How do you feel?” will be assessed and any AEs 
recorded in the CRF.

Subject continued eligibility 

The 4 tubes of study medication will be weighed. The weight of each tube will be 
documented in the CRF

Collect remaining study medication and rescue medication

Review diary
o
Review time and date of each gel application
o
Review scores for Pain Intensity and Pain Relief
o
Review rescued medication use. 

Collect Visit 3 subject diary

Perform a general physical examination including vital signs
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
Urine pregnancy test (women of child bearing potential only)

Safety laboratory blood samples for chemistry and hematology. Any subject with a 
clinically significant abnormality will be followed until its resolution.

POM, tenderness, ankle swelling, and ankle joint function (total score and subcategories) 
will be assessed 

Count and document remaining rescue medication
8.3
Study Conclusion
The Study Conclusion page of the CRF will be completed for all subjects whether they 
completed all study procedures or if they were discontinued from the study early.  If the subject 
discontinued early, at any point during the study, the primary reason for withdrawal should be 
recorded on the Study Conclusion page.
If a subject has any clinically significant, study-related abnormalities or AEs at the conclusion 
of the study, the GSK CH medical monitor (or designated representative) should be notified 
and, the subject may be asked to remain at the clinical site or be asked to return for a follow-up 
visit to ensure any issue is resolved or deemed not clinically significant. 
8.4
Follow-up Visit / “Phone Call”
The study site may contact a subject to follow up an AE post-study completion/withdrawal 
and, in some circumstances, request they return to the site for additional follow-up visits (final 
safety assessments). If needed, additional examinations may be carried out at such visits.
9
STUDY ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are completed 
as described.  However, it is anticipated that from time to time there may be circumstances, 
outside the control of the investigator that may make it unfeasible to complete an assessment.  
In these cases, the investigator must take all steps necessary to ensure the safety and well-being 
of the subject.  When a protocol-required assessment cannot be performed, the investigator (or 
designee) will document the reason for the missed assessment as a protocol deviation and any 
corrective and preventative actions that he or she has taken to ensure that required processes are 
adhered to as soon as possible.  The Sponsor must be informed of any missed assessments in a 
timely manner.
9.1
Screening Assessments
Screening assessments will be performed by appropriately trained staff/clinical examiners at 
the times, and in the order, defined in the Study Procedures section of this protocol 
9.2
Efficacy Assessments
The following efficacy assessments will be performed by appropriately trained staff/clinical 
examiners, at the times and in the order defined in the Study Procedures section of this protocol. 
For individual subjects, the examiner should remain consistent throughout the study period 
where possible.
The following chronological sequence will be observed for the assessments below:
1. Ankle swelling
2. Pain on movement
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3. Tenderness
9.2.1
Ankle Swelling
Ankle swelling is evaluated at Visits 1-4 by the Figure-of-eight-method, a common procedure 
to assess ankle size. The method has been validated on healthy volunteers with an intra-class 
correlation coefficient of 0.99 for inter-tester reliability and 0.99 for intra-tester reliability 
[Tatro Adams 1995, Petersen 1999, Friends 2008].
The Figure-of-eight-method is reproduced by using bony landmarks about the ankle. Common 
sites of ankle sprain swelling are the anterior talofibular ligament, calcaneofibular ligament, 
and anterior tibiofibular ligament. Because the tape spans each of these anatomical areas, the 
figure-of-eight-method may offer a more accurate clinical assessment of ankle swelling.
In detail: a one-quarter-inch wide (about 63 mm), retractable, plastic tape measure is utilized to 
obtain the measurements of each subject’s ankle. All measurements are recorded in cm. Each 
subject is seated comfortably in a long sitting position with both feet extended beyond the end 
of the plinth in a slight dorsiflexion position. The figure of eight-method is applied to both feet 
and the tape measure is wrapped around the ankle along the following course: the beginning of 
the tape is placed midway between the tibialis anterior tendon and lateral malleolus and is then 
continued across anatomically defined points in the form of a figure of eight around the ankle 
joint (for details [Tatro Adams 1995]). The tape localization of the first measurement should be 
marked with an appropriate marker.
Each ankle is measured three times and the average is calculated. The difference in this average 
between ankles tracks the natural course of disease. 
9.2.2
Pain on Movement
The investigator will perform a manipulation of the ankle (i.e., movement) (described below), 
and the pain assessment will be done by the subject. These will occur at the study center on 
Days 1, 3, 5 and 8 (±1) (Visits 1–4) using a 100 mm VAS.
The manipulation will be performed as follows:
The subject is asked to lie down on an even horizontal surface. The investigator gently lifts the 
leg and holds it up in the air at an angle of approximately 45°. While holding the leg with one 
hand, the investigator performs a gentle inversion (i.e., supination) of the foot of the injured 
ankle to reach an angle of approx. 30°.
The extent of ankle pain is evaluated by the subject in answer to the question:
“How would you describe your ankle pain right now?”
The pain-on-movement is registered by the subject by drawing a perpendicular line on the 100 
mm VAS scale with anchors at 0 = “no pain” and 100 = “extreme pain”.
9.2.3
Tenderness
'Tenderness' is the sensation of pain expressed by a subject when pressure is applied to the body. 
A more precise term is 'pressure pain threshold', the minimum pressure required to cause pain. 
Tenderness or pressure pain threshold is one of the major palpatory signs used by practitioners 
for diagnostic and treatment assessment purposes. Tenderness can be quantified with an 
algometer (pressure pain meter). It measures the amount of pressure a subject can endure before 
a pain sensation is elicited. Algometers have been used extensively to measure the efficacy of 
therapeutic interventions for the treatment of pain [Fischer 1987, Ohrbach 1989, Galer 2000, 
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Wetzel 2002, Chesterton 2003]. The reliability of repeated measurements of pressure pain 
threshold has been demonstrated [Fischer 1987, Nussbaum 1998].
Tenderness will be measured by calibrated algometers in an area of 1 cm² at the centre of the 
injured area. The position of measurement will be marked with a water resistant marker on 
subjects’ skin to ensure consistent measuring points throughout the study. The investigator will 
apply the pressure gauge to the marked tender point of maximum sensitivity by placing the 
gauge at a 90° angle vertical to the skin.
The subject is instructed to indicate the onset of pain (pressure pain threshold) with a verbal cue 
such as "Yes" or "Stop". Measurements will be performed with covered scale so that 
investigator and subject cannot see the values. They will be evaluated after measurement.
For assessment of a treatment effect the tenderness of the treated painful area has to be 
compared with the tenderness at the corresponding anatomical position of the healthy uninjured 
contralateral side.
9.2.4
Ankle Joint Function
Evaluated by the subject at the study center at Days 1, 3, 5 and 8 (±1) (Visits 1-4) using the 
Karlsson Scoring Scale [Karlsson 1991 and 1996]. This validated scoring scale measures 
recovery of ankle joint function after an acute ligament injury. Assessments are made in the 
following eight categories (score): pain (20), swelling (10), instability (subjective) (15), 
stiffness (5), stair climbing (10), running (10), work activities (15), and the use of a support 
device (5). The total score ranges in value from 0 to 90.
9.2.5
Diary Pain Intensity and Pain Relief Assessments
Pain intensity will be assessed in the diary on a 4-point categorical scale.
“How would you describe your ankle pain right now?”
0 = “no pain”, 1 = “mild pain”, 2 = “moderate pain”, 3 = “severe pain”.
Spontaneous pain relief will be assessed in the diary on a 5-point categorical scale.
“How would you describe the relief from your ankle pain right now?”
0 = “no relief”; 1 = “a little relief”; 2 = “some relief”; 3 = “a lot of relief ”; 4 = “complete
relief”.
Pain intensity and spontaneous pain relief will both be assessed at baseline (immediately prior 
to first dose) and every 2 hours ± 30 minutes (after starting study drug) until the subject goes to 
bed on the evening of Day 1. The same assessment and recording frequency will also be 
followed starting with the first dose on Day 5. On Day 1 and Day 5 where an assessment time 
point coincides with a dosing time point, the assessment of pain intensity and pain relief should 
be made prior to the dose. For all other time periods, pain intensity and pain relief will be 
assessed and recorded immediately prior to each study drug application.
9.3
Safety and Other Assessments
The following safety assessments will be performed by appropriately trained staff/clinical 
examiners, at the times and in the order defined in the Study Procedures section of this protocol.  
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9.3.1
Laboratory Tests 
The following laboratory tests/analytical measures will be performed by appropriately trained 
staff/clinical examiners, at the times and in the order defined in the Study Procedures section of 
this protocol. 
Table 9-1
Laboratory Tests
Hematology
Chemistry
Other
Hemoglobin
Hematocrit RBC 
count 
Platelet count 
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes (Abs)
BUN/urea and Creatinine
Glucose 
Calcium 
Magnesium 
Sodium 
Potassium 
Chloride
Total CO2(Bicarbonate)
 AST, ALT
Direct Bilirubin
Indirect Bilirubin
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
PT/INR
Urine pregnancy test
Definitions:  RBC= Red blood cell; WBC= White blood cells; BUN=Blood urea nitrogen; AST= 
transaminase; ALT= alanine transaminase; PT/INR= prothrombin time/ international normalized ratio.
Information on the local laboratory and sampling routines, normal ranges, and reporting will be 
provided in the Investigator binder supplied to each center. The local laboratory will report 
results to the center as early as possible in order to allow the Investigator to review the results 
no later than 24 hours after blood samples being taken.
Additional laboratory results may be reported on these samples as a result of the method of 
analysis or the type of analyzer used by the clinical laboratory; or as derived from calculated 
values.  These additional tests would not require additional collection of blood.  Unscheduled 
safety lab tests may be obtained at any time during the study to assess any perceived safety 
concerns. 
9.3.2
Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, will be performed at Day 
1 and Day 8 ± 1. Approximately 30 mL will be collected for testing. Results will be obtained 
prior to dosing.  A female subject will be considered of non-childbearing potential if they satisfy 
at least one of the following criteria:
1. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause; status may be 
confirmed by a serum follicle-stimulating hormone (FSH) level confirming the 
post-menopausal state;
2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
3. Have medically confirmed ovarian failure.
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All other female subjects will be considered to be of childbearing potential.
The investigator and site personnel will remind subjects at each visit to inform site personnel if 
their menstrual cycle has changed or if they have any other reason to suspect they may be 
pregnant (e.g. had unprotected intercourse since the last visit).
A negative pregnancy result is required before the subject may receive the investigational 
product.  Pregnancy tests will also be done whenever one menstrual cycle is missed during the 
active study period (or when potential pregnancy is otherwise suspected). Pregnancy tests may 
also be repeated as per request of IRBs/ECs or if required by local regulations.
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product and from the study.
9.3.3
Physical Examinations 
Physical examinations may be conducted by a physician, trained physician's assistant, or nurse 
practitioner as acceptable according to local regulation.  
A general physical examination will be performed at Day 1 (randomization visit) and upon study 
termination (Day 8 ± 1 - final visit), as well as when judged necessary by the investigator. 
Examination will include: general condition, dermatologic, eyes, ears, nose, throat, neck, thyroid, 
heart, respiratory system, abdomen, kidneys, skeletal system, extremities, lymphatic system, CNS, 
neurological conditions according to the state of the art.
Any untoward findings identified on physical exams conducted after the administration of the 
first dose of investigational product will be captured as an adverse event, if those findings meet 
the definition of an adverse event.
9.3.4
Height and Weight 
Height in cm and body weight in kilograms (kg) to the nearest 0.1 kg will be measured at 
Visits 1 and 4 (height at Visit 1 only).
For measuring weight, a scale with appropriate range and resolution should be used and must 
be placed on a stable, flat surface. Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains. They must also remove the contents of their pockets 
and remain still during measurement of weight. 
9.3.5
Vital Signs (Blood Pressure and Pulse Rate)
Vital signs (including systolic blood pressure, diastolic blood pressure and pulse rate) will be 
measured at Visits 1 and 4:
- Blood pressure: Measurement after at least 5 minutes at rest in sitting position.
- Pulse rate: Measured after at least 5 minutes at rest in the sitting position.
Additional collection times, or changes to collection times of blood pressure and pulse rate will 
be permitted, as necessary at the discretion of the investigator, to ensure appropriate collection 
of safety data.
The same properly sized and calibrated blood pressure cuff will be used to measure blood 
pressure each time. The use of an automated device for measuring BP and pulse rate is 
acceptable, although, when done manually, pulse rate will be measured in the brachial/radial 
artery for at least 30 seconds.  When the timing of these measurements coincides with a blood 
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collection, blood pressure and pulse rate should be obtained prior to the nominal time of the 
blood collection.
9.4
Blood Volume
The total blood sampling volume for each subject in this study is approximately 20 mL 
(approximately 10 mL x 2).  The table below reflects approximate sample volumes needed for 
each measured endpoint.  The actual collection times of blood sampling may change, but the 
total blood volume collected will not increase. Additional blood samples may be taken for safety 
assessments at the discretion of the investigator or GSK CH.
Table 9-2
Blood Volume
Number of Sampling Times
Sample Type
Sample 
Volume 
(mL)
Screening 
(Visit 1)
Study Period 
(Visit 4)
Follow-Up
Total Volume 
(mL)
Safety Labs
<10
1
1
<20
TOTAL
<20
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed 
catheters, if applicable.  
10
ADVERSE EVENT AND SERIOUS ADVERSE EVENTS
10.1
Definition of an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study subject, temporally associated 
with the use of a study product including any washout or lead-in product or investigational 
assessment, whether or not considered related to the study product, including any washout or 
lead-in product or investigational assessment.
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 a study product including any washout or lead-in product or investigational assessment.
Events Meeting the AE Definition:  

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g. ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study product administration even though 
it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug 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 unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE. Such instances will be captured in the efficacy assessments. 
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However, the signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy will be reported as AE if they fulfill the definition of an AE. 
Events NOT meeting the AE definition: 

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 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) is not the AE. The 
condition that leads to the procedure is an AE (e.g. appendicitis).

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. 
10.2
Definition of a Serious Adverse Event (SAE)
A Serious Adverse Event (SAE) is a particular category of an adverse event where the adverse 
outcome is serious. If an event is not an AE per definition above, then it cannot be an SAE even 
if serious conditions are met (e.g. hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death

Is life-threatening 

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;

Requires inpatient hospitalization or prolongation of existing hospitalization 

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 outpatient 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.

Results in persistent or significant disability/incapacity

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, 
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influenza, and accidental trauma (e.g. sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption

Results in congenital anomaly/birth defect

Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
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 events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
Note: Classification of an AE as ‘serious’ is based on the outcome of the event, and is a factor 
in determining reporting requirements.
10.3
Reporting of Adverse Events
10.3.1
Reporting Period 
All AEs, and therefore all SAEs will be collected immediately after a subject consents to 
participate in the study by the completion (signature) of the ICF and until 28 days following 
last administration of the study product (or last procedure). 
Medical occurrences that began before obtaining informed consent will be recorded in the 
Medical History/Current Medical Conditions section of the CRF not the AE section.
Details recorded by the subject on a diary or similar document that meet the definition of an AE 
must also be discussed with the subjects and transcribed in the AE section of the CRF. 
10.4
Reporting Procedures
The investigator and any designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE and remain responsible for following up on AEs that 
are serious, considered related to the study product(s), participation in the study, or a study 
procedure, or that caused the subject to discontinue the study product or study. 
The investigator (or medically qualified designee) is to report all directly observed AEs and all 
AEs spontaneously reported by the study subject. In addition, each study subject will be 
questioned about AEs. 
Each AE is to be assessed to determine if it meets the criteria for a SAE.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
When an AE occurs, it is the responsibility of the investigator (or medically qualified designee) 
to review all documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
The investigator or site staff will then record all relevant information regarding an AE in the 
CRF and all details relating to an SAE in the SAE Form provided.
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It is not acceptable for the investigator (or medically qualified designee) to send photocopies 
of the subject’s medical records to GSK CH in lieu of completion of the AE CRF page/SAE 
form.
There may be instances when copies of medical records for certain cases are requested by GSK 
CH.  In this instance, all subject identifiers, with the exception of the subject number, will be 
redacted on the copies of the medical records prior to submission to GSK CH.
The investigator (or medically qualified designee) will attempt to establish a diagnosis of the 
event based on signs, symptoms, and/or other clinical information.  The diagnosis will be the 
documented as the AE/SAE where known and not the individual signs/symptoms. (e.g. upper 
respiratory tract infection, seasonal allergy, etc. instead of runny nose).
AEs elicited by the investigator (or medically qualified designee) in a standard manner at the 
study visits should also be recorded in the AE section of the CRF and/or using the SAE form 
(subject to the classification of the AE). Care will be taken not to introduce bias when 
questioning a subject about any changes in their health. Open-ended and non-leading verbal 
questioning should be used.
10.4.1
Reporting of an Adverse Event
All AEs will be reported on the AE page of the CRF by the investigator or site staff.  It should 
be noted that the form for collection of SAE information is not the same as the AE CRF.  Where 
the same data are collected, the AE CRF page and the SAE form must be completed in a 
consistent manner.  For example, the same AE term should be used on both.  AEs should be 
reported using concise medical terminology on the CRF as well as on the form for collection of 
SAE information.
10.4.2
Reporting of a Serious Adverse Event
In addition to recording the details of each AE on the AE CRF page, an SAE form should be 
completed, as fully as possible. Hard copies of the ‘paper’ SAE form will be provided in the 
investigator study master file. Original SAE forms will be retained in the investigator study 
master file.
It is essential to enter the following information: 

Protocol and subject identifiers

Subject demography

Description of events, with diagnosis if available

Investigator opinion of relationship to study product (or study procedure, if appropriate)

Criterion for seriousness.
The following are desirable and are of particular relevance for investigator and GSK CH 
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
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St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 4 7  of 6 4

Acti o n ta ke n i n relati o n t o t he st u d y pr o d uct

O utc o me if k n o w n
T he S A E f or m, c o m plete d as f ull y as p ossi ble, m ust be se nt t o C R O m o nit or i m me di atel y a n d 
u n der n o circ u mst a nce s h o ul d t his e xcee d 2 4 h o urs of a ware ness.
C R O will t he n e mail t he S A E f or m t o t he Case Ma na ge me nt Gr o u p, Gl o bal Cli nical Safet y a n d 
P har mac o vi gila nce at G S K C H (
), wit h c o p y t o t he a p pr o priate G S K C H 
St u d y Ma na ger as s o o n as p ossi ble, b ut n ot l ater t h a n 2 4 h o urs after st u d y site pers o n nel lear n 
of t he e ve nt. T he G S K C H St u d y Ma na ger will be res p o nsi ble f or f or war di n g t he S A E f or m t o 
ot her G S K C H pers o n nel as a p pr o priate.
T he I n vesti gat or s h o ul d als o re p ort t o C hi na healt h a ut h orities a n d t he I n de pe n de nt Et hics 
C o m mittee (I E C) wit hi n 2 4 h o urs i n writte n d oc u me ntati o n wit h t he re p ort si g ne d a n d date d.
1 0. 5 
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1 0. 5. 1  
A s s e s s m e nt of I nt e n sit y
T he i n vesti gat or or me dicall y q ualifie d desi g nee will ma ke a n assess me nt of i nte nsit y f or eac h 
A E re p orte d d uri n g t he st u d y a n d will assi g n it t o o ne of t he f oll o wi n g cate g ories:

Mil d:  A n e ve nt t hat is easil y t olerate d b y t he s u bject, ca usi n g mi ni mal disc o mf ort a n d 
n ot i nterferi n g wit h e ver y da y acti vities.

M o derate:  A n e ve nt t hat is s ufficie ntl y disc o mf orti n g t o i nterfere wit h n or mal e ver y da y 
acti vities

Se vere:  A n e ve nt t hat pre ve nts n or mal e ver y da y acti vities. 
N O T E: A n A E t hat is assesse d as se vere s h o ul d n ot be c o nf use d wit h a n S A E. Se vere is a 
cate g or y utilize d f or rati n g t he i nte nsit y of a n e ve nt; a n d b ot h n o n-seri o us A Es a n d S A Es ca n 
be assesse d as se vere. F or e xa m ple, a hea dac he ma y be se vere (i nterferes si g nifica ntl y wit h t he 
s u bject's us ual f u ncti o n) b ut w o ul d n ot be classifie d as seri o us u nless it met o ne of t he criteria 
f or S A Es, liste d a b o ve. A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least 1 of t he pre defi ne d 
o utc o mes as descri be d i n t he defi niti o n of a n S A E, N O T w he n it is rate d as se vere.
1 0. 5. 2  
A s s e s s m e nt of C a u s alit y
T he ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
re q uire me nts. F or eac h A E (seri o us a n d n o n-seri o us), t he i n vesti gat or ( or me dicall y q ualifie d 
desi g nee) m ust  pr o vi de a n assess me nt of ca usalit y o n t he A E C R F pa ge a n d t he S A E f or m 
(s u bject t o t he classificati o n of t he A E). T he i n vesti gat or will als o d oc u me nt i n t he me dical 
n otes t hat he/s he has re vie we d t he A E a n d assesse d ca usalit y, w here a p plica ble. 
A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d o ut. 
Ge nerall y, t he facts (e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p s h o ul d be pr o vi de d.
T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p a n d will als o c o ns ult 
t he I n vesti gat or Br oc h ure (I B), Safet y State me nt a n d/ or Pr o d uct I nf or mati o n, f or mar kete d 
pr o d ucts, i n t he deter mi nati o n of his/ her assess me nt.  Alter nati ve ca uses, s uc h as u n derl yi n g 
disease(s), c o nc o mita nt t hera p y, ot her ris k fact ors, a n d t he te m p oral relati o ns hi p of t he e ve nt t o 
t he st u d y pr o d uct will be c o nsi dere d a n d i n vesti gate d.
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
P P D


Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 4 8  of 6 4
F or eac h A E/ S A E, t he i n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he has re vie we d 
t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y.
T he i n vesti gat or’s assess me nt of ca usalit y m ust be pr o vi de d f or all A Es (seri o us a n d n o n-
seri o us); t he i n vesti gat or m ust rec or d t he ca usal relati o ns hi p i n t he C R F, as a p pr o priate, a n d 
re p ort s uc h a n assess me nt i n acc or da nce wit h t he S A E re p orti n g re q uire me nts if a p plica ble.
T here ma y be sit uati o ns w he n a n S A E has occ urre d a n d t he i n vesti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o G S K.  H o we ver, it is ver y i m p ort a nt t h at t he 
i n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y f or e ver y e ve nt pri or t o t he i niti al 
tr a ns missi o n of t he S A E d at a t o G S K C H. T he i n vesti gat or ma y c ha n ge his/ her o pi ni o n of 
ca usalit y i n li g ht of f oll o w- u p i nf or mati o n a n d se n d a n S A E f oll o w- u p re p ort wit h t he u p date d 
ca usalit y assess me nt. 
1 0. 6 
F oll o w- u p of A d v er s e E v e nt s 
After t he i nitial re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w u p wit h eac h s u bject 
a n d pr o vi de f urt her i nf or mati o n o n t he s u bject’s c o n diti o n.
All A Es (seri o us a n d n o n-seri o us) will be f oll o we d u ntil res ol uti o n, or u ntil t he c o n diti o n 
sta bilizes, or u ntil t he e ve nt is ot her wise e x plai ne d, or u ntil t he s u bject is l ost t o f oll o w- u p.  
T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as ma y be i n dicate d or as re q ueste d b y G S K C H t o el uci date 
as f ull y as p ossi ble t he nat ure a n d/ or ca usalit y of t he A E. T his ma y i ncl u de a d diti o nal la b orat or y 
tests or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care 
pr ofessi o nals.
Ne w or u p date d i nf or mati o n will be rec or de d o n t he A E C R F pa ge a n d o n t he S A E f or m (s u bject 
t o t he classificati o n of t he A E).
T he i n vesti gat or will s u b mit a n y u p date d S A E data t o G S K C H wit hi n 2 4 h o urs of recei pt of 
t he i nf or mati o n.
I n vesti gat ors are n ot o bli ge d t o acti vel y see k A Es i n f or mer s u bjects.  H o we ver, if t he 
i n vesti gat or lear ns of a S A E, i ncl u di n g deat h, at a n y ti me after a s u bject has bee n disc har ge d 
fr o m t he st u d y, a n d c o nsi ders t he e ve nt reas o na bl y relate d t o t he st u d y pr o d uct or st u d y 
partici pati o n, t he i n vesti gat or will pr o m ptl y n otif y G S K C H b y e maili n g t he i nf or mati o n t o t he 
G S K C H Cli nical O perati o ns Safet y Re p orti n g e mail b o x (
). 
T he G S K C H St u d y Ma na ger or desi g nee will be res p o nsi ble f or f or war di n g t he i nf or mati o n t o 
t he Case Ma na ge me nt Gr o u p, Gl o bal Cli nical Safet y a n d P har mac o vi gila nce gr o u p mail b o x at 
G S K (
).
T he i n vesti gat or will s u b mit a n y u p date d S A E data t o G S K C H wit hi n t he desi g nate d re p orti n g 
ti me fra mes.
1 0. 7  
Wit h dr a w al D u e t o a n A d v er s e E v e nt 
Wit h dra wal d ue t o A Es s h o ul d be disti n g uis he d fr o m wit h dra wal d ue t o ot her ca uses, acc or di n g 
t o t he defi niti o n of a n A E n ote d earlier, a n d rec or de d o n t he a p pr o priate A E C R F pa ge. 
W he n a s u bject wit h dra ws beca use of a n S A E, t he S A E m ust be re p orte d i n acc or da nce wit h 
t he re p orti n g re q uire me nts defi ne d.
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
P P D
P P D


Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 4 9  of 6 4
1 0. 7. 1 
S p o n s or’ s R e p orti n g R e q uir e m e nt s t o R e g ul at or y A ut h oriti e s a n d 
Et hi c s C o m mitt e e s
G S K C H has a le gal res p o nsi bilit y t o n otif y, as a p pr o priate, t he l ocal re g ulat or y a ut h orit y a n d 
ot her re g ulat or y a ut h orities a b o ut t he safet y of a pr o d uct u n der cli nical i n vesti gati o n.  Pr o m pt 
n otificati o n of S A Es b y t he i n vesti gat or t o G S K C H is esse ntial s o t hat le gal o bli gati o ns a n d 
et hical res p o nsi bilities t o war ds t he safet y of s u bjects are met.
G S K C H will c o m pl y wit h c o u ntr y s pecific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g 
t o t he re g ulat or y a ut h orit y, I R B/ E C a n d i n vesti gat ors.
I n vesti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire me nts a n d s p o ns or p olic y a n d f or war de d t o 
i n vesti gat ors as necessar y.
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her s pecific 
safet y i nf or mati o n e. g. s u m mar y or listi n g of S A E fr o m t he s p o ns or will re vie w a n d t he n file it 
al o n g wit h t he I n vesti gat or’s Br oc h ure i n t he i n vesti gat or st u d y master file, a n d will n otif y t he 
I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
1 0. 8 
Pr e g n a n c y
1 0. 8. 1 
Ti m e P eri o d f or C oll e cti n g Pr e g n a n c y I nf or m ati o n
Pre g na nc y i nf or mati o n will be c ollecte d o n all pre g na ncies re p orte d w hile a fe male s u bject is 
partici pati n g i n t he st u d y fr o m t he si g ni n g of i nf or me d c o nse nt u ntil at least 2 1 da ys after last 
a d mi nistrati o n of st u d y pr o d uct.
1 0. 8. 2  
A cti o n t o b e T a k e n if Pr e g n a n c y O c c ur s
T he i n vesti gat or will c ollect pre g na nc y i nf or mati o n o n a n y s u bject w h o bec o mes pre g na nt 
w hile partici pati n g i n t he st u d y after a d mi nistrati o n of t he i n vesti gati o nal pr o d uct. T he 
i n vesti gat or will rec or d pre g na nc y i nf or mati o n o n t he a p pr o priate f or m a n d s u b mit it t o C R O 
wit hi n 2 4 h o urs of lear ni n g of t he s u bject bec o mi n g pre g na nt. T he s u bject will be f oll o we d t o 
deter mi ne t he o utc o me of t he pre g na nc y. I nf or mati o n o n t he stat us of t he m ot her a n d 
i nfa nt/ ne o nate (i ncl u di n g c o nc o mita nt me dicati o ns ta ke n b y t he m ot her d uri n g t he pre g na nc y) 
will be f or war de d t o C R O. Ge nerall y, f oll o w- u p will be n o l o n ger t ha n 6 t o 8 wee ks f oll o wi n g 
t he esti mate d deli ver y date. A n y ter mi nati o n of t he pre g na nc y will be re p orte d. 
C R O will sca n a n d e mail t he pre g na nc y f or m t o t he Case Ma na ge me nt Gr o u p, Gl o bal Cli nical 
Safet y a n d P har mac o vi gila nce gr o u p mail b o x at G S K C H (
) wit h c o p y 
t o t he a p pr o priate G S K C H St u d y Ma na ger. Ori gi nal pre g na nc y i nf or mati o n f or ms will be 
retai ne d i n t he i n vesti gat or st u d y master file. 
1 1  
D A T A M A N A G E M E N T
As use d i n t his pr ot oc ol, t he ter m case re p ort f or m ( C R F) is u n derst o o d t o refer t o eit her a pa per 
f or m or a n electr o nic data rec or d or b ot h, de pe n di n g o n t he data c ollecti o n met h o d. 
F or t his st u d y, s u bject data will be e ntere d i nt o a n electr o nic C R F (e C R F), usi n g a vali date d 
s yste m. Data relati n g t o S A Es, pre g na nc y a n d i nci de nts will als o be c ollecte d o n pa per f or ms.
T he i n vesti gat or is res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y 
p h ysicall y or electr o nicall y si g ni n g t he C R F.
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
P P D


Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 5 0  of 6 4
T he s o urce d oc u me nts (e. g. h os pital rec or ds, cli nical a n d office c harts, la b orat or y n otes, 
me m ora n da, e val uati o n c hec klists, p har mac y dis pe nsi n g rec or ds, rec or de d data fr o m a ut o mate d 
i nstr u me nts, micr ofic hes, p h ot o gra p hic ne gati ves, micr ofil m or ma g netic me dia, x-ra ys, s u bject 
files a n d rec or ds ke pt at t he p har mac y, at t he la b orat or y a n d at t he me dic o-tec h nical de part me nts 
i n v ol ve d i n t he cli nical st u d y) w hic h c o ntai n t he s o urce of data rec or de d i n t he C R F s h o ul d be 
s pecifie d i n Secti o n 8 a n d 9.  T he  C R F ca n be use d as a s o urce d oc u me nt at t he discreti o n of 
data ma na ge me nt.
Eac h s u bject will be assi g ne d a n d i de ntifie d b y a u ni q ue Scree ni n g S u bject N u m ber. A n y 
refere nce ma de t o a n i n di vi d ual s u bject wit hi n t he st u d y m ust be d o ne usi n g t heir u ni q ue 
Scree ni n g S u bject N u m ber.
1 1. 1  
C a s e R e p ort F or m
A C R F is a pri nte d, o ptical, or electr o nic d oc u me nt desi g ne d t o rec or d t he pr ot oc ol re q uire d 
i nf or mati o n t o be re p orte d t o t he s p o ns or o n eac h trial s u bject.
F or eac h s u bject w h o has gi ve n i nf or me d c o nse nt/asse nt t he C R F m ust be c o m plete d a n d si g ne d 
b y t he Pri nci pal I n vesti gat or ( or a ut h orize d desi g nee) t o certif y t hat t he data are c o m plete a n d 
c orrect.  T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t he C R F.
Ma na ge me nt of cli nical data will be perf or me d i n acc or da nce wit h T hir d Part y B D M Ve n d or 
a p plica ble sta n dar ds a n d data clea ni n g pr oce d ures wit h o versi g ht b y G S K C H t o e ns ure 
i nte grit y of t he data, f or e xa m ple, t o re m o ve err ors a n d i nc o nsiste ncies i n t he data. 
T o pr otect t he pri vac y of s u bjects, n o Pers o nall y I de ntifia ble I nf or mati o n ( PII) (i ncl u di n g t he 
s u bject's na me or i nitials or f ull birt h date) is t o be rec or de d i n t he C R F or as part of t he q uer y 
te xt.
All C R F pa ges s h o ul d be c o m plete d d uri n g a s u bject assess me nt w he n t he C R F has bee n 
desi g nate d as t he s o urce.  Data t hat is s o urce d else w here s h o ul d be e ntere d i nt o t he C R F i n a n 
a gree d u p o n ti mefra me bet wee n t he I n vesti gat or a n d S p o ns or.  
G S K C H will o btai n a n d retai n all C R Fs a n d ass ociate d st u d y data as a p plica ble at t he 
c o m pleti o n of t he st u d y. 
1 1. 2  
D at a H a n dli n g
D oc u me ntati o n of all data ma na ge me nt acti vities s h o ul d all o w ste p- b y-ste p retr os pecti ve 
assess me nt of data q ualit y a n d st u d y perf or ma nce. 
A n y c ha n ges or c orrecti o ns t o data will be perf or me d i n t he Electr o nic Data Ca pt ure ( E D C) 
S yste m, a n d it will i ncl u de rati o nale f or c ha n ges. T he E D C s yste m has a n a u dit trail, w hic h will 
pr o vi de a c o m plete rec or d of t he c ha n ges a n d c orrecti o ns e n d orse d b y t he I n vesti gat or.
A d verse e ve nts will be c o de d usi n g Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
a n d a n y c o nc o mita nt me dicati o ns ter ms (if a p plica ble) usi n g a n i nter nal vali date d me dicati o n 
dicti o nar y,  
.  
1 1. 2. 1  
D at a Q u eri e s
Pr o gra m me d e dit c hec ks will be ge nerate d a ut o maticall y, as t he data are bei n g e ntere d i nt o t he 
s yste m. Re p orts a n d listi n gs o n t he C R F data will als o be r u n, i n a d diti o n t o t he q ueries alrea d y 
pr o gra m me d a n d ge nerate d b y t he s yste m, t o raise ma n ual q ueries as nee de d f or site 
clarificati o n or c orrecti o n. T he Cli nical Dicti o nar y De vel o p me nt a n d Ma na ge me nt Gr o u p will 
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
C CI


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raise queries as needed on safety data to code the terms (AEs and Drugs or concomitant 
medication) appropriately. 
The study monitor will perform ongoing review the of the CRFs in accordance with the 
monitoring plan, to confirm that data entered into the CRF by authorized site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.
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. The study monitor can also 
run reports and listings on the CRFs, to raise manual queries as needed for site clarification or 
correction.
11.3
Processing Subject Reported Outcomes
Paper based subject reported outcome (PRO) data may be collected from a diary, questionnaire, 
or other specified document, etc. and entered into the data management system (DMS).  
All PRO source data should be reviewed by the study staff and the study monitor in order to 
ensure accurate transcription of data and that any potential AEs or concomitant medications 
reported on these documents are discussed with the subject and transcribed accurately to the 
CRF and/or DMS. Site staff cannot make any changes to subject diaries. If a subject makes a 
change to the subject diary, they must initial and date the change. PROs that are classed as 
source data will be retained by the investigator and true/certified copies may be sent to a 
designated vendor or GSK CH as required.
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 any PRO/ePRO that will be 
forwarded to GSK CH or Third-Party Vendor.
12
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
12.1
Sample Size Determination
Approximately 300 subjects will be randomized to ensure at least 240 evaluable subjects 
complete the study for the PP analysis population. A maximum of 40 randomized subjects per 
center will be allowed.
Approximately 120 subjects per treatment arm has been determined to provide 80% power to 
demonstrate non-inferiority of DDEA 2.32% gel b.i.d with DDEA 1.16% gel q.i.d. by 
comparing the two-sided 95% CI of the difference in mean change from baseline of VAS POM 
score between the two products with the non-inferiority margin of 13 mm.  This assumes a 
treatment standard deviation of 22mm and allows for a possible small true treatment difference 
of 5mm in favor of DDEA 1.16%.
The margin of 13 mm (on a 100 mm VAS scale) was chosen as the literature reported minimally 
important clinical difference for an acute musculoskeletal injury (Todd et al 1995), with 
treatment differences smaller than 13mm considered as not clinically important.  The standard 
deviation was obtained from a previous placebo-controlled ankle sprain study VOPO-P-307 
with DDEA 2.32% gel.
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12.2
Statistical Methods and Analytical Plan
Additional details of the proposed statistical analysis will be documented in the statistical 
reporting and analysis plan (RAP), which will be written following finalization of the protocol 
and prior to study unblinding.
12.2.1
Definition of Analysis Populations
The safety population will include all subjects who are randomized and have received at least 
one dose of investigational product.
The modified intent-to-treat (mITT) population will consist of all randomized subjects who 
have at least one post baseline POM VAS assessment
The PP population includes all subjects from the mITT population who do not have any major 
protocol deviations that could confound the interpretation of the efficacy analyses. Protocol 
deviations that would exclude subjects from the PP population are defined in Section 12.2.2.
Before the study is unblinded, each actual post-baseline visit will be mapped to the target visit date 
to which it is chronologically closest. This corresponds to the following visit windows: Visit 2 (Days 
2–4), Visit 3 (Days 4–6), Visit 4 (Days 7+). The numbering of the actual visits (from Visit 1 to Visit 
4) will then be changed as needed to improve the correspondence of the actual visit dates to the 
protocol-specified schedule of visits, particularly in relation to Visit 3 (primary). Final 
determinations will also be made and documented before the study is unblinded to address visits 
that occur on Day 4 (which maps to two visit windows) or visits occurring well beyond the target 
date for the final visit or any other irregularities. Further detail is provided in the statistical analysis 
plan. 
12.2.2
Exclusion of Data from Analysis 
Exclusion of any data from the analyses will be determined during a Blind Data Review 
Meeting prior to database lock. Any reasons for exclusion from an analysis population will be 
listed, if applicable.  
Protocol deviations that would exclude subjects from the PP population may include (but are 
not limited to) the following:

Subjects failing to meet inclusion and exclusion criteria but were included in the study.

Subjects without a Day 5 pain on movement VAS assessment

Subjects with poor or moderate compliance with study treatment

Subjects taking prohibited medication 

Subjects identified with other major protocol deviations 
Further detail is provided in the statistical analysis plan.
12.2.3
Demographic and Baseline Characteristics
Demographic data, including age, gender and race, and other baseline data will be presented 
using descriptive statistics. 
Categorical variables will be summarized by the number and percentage of subjects with each 
relevant characteristic. Continuous variables will be summarized by calculating the mean, 
standard deviation, median, minimum and maximum.
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Template Version Effective: 18-May-18 (CCR #11475)
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12.2.4
Study Drug/Product Compliance and Use of Other Therapies
12.2.4.1 Study Drug/Product Compliance
Compliance is defined in terms of the total weight of study medication used and total number 
of applications made as follows:
• Good: > 80% of the gel has been applied and > 80% of scheduled applications made,
• Moderate: not Good and not Poor
• Poor: < 50% of the gel has been applied or < 50% of scheduled applications made.
The % of gel used will be computed relative to the actual number of applications made from 
randomization through the final visit multiplied by 2 g. This value is to be recorded in the CRF. 
Scheduled applications will include all scheduled applications through the day before the final 
visit. On day 1, the percentage of gel used will be calculated based on the possible number of 
administrations on that day. If only 3 were possible, then 100 % compliance on that day will be 
considered 3 applications.
Compliance will be summarized descriptively as (1) % of scheduled applications made, (2) % 
of gel used relative to number of actual applications * 2g, and (3) compliance category 
(Good/Moderate/Poor). Exposure to study drug will be summarized descriptively as (1) number 
of applications made and (2) total amount of gel used.
For subjects applying active gel only twice per day (DDEA 2.32%), and additional compliance 
and exposure computation will be performed relative to the tubes and applications of active gel.
12.2.4.2 Prior and Concomitant Medications
Prior and concomitant medications will be listed in the safety population. Concomitant 
medications will be summarized by preferred term, and the number and percentage of subjects 
who took any concomitant medication, will be presented.
12.2.5
Primary Analysis(es) 
The primary efficacy endpoint will be change from baseline in POM on Day 5 of treatment as 
assessed by a 100 mm VAS scale.
The following primary non-inferiority hypothesis will be tested for DDEA 2.32% vs DDEA 
1.16%:
The null hypothesis is Diclofenac 2.32% DDEA Gel administered BID is inferior to Diclofenac 
1.16% DDEA gel administered QID with the alternative hypothesis being Diclofenac 2.32% 
DDEA Gel administered BID is non-inferior to Diclofenac 1.16% DDEA gel administered QID.
Diclofenac 2.32% DDEA Gel administered BID will be declared non-inferior to Diclofenac 
1.16% DDEA gel administered QID if the upper limit of the two-sided 95% confidence interval 
of the difference between their mean changes from baseline VAS POM responses is less than 
the established margin of 13 mm.
The primary analysis will be based on an analysis of covariance (ANCOVA) with treatment 
and center as factors and baseline value as a covariate to estimate the treatment difference two-
sided 95% confidence interval for the primary endpoint to assess non-inferiority, using the per 
protocol and mITT analysis populations. 
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Evidence of a treatment-by-center interaction will be assessed by adding a factor for this 
interaction in a separate additional analysis model of the primary endpoint. If there is evidence 
of an interaction (p<0.05), then the primary endpoint outcome will also be summarized by 
center for further investigation and assessment
12.2.6
Secondary Analysis(es)
Secondary outcome measures (endpoints) include:

Change from baseline of POM on VAS on Days 3 and 8 respectively

Tenderness measured by pressure algometry on Days 3, 5 and 8 (change from baseline 
and difference between the measurement in injured area and contralateral area)

Change from baseline Ankle Joint Function (Karlsson Scoring Scale) on Days 3, 5 and 
8

Circumference measurement of swelling (change from baseline in circumference of 
affected ankle and comparison to non- affected ankle by Figure of Eight method on 
Days 3, 5 and 8)

Pain Intensity and Pain Relief 
o
Sum of Pain Intensity Difference (SPID) – From hours 0 – 24 post first dose 
(corresponding to Day 1) and from hours 96 – 120 post first dose (corresponding 
to Day 5)
o
Total Pain Relief (TOTPAR)– From hours 0 – 24 post first dose (corresponding 
to Day 1) and from hours 96 – 120 post first dose (corresponding to Day 5)
TOTPAR and SPID will be calculated as weighted sums of the Pain Relief Score and Pain 
Intensity Difference at each timepoint respectively:
TOTPAR = ΣRtx (timet – timet-1)
Where Rt = the pain relief score at time t and timet = time in hours post first dose
SPIDt = ΣPIDt (timet – timet-1)(h)
Where PI is pain intensity

Use of rescue medication, for ankle sprain and overall
o
Total number of tablets used
o
Total number of days on which rescue medication was used
Figures will show the time course of outcomes by treatment group for key quantitative outcomes. 
For POM, Karlsson score, tenderness, swelling and diary assessments (SPID and TOTPAR), 
an ANCOVA model including treatment group and center as main effects, and the baseline 
value as covariate (those outcomes for which there is a baseline) will be used for analysis, with 
the treatment difference and 95% confidence interval (two-sided) presented for each assessment.
Use of rescue medication (number of tablets and days used) will be compared between 
treatments using the CHM method (modridit scores) stratified by center, with the median 
treatment differences and 95% confidence intervals (2-sided) presented using Hodges-Lehmann 
estimation.
These secondary endpoints will be analyzed using the per protocol and mITT populations. 
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12.2.7
Safety Analysis(es)
Safety variables will be summarized on the safety population.
Exposure to study drug (number of applications, total weight of gel used) will be summarized 
by treatment group.
Treatment Emergent adverse events (TEAE, i.e. AEs that start or worsen after first study 
treatment administration) will be summarized by presenting, for each treatment group, the 
number and percentage of subjects having any TEAE, any TEAE in each MedDRA primary 
System Organ Class (SOC) and having each individual TEAE (using MedDRA preferred term). 
This will be done separately for all TEAEs and for TEAEs that are suspected to be drug-related. 
All TEAEs will also be tabulated in corresponding fashion by severity. Any other information 
collected (e.g. action taken, duration, outcome, seriousness) will be listed as appropriate. 
All adverse events (prior to treatment and treatment emergent) will be listed.
Chemistry and hematology results at Visit 1 and at Visit 4 will be summarized by the mean, 
standard deviation, median, minimum and maximum values in each treatment group. Shift 
tables (between Visit 1 and Visit 4) will also be presented. Laboratory normal ranges and all 
laboratory test results will be listed.
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate) recorded at Visit 
4 and changes in vital signs from Visit 1 (baseline) to Visit 4 will be summarized by the mean, 
standard deviation, median, minimum and maximum values in each treatment group. Vital signs 
at each assessment will also be listed.
12.2.8
Other Analysis(es)
Not applicable.
12.2.9
Handling of Dropouts and Missing Data 
Multiple imputation using a simulation-based statistical technique for handling missing data as 
proposed by [Rubin, 1987] will be used. Multiple imputation will consist of three steps:
1.
Imputation step. Missing values will be identified and replaced by a random sample of 
plausible values imputations (completed datasets). Under assumption of monotone missingness 
an imputation model with regression baseline parameters will be applied. Five imputed datasets 
have traditionally been suggested to be sufficient on theoretical grounds, but 50 datasets seem 
preferable and will be used to reduce sampling variability from the imputation process.
2.
Completed-data analysis (estimation) step. The desired analysis will be performed 
separately for each dataset generated during the imputation step, following the ANCOVA 
method described in section 12.2.5.
3.
Pooling step. The results obtained from each completed-data analysis will be combined 
into a single multiple-imputation result.
A sensitivity analysis will also be performed with no imputations for missing data and using a 
repeated measure mixed effect model with subject as random, and with center, treatment and 
timepoint (Day 3, 5 and 8) as factors and baseline value as a covariate. The treatment differences 
and two-sided 95% CIs for the primary end-point will be estimated for the PP and mITT analysis 
populations.
No imputation is planned for missing diary card pain intensity and relief assessments.
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12.2.10
Interim Analysis 
No interim analysis is planned for this study
13
STUDY GOVERNANCE CONSIDERATIONS
13.1
Quality Control 
In accordance with applicable regulations including GCP, and GSK CH procedures, GSK CH 
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 CH requirements.
When reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the CRF will serve as the source 
document.
GSK CH 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 
GSK CH. 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.
13.2
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK CH 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 investigator(s) will notify GSK CH or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with GSK CH 
or its agents to prepare the study site for the inspection and will allow GSK CH or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly apply 
copies of the inspection finding to GSK CH or its agent. Before response submission to the 
regulatory authority, the investigator will provide GSK CH or its agents with an opportunity to 
review and comment on responses to any such findings. 
The sponsor will be available to help investigators prepare for an inspection.
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13.3
Regulatory and Ethical Considerations
13.3.1
Institutional Review Board/ Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, investigator brochure/safety statement 
(including any updates) and other relevant documents, e.g. recruitment advertisements, if 
applicable, from the IRB/EC.  All correspondence with the IRB/EC should be retained in the 
investigator file.  Copies of IRB/EC approvals should be forwarded to GSK CH prior to the 
initiation of the study, and also when subsequent amendments to the protocol are made.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/EC and GSK CH in writing immediately after the 
implementation.
13.3.2
Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), 
International Ethical Guidelines for Health-Related Research Involving Humans (Council for 
International Organizations of Medical Sciences, 2016), guidelines for GCP (ICH 1996 and 
revision 2), and the Declaration of Helsinki (World Medical Association 2013). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws.
13.3.3
Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names or 
other identifiable data in any reports, publications, or other disclosures, except where required 
by laws. 
When study data are compiled for transfer to GSK CH and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by GSK CH/CRO in order to de-identify study subjects.  
The study site will maintain a confidential list of subjects who participated in the study, linking 
each subject’s numerical code to his or her actual identity.  In case of data transfer, GSK CH 
will maintain high standards of confidentiality and protection of subjects’ personal data 
consistent with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be reviewed 
and approved by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject, is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
13.3.4
Subject Recruitment 
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures.  Use of ethics committee approved, generic, prescreening questionnaire to assess 
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basic subject characteristics to determine general eligibility for this study is allowed.  This 
generic questionnaire may be used by sites as a phone script and/or to review internal databases 
to identify subjects.  
GSK CH will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
13.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
Within GSK CH a serious breach is defined as a breach likely to affect to a significant degree 
the safety and rights of a subject or the reliability and robustness of the data generated in GSK 
CH-sponsored human subject research studies. 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, GSK CH should be informed immediately. 
In addition, the investigator will inform GSK CH immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13.4
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of subjects begins in accordance with applicable GSK CH processes.
GSK intends to make anonymized subject-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance medical 
science or improve subject care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding
13.5
Provision of Study Results to Investigators
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 CH site or other mutually-agreeable location.
GSK CH 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 CH Policy.
A manuscript will be progressed for publication in the scientific literature if the results provide 
important scientific or medical knowledge.
13.6
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.  
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The records (study/ site master file) must be maintained to allow easy and timely retrieval, when 
needed (e.g. for a GSK CH 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 GSK CH, 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 GSK CH, e.g. subjects’ written consent 
forms, should be maintained by the investigator in strict confidence.
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the investigator for 15 years from the issue of the final Clinical Study Report (CSR) 
or equivalent summary, unless local regulations or institutional policies require a longer 
retention period. 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 
CH standards/procedures, and/or institutional requirements.  
No study document should be destroyed without a prior written agreement between GSK CH 
and the investigator. The investigator must notify GSK CH 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.
13.7
Conditions for Terminating the Study 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or study product safety problems, or at the discretion of GSK 
CH.  In addition, GSK CH retains the right to discontinue development of DDEA 2.32% at any 
time. For multicenter studies (if applicable), this can occur at one or more or at all sites.  
If a study is prematurely terminated, GSK CH will promptly notify the investigator.  After 
notification, the investigator must promptly contact all participating subjects and should assure 
appropriate therapy/ follow-up for the subjects.  As directed by GSK CH, all study materials 
must be collected and all CRFs completed to the greatest extent possible. Where required by 
the applicable regulatory requirements, GSK CH should inform the regulatory authority(ies) 
and the investigator should promptly inform the IRB/EC and provide the IRB/EC a detailed 
written explanation of the termination or suspension. 
If the IRB/EC terminates or suspends its approval/favorable opinion of a trial, the investigator 
should promptly notify the GSK CH and provide GSK CH with a detailed written explanation 
of the termination or suspension.
Upon completion or premature discontinuation of the study, the GSK CH monitor will conduct 
site closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and GSK CH Standard Operating Procedures.
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Dicl ofe nac Diet h yla mi ne 2. 3 2 %
St u d y 2 1 1 2 0 6
Pr ot oc ol A me n d me nt 1
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial 
Te m plate Versi o n Effecti ve: 1 8- Ma y- 1 8 ( C C R # 1 1 4 7 5)
Pa ge 6 0  of 6 4
1 4  
R E F E R E N C E S
1. [ St u d y V O P O- P- 3 0 7] Cli nical St u d y re p ort. A ra n d o mize d, d o u ble- bli n d, m ulti-ce nter, 
place b o c o ntr olle d, 3-treat me nt ar m, parallel gr o u p st u d y t o e val uate t he efficac y a n d 
safet y of dicl ofe nac diet h yla mi ne 2. 3 2 % gel a p plie d t wice or t hree ti mes dail y i n patie nts 
wit h ac ute a n kle s prai n, date d 0 4 Ma y 2 0 1 0
2. [ St u d y V O P O- P E- 1 0 2] Cli nical St u d y re p ort. A ra n d o mize d, 4- peri o d, cr oss o ver st u d y o n 
t he s yste mic e x p os ure t o dicl ofe nac i n healt h y v ol u nteers after treat me nt wit h t o pical 
dicl ofe nac diet h yla mi ne 2. 3 2 % gel u n der n o n- occl usi ve a n d se mi- occl usi ve c o n diti o ns, 
t o pical dicl ofe nac diet h yla mi ne 1. 1 6 % gel, a n d oral dicl ofe nac s o di u m 5 0 m g ta blets, 
date d 2 3 Oct 2 0 0 3
3.
 
4. [ St u d y N F 1 1 3] Cli nical St u d y re p ort. A m ultice nter, parallel gr o u p, ra n d o mize d, d o u ble-
bli n d, place b o-c o ntr olle d st u d y i n vesti gati n g efficac y of V oltare n E m ul gel 1. 1 6 % gel 
c o m pare d wit h place b o gel i n patie nts wit h s oft tiss ue tra u ma 
5.
 
6.
C hestert o n L S, Barlas P, F oster N E et al. ( 2 0 0 3) Ge n der differe nces i n press ure pai n 
t hres h ol d i n healt h y h u ma ns. Pai n; 1 0 1: 2 5 9- 2 6 6
7.
Fisc her A A ( 1 9 8 7) Press ure al g o metr y o ver n or mal m uscles: Sta n dar d val ues, vali dit y a n d 
re pr o d uci bilit y of press ure t hres h ol d. Pai n; 3 0( 1): 1 1 5- 1 2 6
8.
F o n g D T, H o n g Y, C ha n L K et al. ( 2 0 0 7) A s yste matic re vie w o n a n kle i nj ur y a n d a n kle 
s prai n i n s p orts. S p orts Me d; 3 7: 7 3- 9 4
9.
Frie n ds J, A u g usti ne E, Da n off J ( 2 0 0 8) A c o m paris o n of differe nt assess me nt tec h ni q ues 
f or meas uri n g f o ot a n d a n kle v ol u me i n healt h y a d ults. J A m P o diatr Me d Ass oc; 9 8: 8 5-
9 4.
1 0. Galer B S, R o w b ot ha m M, Pera n der J et al. ( 2 0 0 0) T o pical dicl ofe nac patc h relie ves mi n or 
s p orts i nj ur y pai n: res ults of a m ultice nter c o ntr olle d cli nical trial. J Pai n S y m pt o m 
Ma na ge; 1 9: 2 8 7- 2 9 4
1 1. Ga n TJ. ( 2 0 1 0) Dicl ofe nac: a n u p date o n its mec ha nis m of acti o n a n d safet y pr ofile. C urr 
Me d Res O pi n; 2 6: 1 7 1 5- 1 7 3 1
1 2. I C H T o pic E 6 ( R 2) G ui deli ne f or G o o d Cli nical Practice, N o v 2 0 1 6 
1 3. Hatc her R A, Tr ussell J, Nels o n A L, Cates W Jr, Ste wart F, K o wal D, e dit ors. 
C o ntrace pti ve Tec h n ol o g y. 1 9t h e diti o n. Ne w Y or k: Ar de nt Me dia, 2 0 0 7( b): 2 8.
1 4. He y ne ma n C, La wless- Li da y C, a n d Wall G C ( 2 0 0 0) Oral vers us t o pical N S AI Ds i n 
r he u matic diseases. A c o m paris o n. Dr u gs; 6 0: 5 5 5- 5 7 4
1 5. Karlss o n J, Peterse n L ( 1 9 9 1) E val uati o n of a n kle j oi nt f u ncti o n: t he use of a sc ori n g 
scale. T he F o ot 1; 1: 1 5- 1 6
1 6. Karlss o n J, Eri kss o n B, S wa n d L ( 1 9 9 6) Earl y f u ncti o nal treat me nt f or ac ute li ga me nt 
i nj uries of t he a n kle j oi nt. Sca n d J Me d Sci S p orts; 6: 3 4 1- 3 4 5
1 7.
Mas o n L, M o ore R A, E d war ds J E, et al. ( 2 0 0 4) T o pical N S AI Ds f or ac ute pai n: a 
metaa nal ysis. B M C Fa m Pract; 5: 1 0.
2 1 1 2 0 6 | Pr ot oc ol A me n d me nt  1 0 Se p 2 0 1 9 | T M F- 2 9 1 2 6 | 1. 0
P P D
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18. Niethard FU, Gold MS, Solomon GS et al. (2005) Efficacy of diclofenac diethylamine gel 
in osteoarthritis of the knee. J Rheumatol; 32:2384 – 92.
19. Nussbaum EL, Downes L. (1998) Reliability of clinical pressure-pain algometric 
measurements obtained on consecutive days. Phys Ther; 78: 160-169.
20. Ohrbach R, Gale EN (1989) Pressure pain threshold in normal muscles: reliability, 
measurement effects, and topographic differences. Pain; 37: 257-263
21. Petersen EJ, Irish SM, Lyons CL et al. (1999) Reliability of water volumetry and the 
figure of eight method on patients with ankle joint swelling. J Orthop Sports Phys Ther; 
29: 609-915.
22. Predel HG, Hamelsky S, Gold M, et al. (2012) Efficacy and safety of diclofenac 
diethylamine 2.32% gel in acute ankle sprain. Med Sci Sports Exer; 44:1629-36.
23. Predel HG, Koll R, Pabst H et al. (2004) Diclofenac patch for topical treatment of acute 
impact injuries: a randomised, double-blind, placebo-controlled, multicentre study. Br J 
Sports med; 38: 318-323
24. Rademacher J, Jentsch D, Scholl M A (1991) Diclofenac concentrations, in synovial fluid 
and plasma after cutaneous application in inflammatory and degenerative joint disease. Br 
J Clin Pharm; 31: 537-541.
25. Rainsford KD, Kean WF, Ehrlich GE (2008) Review of the pharmaceutical properties and 
clinical effects of the topical NSAID formulation, diclofenac epolamine. Curr Med Res 
Opin; 24: 2967-2992.
26. Rimando MP (2008) Ankle sprains. eMedicine, Physical Medicine and Rehabilitation, 
Lower Limb Musculoskeletal Conditions
27. Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & 
Sons, Inc 1987.
28. Stöckle U, Hoffmann R, Schütz M et al. (1997) Fastest reduction of posttraumatic edema: 
continous cryotherapy or intermittent impulse compression? Foot Ankle Int; 18: 432-438.
29. Tatro Adams D, Mcgann SF, Carbone W (1995) Reliability of the figure-of eight method 
of ankle measurement. J Orthop Sports Phys Ther; 22: 161-163
30. Todd KH, Funk KG, Funk JP, et al. (1996) Clinical significance of reported changes in 
pain severity. Ann Emerg Med; 27:485-9. 
31. Vaile JH, Davis P (1998) Topical NSAIDs for musculoskeletal conditions. A review of the 
literature. Drugs; 56: 783-799.
32. Wetzel D, Menke W, Dieter R et al. (2002) Escin/diethylammonium salicylate/heparin 
combination gels for the topical treatment of acute impact injuries: a randomised, double 
blind, placebo controlled, multicentre study. Br J Sports Med; 36: 183-188
33. Wolfe M, Uhl T, Mattacola C, McCluskey L. (2001) Management of ankle sprains. 
American Family Physician; 63: 93-104
34. World Medical Association Declaration of Helsinki, 64th General Assembly, Fortaleza 
2013.
35. Zacher J, Altman R, Bellamy N et al. (2008) Topical diclofenac and its role in pain and 
inflammation: an evidence-based review. Curr Med Res Opin; 24: 925-950.
15
APPENDIX
15.1
ABBREVIATIONS
The following is a list of abbreviations that may be used in the protocol.
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GlaxoSmithKline Consumer Healthcare Confidential 
Template Version Effective: 18-May-18 (CCR #11475)
Page 62 of 64
Table 15-1
Abbreviation
Abbreviation
Term
Abs
absolute
AE
adverse event
ALT
alanine transaminase
ANOVA
analysis of variance
AST
aspartate transaminase
AUC
area under the curve
AUC24
area under the concentration‑time curve from time 0 to 24 hours
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration
BA
bioavailability
BE
bioequivalence
BP
blood pressure
BPM
beats per minute
BUN
blood urea nitrogen
Cav
average concentration
CDS
core data sheet
Ceff
efficacious concentration
CI
confidence interval
CL/F
apparent oral clearance
CLr
renal clearance
Cmax
peak or maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CRF
case report form
CRO
contract research organization
CSA
clinical study agreement
CSF
cerebrospinal fluid
CTA
clinical trial application
DCT
data collection tool
DDEA
diclofenac diethylamine
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
eCRF
Electronic Case Report Form
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FRP
Females of Reproduction Potential
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
HDL-C
high density lipoprotein cholesterol
211206 | Protocol Amendment  10 Sep 2019 | TMF-29126 | 1.0


Diclofenac Diethylamine 2.32%
Study 211206
Protocol Amendment 1
GlaxoSmithKline Consumer Healthcare Confidential 
Template Version Effective: 18-May-18 (CCR #11475)
Page 63 of 64
Abbreviation
Term
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IEC
Independent Ethics Committee
IND
investigational new drug 
INR
international normalized ratio
IRB
institutional review board
IRC
internal review committee
IUD
intrauterine device
IUS
Intrauterine system
K2EDTA
dipotassium ethylene diamine tetraacetic acid
LDL-C
low density lipoprotein-cholesterol
LFT
liver function test
LSLV
last subject last visit 
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
medical Dictionary for Regulatory Activities
mITT
modified intention to treat
MTD
maximum tolerated dose
N/A
not applicable
NOAEL
no observed adverse effect level
NOEL
no observed effect level
NSAID
non-steroidal anti inflammatory drug
PD
pharmacodynamics
PG 
pharmacogenomics
PI
principal investigator
PK
pharmacokinetics
POM
pain on movement
PP
per protocol
PR
pulse rate
PT
prothrombin time
QC
quality control
QTc
corrected QT
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SCr
serum creatinine
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SmPC
summary of product characteristics
SOP
standard operating procedure
SRSD
single reference study document
SS
safety statement
211206 | Protocol Amendment  10 Sep 2019 | TMF-29126 | 1.0


Diclofenac Diethylamine 2.32%
Study 211206
Protocol Amendment 1
GlaxoSmithKline Consumer Healthcare Confidential 
Template Version Effective: 18-May-18 (CCR #11475)
Page 64 of 64
Abbreviation
Term
T1/2
terminal half-life
THC
tetrahydrocannabinol
Tmax
time to reach maximum concentration
ULN
upper limit of normal
US
United States
USPI
United States package insert
VAS
visual analogue scale
Vz/F
apparent oral volume of distribution
WBC
white blood cell
211206 | Protocol Amendment  10 Sep 2019 | TMF-29126 | 1.0

SAP_001.pdf: 
Page 1 of 36 
Diclofenac Diethylamine 2.32% 
211206 
Statistical Reporting and Analysis plan V2.0 20JAN2021 
STATISTICAL REPORTING AND ANALYSIS PLAN 
A randomized, double blind, multi center, active-controlled, 2 
treatment arm, parallel group non inferiority study to evaluate the 
efficacy and safety of diclofenac diethylamine 2.32% gel applied 
twice daily versus diclofenac diethylamine 1.16% gel applied four 
times daily for one week in subjects with acute ankle sprain 
Protocol Number: 211206 
Phase: 
Phase III 
Property of GSK Consumer Healthcare 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of GSK 
Template Version Effective: 15-Jul-2017 
This document contains confidentiality statements that are 
not relevant for this publicly available version


Diclofenac Diethylamine 2.32% 
211206 
Statistical Reporting and Analysis plan Draft V2.0 20JAN2021 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 2 of 36 
RAP Text Signature Page 
RAP Final v2.0(Dated 20Jan2021) for Protocol 211206 
Name 
Signature 
Date 
Author: 
 
Position: 
Biostatistician 2
Company: 
IQVIA 
Upon review of this document, the undersigned approves this version of the Output Templates, 
authorizing that the content is acceptable for the reporting of this study. 
Name 
Signature 
Date 
Approved By: 
 
Position: 
Senior Biostatistician 
Company: 
IQVIA 
Name 
Signature 
Date 
Approved By: 
 
Position: 
Manager, Biostatistics, 
 (SAE) and Family 
Oral Health (FOH) 
Company: 
GSK Ltd. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Document History 
 
 
Document 
Version Date 
Summary of Changes (New analysis or Change 
in planned analysis) 
0.1 
02FEB2020 
Not Applicable 
0.2 
03SEP2020 
Updated client comments received on Draft 1 and 
added COVID-19 analysis. 
1.0 
11JAN2021 
Updated Per Protocol definition. 
Made changes to PP exclusion reason w.r.t 
compliance category. 
Added sensitivity analysis for primary endpoint. 
2.0 
20JAN2021 
Made changes to PP exclusion reason w.r.t 
compliance category. 
 
Amendments incorporate all revisions to date. 


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Table of contents 
Document History ............................................................................................................... 2 
Table of contents ................................................................................................................. 4 
1 
Summary of Key Protocol Information ............................................................................... 6 
1.1 
Study Design ............................................................................................................ 6 
1.2 
Study Objectives ...................................................................................................... 7 
1.3 
Treatments ............................................................................................................... 8 
1.4 
Sample Size Calculation .......................................................................................... 9 
2 
Planned Analyses ................................................................................................................. 9 
2.1 
Interim Analysis ....................................................................................................... 9 
2.2 
Final Analyses ......................................................................................................... 9 
3 
Considerations for data analyses and Data Handling Conventions ................................... 10 
3.1 
Baseline Definition ................................................................................................ 10 
3.2 
Centers Pools ......................................................................................................... 10 
3.3 
Timepoints and Visit Windows ............................................................................. 10 
4 
Data Analysis ..................................................................................................................... 10 
4.1 
Subgroups/Stratifications ....................................................................................... 10 
4.2 
Populations for Analysis ........................................................................................ 11 
4.2.1 
Subject Disposition ............................................................................... 11 
4.2.2 
Protocol Deviations ............................................................................... 11 
4.2.3 
Analysis Populations ............................................................................. 12 
4.3 
Subject Demographics and Other Baseline Characteristics ................................... 13 
4.3.1 
Demographic Characteristics ................................................................ 14 
4.3.2 
General Medical History ....................................................................... 14 
4.3.3 
Characteristics of Disease ..................................................................... 14 
4.4 
Treatments (Study Drug, Rescue Medication, other Concomitant Therapies, 
Compliance) ........................................................................................................... 15 
4.4.1 
Study Drug Compliance and Exposure ................................................. 15 
4.4.2 
Prior and Concomitant Medication/Non-Drug Therapies or 
Procedures ............................................................................................. 17 
4.4.3 
Rescue Medication ................................................................................ 18 
4.5 
Analysis of Efficacy .............................................................................................. 19 
4.5.1 
Primary Efficacy Endpoint .................................................................... 19 


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4.5.2 
Secondary Efficacy Variables ............................................................... 21 
4.5.3 
Handling of Missing Values/Censoring/Discontinuations .................... 22 
4.6 
Analysis of Secondary Objectives ......................................................................... 23 
4.6.1 
Efficacy (Secondary) ............................................................................. 23 
4.6.2 
Pharmacokinetic (Secondary) ............................................................... 24 
4.7 
Analysis of Safety .................................................................................................. 24 
4.7.1 
Adverse Events and Serious Adverse Events ........................................ 24 
4.7.2 
Laboratory Tests .................................................................................... 25 
4.7.3 
Vital Signs ............................................................................................. 26 
4.7.4 
Findings on Physical Examination ........................................................ 27 
4.7.5 
COVID-19 Assessment ......................................................................... 27 
4.8 
Analysis of Other Variables ................................................................................... 27 
4.8.1 
Quality of Life ....................................................................................... 27 
4.8.2 
Patch Adhesion Performance ................................................................ 27 
5 
Changes to the Protocol Defined Statistical Analysis Plan ............................................... 27 
6 
References ......................................................................................................................... 30 
Appendix 1: Subgroups. .................................................................................................... 31 
Appendix 2: Center pools in multicenter studies. ............................................................. 31 
Appendix 3: Major Protocol Deviations Definitions. ........................................................ 31 
Appendix 4: Sample SAS Code ........................................................................................ 32 
Appendix 5: Prohibited Medication .................................................................................. 35 
Attachment 1: List of Data Displays ........................................................................................ 36 


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The purpose of this Statistical Reporting and Analysis Plan (RAP) is to describe the planned 
analyses and outputs to be included in the Clinical Study Report (CSR) for Protocol 211206. 
This RAP is intended to describe the Final analyses required for the study. 
 
 
1 
Summary of Key Protocol Information 
Topical diclofenac products are well established globally for the treatment of pain and 
inflammation due to acute trauma as well as the relief of pain associated with non-serious 
osteoarthritis (OA) of the peripheral joints e.g. knee and fingers. The originator product 
diclofenac diethylamine (DDEA) 1.16% gel (Volatran Emulgel in the UK) was first registered 
in 1985 in Switzerland and Romania for use at a doce of 2-4gram applied three to four times 
daily and is currently registered in over 130 countries of which over 80 countries market this 
product as over-the-counter (OTC). 
As part of global expansion for the product, China has been identified as a desirable market 
for registration of DDEA 2.32% gel. The identified registration pathway in China for the 
DDEA 2.32% gel is variation specifying addition of a new strength to the already registered 
DDEA 1.16% gel (License Number H20160648/H20160649 issued on 12 March 2013), with 
the same indications as currently registered for DDEA 1.16% gel, i.e. for relief of mild to 
moderate pain in muscles, soft tissues, joints, e.g., muscles and soft tissue pains caused by 
sprain, pilling injury, contusions, strain, waist-back injury and various arthralgia etc, and 
symptomatic treatment of OA. 
In support of the proposed registration, the National Medical Products Administration 
(NMPA) approved a clinical trial application (CTA) on November 06, 2016 (CTA No. 
2016L09875). The approved CTA stipulated that a non-inferiority study assessing the efficacy 
and safety of the DDEA 2.32% versus that of the registered DDEA 1.16% should be conducted 
in a local population. 
To this effect, Glaxo SmithKline Consumer Health (GSKCH) intends to conduct a 
randomized, double-blind, multiple-dose, multi-center parallel group, non-inferiority study to 
evaluate the efficacy and safety of DDEA 2.32% gel applied twice daily versus DDEA 
1.16% gel applied four times daily in subjects with ankle sprain in China. 
 
1.1 
Study Design 
 
This is a Phase III, randomized, double blind, multi-center, active controlled, 2 treatment arm, 
parallel group, non-inferiority study to evaluate the efficacy and safety of diclofenac 
diethylamine 2.32% gel applied twice daily versus diclofenac diethylamine 1.16% gel applied 
four times daily for 1 week in subjects with acute ankle sprain. 


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To qualify, subjects must experience an acute Grade I -II sprain of the ankle within the past 24 
hours. Subjects should be randomized as soon as possible after the injury. 
 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1 ratio to one of the following two treatment arms: 
Table 1-1 
Treatment Schedule Details 
 
Treatment Arms 
Morning(Upon Rising) 
Noon 
LateAfternoon 
Late 
Evening 
(Evening) 
(Bed Time) 
DDEA 2.32% 
times daily 
four 
DDEA 2.32% Gel 
Placebo 
Gel 
DDEA 2.32% Gel 
Placebo Gel 
DDEA 1.16% 
times daily 
four 
DDEA 1.16% Gel 
DDEA 
1.16% Gel 
DDEA 1.16% Gel 
DDEA 1.16% Gel 
 
 
1.2 
Study Objectives 
Table 1-2 
Objectives 
 
 
 
• 
To demonstrate non-inferiority between 
DDEA 2.32% and DDEA 1.16% with 
regard to pain relief after acute ankle 
sprain 
Change from baseline in pain on movement 
(POM) on Day 5 of treatment as assessed by a 
100 mm VAS scale 
 
Secondary Objective 
Secondary Endpoint 
Efficacy 
• 
To assess efficacy of treatments for pain 
relief as measured by POM on Days 3 
and 8 
• 
To assess efficacy of treatments for 
inflammation of the affected ankle as 
measured by pressure algometry on 
Days 3, 5, and 8 
• 
To assess efficacy of treatments for 
inflammation of the affected ankle as 
measured by pressure algometry on 
Days 3, 5, and 8 
• 
To assess efficacy of treatments for 
ankle joint function as measured on the 
Karlsson Scoring Scale 
• 
To assess efficacy of treatments for 
swelling of affected ankle as measured 
Figure of Eight Method 
Change from baseline of POM on VAS on Day 3 
and Day 8 of treatment assessed by 100 mm VAS 
scale 
Change from baseline in tenderness as 
measured by pressure algometry on Days 3,5 
and 8 
Difference between measurement in affected 
ankle and contralateral ankle on Days 3,5 and 8 
 
 
Change from baseline in Ankle Joint Function 
(Karlsson Scoring Scale) on Days 3,5 and 8 
 
Change from baseline in circumference of 
affected ankle as measured by Figure of Eight 
method on Days 3,5 and 8 
 
Objectives 
Primary Objective 
Endpoints 
Primary Endpoint 


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Objectives 
Endpoints 
• 
To assess efficacy of treatments for 
swelling of affected ankle as measured 
by Figure of Eight method 
• 
To assess efficacy of treatments for 
effect on pain intensity as measured by 
Sum of Pain Intensity Difference (SPID) 
• 
To assess effect of treatments for effect 
on pain relief as measured by Total Pain 
Relief (TOTPAR) 
• 
To assess the use of rescue medication 
among subjects 
• 
To assess the use of rescue medication 
among subjects 
Difference between circumference of affected 
ankle to unaffected ankle by Figure of Eight 
method on Days 3, 5 and 8 
SPID from 0 – 24 hours post first dose (Day 1) 
and from 0 – 24 hours post first dose (Day 5) 
 
TOTPAR from 0 – 24 hours post first dose (Day 
1) and from 0 – 24 hours post first dose (Day 5) 
 
Number of tablets usedto treat ankle pain and 
overall 
Number of days on which rescue medication was 
used to treat ankle pain and overall 
Safety 
• 
To assess safety of DDEA 1.16% and 
DDEA 2.32% gels after 1 week of use 
 
1.3 
Treatments 
 
Number, incidence, and severity of adverse 
events following dosing with study medication 
The following treatments will be administered in the study 
 
Table 1-3 
Study Product Details 
Active Treatmenta 
Active Comparatorb 
Placebo Product for 
Blinding 
of 
Active 
Treatmenta 
Product Name 
DDEA 2.32% gel 
DDEA 1.16% gel 
Placebo 
gel 
-0% 
diclofenac gel 
Pack Design 
2 x 50 g tubes 
4 x 50 g tubes 
2 x 50 g tubes 
Dispensing Details 
1 kit per subject at visit 
1 kit per subject at visit 
1 kit per subject at visit 
1a 
1b 
1a 
Product 
Master 
 
Commercial Product 
 
Formulation 
Code 
(MFC) 
Dose/Application 
Gel – 5 cm (2 g) on 200 Gel – 5 cm (2 g) on 200 Gel – 5 cm (2 g) on 200 
cm2 
cm2 
cm2 
Route of Administration 
Topical 
Topical 
Topical 
Usage Instruction 
Two times daily (BID) 
Four times daily (QID) 
Two times daily (BID) 
morning 
and 
late 
morning 
and 
late 
afternoon 
afternoon 
a The study treatments for the Active Treatment and Placebo for blinding of Active Treatment will be provided in a single kit containing 4 tubes (2 tubes each of 
study treatment) 
b The study treatments for the Active Treatment will be provided in a single kit containing 4 tubes 
CCI
CCI


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1.4 
Sample Size Calculation 
 
Approximately 300 subjects will be randomized to ensure at least 240 evaluable subjects 
complete the study for the Per Protocol (PP) analysis population. A maximum of 40 
randomized subjects per center will be considered. 
 
Approximately 120 subjects per treatment arm has been determined to provide 80% power to 
demonstrate non-inferiority of DDEA 2.32% gel b.i.d with DDEA 1.16% gel q.i.d. by 
comparing the two-sided 95% CI of the difference in mean change from baseline of VAS 
POM score between the two products with the non-inferiority margin of 13 mm. This assumes 
a treatment standard deviation of 22mm and allows for a possible small true treatment 
difference of 5mm in favor of DDEA 1.16%. 
 
The margin of 13 mm (on a 100 mm VAS scale) was chosen as the literature reported minimally 
important clinical difference for an acute musculoskeletal injury (Todd et al 1995), with 
treatment differences smaller than 13mm considered as not clinically important. The standard 
deviation was obtained from a previous placebo-controlled ankle sprain study VOPO-P-307 
with DDEA 2.32% gel. 
 
 
2 
Planned Analyses 
2.1 
Interim Analysis 
No interim analysis is planned. 
 
2.2 
Final Analyses 
The final planned analyses will be performed after the completion of the following sequential 
steps: 
1. All subjects have completed the study as defined in the protocol 
2. Finalization and signature the RAP. 
3. All required database cleaning activities have been completed and database has been locked. 
4. All criteria for unblinding the randomization codes have been met and the randomization 
codes have been distributed. 


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3 
Considerations for data analyses and Data Handling 
Conventions 
3.1 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-missing 
value. Unless otherwise stated, if baseline data is missing no derivation will be performed and 
will be set to missing. 
 
3.2 
Centers Pools 
In this study, maximum subject per centre will be approximately 40. Since, it is a small sample 
size, the pooling of centres is not required and we will be summarizing the analysis by centre. 
All centers will be analyzed together. 
 
3.3 
Timepoints and Visit Windows 
Before the study is unblinded, each actual post-baseline visit will be mapped to the target visit 
date to which it is chronologically closest. This corresponds to the following visit windows: 
Visit 2 (Days 2–4), Visit 3 (Days 4–6), Visit 4 (Days 7+). The numbering of the actual visits 
(from Visit 1 to Visit 4) will then be changed as needed to improve the correspondence of the 
actual visit dates to the protocol-specified schedule of visits, particularly in relation to Visit 3 
(primary). Final determinations will also be made and documented before the study is unblinded 
to address visits that occur on Day 4 (which maps to two visit windows) or visits occurring well 
beyond the target date for the final visit or any other irregularities. 
 
4 
Data Analysis 
Data analysis will be performed by Biostatistics and Programming Team at IQVIA Biotech Pvt. 
Ltd. The statistical analysis software used will be SAS version 9.4 or higher in a WINDOWS 
environment. 
Prior to database closure a Blind Data Review Meeting (BDRM) will be conducted in which 
various aspects of the trial will be discussed and agreed. 
Except as described below, all listings will be produced for Enrolled and/  or Intent To Treat   
( ITT) subjects. 
 
 
4.1 
Subgroups/Stratifications 
Center/Site will be used as stratification factor where ever it is required. Based on study 
requirement sub group analyis will be conducted. 


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4.2 
Populations for Analysis 
Tables described in this section will be produced for all ITT subjects, unless otherwise specified 
in the sub section. 
 
4.2.1 Subject Disposition 
Subject disposition summary will include the number of screened subjects and screen failures, 
number of subjects randomized, number of subjects treated, number of subjects completed the 
study and number of subjects permanently discontinued by overall using enrolled population. 
The number and percentage of subjects, in the Safety, ITT , mITT and PP populations will be 
presented by treatment and overall. The percentages will be based upon the total number of 
subjects in the enrolled population. 
The number and percentage of subjects completing the study and those who discontinuing the 
study, including a breakdown of the reasons (reason for discontinuation will be due to adverse 
event, subject did not meet study criteria, protocol deviation, lost to follow-up, withdrawal of 
consent and other) for not completing the study, will be presented per treatment group and 
overall. The percentages are based upon the total number of subjects in ITT population (
 
). 
Subject disposition including the subject status (completer, Yes/No), demographic data (age, 
gender, race), the duration of treatment before discontinuation and the specific reason for 
discontinuation ( related to COVID also, etc.), will be listed in 
. by treatment 
group and center. 
 
4.2.2 Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study. Data 
will be reviewed during Blinded Data Review Meeting (BDRM) prior to database lock to ensure 
all important deviations are captured and categorised. 
Protocol deviations that would exclude subjects from PP population may include (but are not 
limited to) the following: 
• Subjects failing to meet inclusion and exclusion criteria but are included in the study 
• Subjects without a Day 5 POM VAS assessment 
• Subjects with get application compliance <=80% or weight compliance <=65% or 
weight compliance >=143% or application compliance >=143% with study treatment. 
• Subjects taking prohibited medication (Refer Appendix 4) 
• Subjects identified with other major protocol deviations 
PPD
PPD


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Full details of the major and minor protocol deviations are provided in Appendix 3. 
The number and percentage of subjects with any major protocol deviations and with each type 
of major protocol deviations will be presented by treatment group (
) using ITT 
population and listed in 
. Any minor protocol deviations will also be listed 
similarly 
. 
 
 
4.2.3 Analysis Populations 
There are five analysis populations defined as below: 
PPD
PPD
PPD


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Table 4-1 
Analysis Population 
Population 
Definition / Criteria 
Analyses 
Treatment 
Evaluated 
s to used 
for 
Analyses 
Enrolled 
Comprise of all the subjects who have signed ICF, 
Disposition 
though may or may not be randomized later into the 
study. 
Intent-To- 
Comprise of all randomized subjects. 
Efficacy 
Planned 
Treat 
This population will be based on the treatment to which 
Demographics/Di 
treatment 
(Randomised) 
the subject was randomized. 
sposition/Medical 
received 
Any subject who receives a treatment randomization 
number will be considered to have been randomized. 
History/Concomit 
ant 
Mediaction/Comp 
liance 
Safety 
Comprise of all subjects who receive at least one dose 
of study treatment. 
Study Population 
Safety 
Actual 
treatment 
This population will be based on the treatment the 
received 
subject actually received. 
Intent-To- 
Comprise of all randomized subjects who have at least 
Efficacy 
Planned 
Treat 
(Modified) 
Per-Protocol 
(PP) 
one post baseline POM VAS assessment. 
 
All subjects from the mITT population who do not have 
any major protocol deviations (which are not affecting 
primary 
efficacy 
endpoint) 
and 
also 
weight  
compliance > 65% and application compliance > 
80%that could confound the interpretation of the 
efficacy analyses. 
Protocol deviations that would exclude subjects from 
the PP population will be discussed in the BDRM. 
Demographics 
 
Primary Efficacy 
Demographics. 
treatment 
received 
Actual 
treatment 
received 
 
The numbers of subjects included in each of the analysis populations, and the number excluded 
from each population broken down by the reason for exclusion will be presented (
 
) using enrolled population. Subjects excluded from any of the analysis populations 
will be listed in 
, with the reason for exclusion. 
 
4.3 
Subject Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics summaries will be produced for the ITT, mITT, PP 
and SAF. 
PPD
PPD


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4.3.1 Demographic Characteristics 
Categorical demographic variables include gender (Male, Female), race (American Indian or 
Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, 
White). These variables will be summarized by the number and percentage of subjects with 
each relevant characteristic in each treatment group. 
Body Mass Index (BMI) will be calculated as weight (kg)/[height (m)]2. Age in years, weight 
in kg, height in cm and BMI in kg/m2 will be summarized by the mean, standard deviation, 
median, minimum and maximum values in each treatment group. 
All the demographic related information will be taken from Demographic CRF page. Other 
baseline characteristics information will be taken from the corresponding CRF page for the 
baseline visits. 
Examination on Ankle sprain will be taken from the Examination of Ankle Sprain/Diagnostic 
Testing for Ankle CRF page. 
All demographic information will also be tabulated for ITT, mITT and SAF populations in 
. 
Demographic variables will be listed in 
 using ITT population. 
 
4.3.2 General Medical History 
Medical diagnoses/surgeries will be listed by subject using ITT population, with date of 
diagnosis/surgery, and whether or not the diagnosis/surgery was an active problem at the start 
of study drug administration (
) (CRF page: Medical History). 
The presence/absence of any relevant medical history or current medical conditions will be 
tabulated. 
Medical conditions will also be summarized using ITT population by numbers and percentages 
of subjects having a condition (
). 
 
4.3.3 Characteristics of Disease 
Baseline disease characteristics will be tabulated from the screening CRF page of Pain on 
Movement, Tenderness, Ankle Joint Function, Ankle Swelling. 
The tables will be provided using ITT population (
). All 
information will be listed in the listing (
). 
PPD
PPD
PPD
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4.4 
Treatments (Study Drug, Rescue Medication, other Concomitant 
Therapies, Compliance) 
Compliance data will be summarized for the safety population and ITT population. Exposure 
and other medications will be summarized on the safety population. 
 
4.4.1 Study Drug Compliance and Exposure 
Compliance: 
Compliance will be summarized descriptively based on the following points in 
 
 using ITT and Safety population respetively, 
 by ITT 
population on the following three : 
 
1. % of scheduled applications made 
2. % of gel used relative to number of actual applications * 2g, and 
3. compliance category (Good/Moderate/Poor). 
1. % of scheduled applications made will be calculated in following way - 
a. % of scheduled applications compliance per tube: 
 Total number of applications made: Compliance will be summerized based on the 
percent of scheduled application made. Percent of scheduled application made for 
each dosing time morning, noon, late afternoon and late evening respectively will 
be calculated in the following manner. 
 If replacement kit number and replacement date (CRF: Study Medication 
Replacement) are missing - 
o Expected number of application from tube k=(number of applications per 
day from tube k) * duration of days in the study ; where, k=1,2,3,4 
o Actual number of application from tube k= (Expected number of application) 
–[sum of (number of missed applications per day from tube k)* duration of 
days gel is applied i.e. (Day i – Day 1)]; where, i=1,2,3,4,5,6,7,8; k=1,2,3,4 
o Percent of scheduled application made from tube k= (Actual number of 
application from tube k ( where k= 1 to 4) / Expected number of application 
from tube k) *100. 
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 If replacement kit number and replacement date (CRF: Study Medication 
Replacement) are non-missing then 
o Expected number of application from tube k=Sum of [ (number of 
applications per day from tube k from kit no. x) +(number of applications 
per day from tube k from kit no. y)* duration of days in the study] ; where 
x= Old kit # and y= New kit #, k=1,2,3,4 
o Actual number of application from tube k= (Expected number of application 
from tube k from kit no. x) –[sum of (number of missed applications per day 
from tube k from kit x)+ sum of (number of missed applications per day from 
tube k from kit y)]* duration of days gel is applied i.e. (Day i – Day 1)]; 
where, i=1,2,3,4,5,6,7,8; k=1,2,3,4; x= Old kit # and y= New kit # 
• Percent of scheduled application made from tube k= (Actual number of application from 
tube k ( where k= 1 to 4) / Expected number of application from tube k) *100% of 
scheduled applications compliance overall: 
 
 Over all Compliance % = [sum of (actual # of application from each tube)/sum of 
(expected # of application from each tube)*100] 
 
Scheduled applications will include all scheduled applications through the day before the final 
visit. On day 1, the percentage of gel used will be calculated based on the possible number of 
administrations on that day. If only 3 were possible, then 100 % compliance on that day will be 
considered 3 applications. 
 
• % of gel used relative to number of actual applications * 2g will be derived as following - 
• Total weight of study medication used:The percent (%) of gel used will be 
computed relative to the actual number of application made from randomization 
through the final visit multiplied by 2 g.in two ways – 
• If replacement kit number and replacement date (CRF: Study Medication 
Replacement) are missing then 
• Expected weight of study medication used from tube k= (number of applications 
per day from tube k )*2g * Expected number of days gel to be applied from tube 
k 
• Actual weight of study medication used from tube k= [(Baseline weight of tube 
k – (weight of tube k after last day of application ; k=1, 2, 3, 4 


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Percent of total medication used = (Actual weight of medication used/Expected weight of 
medication used)*100 
In case there is repeated usage of single tube in a day then the over usage of the medication will 
be reflected in weight compliance. 
• Compliance category: Compliance category will be defined in the following way - 
 
• Good: > 80% of the gel has been applied and > 80% of scheduled applications made, 
• Moderate: not Good and not Poor 
• Poor: < 50% of the gel has been applied or < 50% of scheduled applications made. 
 
For subjects applying active gel only twice per day (DDEA 2.32%), an additional compliance 
computation will be performed relative to the tubes and applications of active gel. If a subject 
is falls into good compliance category in both (separately for the active gel and also combined 
with placebo) then that subject will be included in the PP protocol population. 
 
For each subjects time of the first application, application of the study drug each time point 
each day and the weight of the four tubes on Day 1, 3, 5 and 8 will be listed in
 : 
 
Exposure: 
Exposure to study drug will be summarized descriptively using safety population in 
 
 as : 
• number of applications made 
• total amount of gel used. 
 
Study drug exposure will also be listed using safety population along with the drug compliance 
in the 
. 
 
4.4.2 Prior and Concomitant Medication/Non-Drug Therapies or Procedures 
Prior medications (stopped prior to day 1) will be listed by subject, with preferred term, 
indication, dose, dose form, frequency, route, start date and start and end day (
). 
Prior medications will be summerized using ITT population in 
. 
Concomitant medications (ongoing at Day 1 or started on or after Day 1) will be listed similarly, 
with the addition of a flag for forbidden concomitant therapies (
). 
Tables and listings described in this section will be presented for the ITT population. The 
medication listing will include the preferred term, indication, single dose, frequency, route, start 
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date, and end date or ongoing at final visit (when appropriate) and a flag whether the medication 
was Prior or Concomitant (
). 
Concomitant medications (ongoing at randomization or started after randomization) will be 
summarized by treatment, anatomical area and therapeutic use or preferred term, and the 
number and percentage of subjects who took any concomitant medication will be presented 
(
) using ITT population. 
The number and percent of subjects taking disallowed concomitant medications will be 
summarized similarly (
). 
All the information related to concomitant medication will be obtained from 
Current/Prior/Concomitant Medication CRF page. 
Non-drug therapies/procedures will be listed using ITT population (
). 
Information related to non-drug procedures/therapies will be taken from Non-Drug 
Treatments/Procedures CRF Page. 
 
4.4.3 
Rescue Medication 
The investigator will provide rescue medication (paracetamol 500mg tablets) to the subjects at 
the baseline visit. Rescue medication will be re-dispensed on Day 5 i.e.at Visit 3. Subjects are 
not allowed to take rescue medication within 6 hours of study visits and within 12hours of Day 
5. Following information will be documented in the Rescue Medication CRF page – 
• Rescue medication taken (yes/no) (RMYN) 
• Pain intensity (RMPI) and pain relief (RMPR) before taking rescue medication 
• Reason for use of rescue medication (RMREAS) 
• Time (RMSTTM) and date (RMSTDTC) of rescue medication 
• Number of tablets taken (RMNUM) 
Summuary of all the above mentioned points will be displayed in 
. and will be 
listed in 
. 
Time to first use of rescue medication will be analyzed using the survival estimate of median 
time to event for each treatment group along with the CI for median. P-value from Log Rank 
test will be used to compare the median times between the treatment groups (
). 
Kaplan Meier plot will be presented for the survival probabilities against the time points for 
both the treatment groups (In case number of events are considerable). 
Subjects with no use of rescue medication will be censored at their last available date in the 
study. 
Censoring Rule: 
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Event : If event occurred then value of censor is 0, time will be derived as follows: 
Date of First Occurrence of Event- Date of Randomization + 1 
 
Censor: If event not occurred then value of censor is 1, time will be derived as follows: 
Last Available Date in the study - Date of Randomization + 1 
Where, Last Available Date in the study = Maximum of (Date of Discontinuation, Date of 
Death, Date of Follow-up, Study Completion Date) 
 
 
4.5 
Analysis of Efficacy 
4.5.1 Primary Efficacy Endpoint 
 
4.5.1.1 
Primary Efficacy Endpoint Definition 
The primary efficacy endpoint is change from baseline in Pain On Movement (POM) on Day 5 
of treatment as assessed by a 100 mm VAS scale. 
 
4.5.1.2 
Statistical Hypothesis, Model, and Method of Analysis 
The hypothesis of the study is stated below: 
H0: The Diclofenac 2.32% DDEA Gel administered BID is inferior to Diclofenac1.16% DDEA 
gel administered QID. 
µT -µS ≥ δ 
Where, µS is the mean for a standard therapy (Diclofenac 1.16% DDEA Gel administered QID) 
and µT is the mean for test therapy (Diclofenac 2.32% DDEA Gel administered BID). δ is the 
non-inferiority margin of 13 mm. 
 
H1: Diclofenac 2.32% DDEA Gel administered BID is non-inferior to Diclofenac 1.16% 
DDEA gel administered QID. 
µT -µs < δ 
δ=13mm 
The primary efficacy analysis will be performed on PP population without imputation of 
missing data.The primary endpoint (Change from baseline in POM )will be analysed using 


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Analysis of Covariance (ANCOVA) model with treatment and center as factors and baseline 
POM as covariate. 
Diclofenac 2.32% DDEA Gel administered BID will be declared non-inferior to Diclofenac 
1.16% DDEA gel administered QID if the upper limit of the two-sided 95% confidence interval 
of the difference between their mean changes from baseline VAS POM responses is less than 
the established margin of 13 mm. 
Refer sample SAS code in APPENDIX 4. 
 
 
Assumptions of normality and homogeneity of variances in the ANCOVA model will be 
evaluated after study un-blinding. If violations are observed then the following will be 
performed as a post-hoc sensitivity analysis and results will be compared with primary analysis 
results: 
1. Suitable data transformations will be tried to achieve the assumptions. 
2. If suitable transformations cannot be found, then the non-parametric Van Elteren tests 
will be performed using center as strata.Two sided 95% CI and p value will be presented. 
POM by 100 mm VAS analogue scale (CRF page: Pain on Movement ; variable VASSCRL)will 
be summarized over time (
) using mITT population. Also POM 
by 100 mmVAS analogue scale will be summerarized over time by center using mITT 
population (
). Above tables (
) will 
be repeated for the PP population. POM by 100 mm VAS analogue scale for COVID 19 patients 
if any will be summarized in 
 using mITT population. 
 
Statistical analysis for the primary endpoint will be dispayed in the tables (
 
) with mITT and PP population respectively. 
 
 
4.5.1.3 
Supportive Analyses 
 
1. To assess the treatment-by-center interaction an additional analysis will be 
performed for the primary endpoint on mITT population as following , where change 
from baseline on POM will be analysed using ANCOVA model with treatment, 
center as fixed factor, baseline POM as covariate and treatment-by-center as 
interaction (
) 
If there is evidence of an significant interaction (p<0.05) effect, then the primary 
endpoint outcome will also be summarized by center for further investigation and 
assessment. 
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Reference SAS code is given in APPENDIX 4: 
 
. 
2. Sensitivity analysis will be perfomed on POM for compliance category -good. For 
good category greater than or equal to 80% compliance will be considered for both 
in application and amount of gel used for this sensitivity analysis. The sensitivity 
analysis for the primary endpoint will be dispayed in the tables (
) . 
3. The primary efficacy endpoint will be analyzed using ANCOVA model on ITT 
population using imputed data. 
4.  The Change from baseline on POM will be analyzed using Mixed Model Repeated 
Measure (MMRM) with multiple imputation (day 3,5,8) model with treatment, 
center as fixed factor, baseline POM as covariate and visit as repeated measure; 
using ITT population. 
5. Same as above mentioned point 3 without imputed data, ie, observed data. 
6. Same as above point 3 using PP population. 
7. Same as above point 4 using PP population. 
Early discontinued subjects data due to any reason- will be analyzed in this section using 
imputation. 
 
4.5.2 Secondary Efficacy Variables 
The secondary efficacy analyses will be performed and also be listed on mITT and PP 
population. 
• Change from baseline of POM (CRF page: Pain on Movement; VAS score will be obtained 
from VASSCRL) on VAS on days 3 and 8 respectively (
). 
• Tenderness measured by pressure algometry on days 3, 5 and 8 which will be analysed using 
change from baseline and difference between the measurement in injured area (CRF page: 
Tenderness; measurement for study ankle : QS_INJA) and contralateral area (CRF page: 
Tenderness; measurement for study ankle : QS_CLTA) (
).. 
• Change from baseline Ankle Joint Function (Karlsson Scoring Scale; CRF page: Ankle Joint 
Function: Variable : Total Score KSSTS) on days 3, 5 and 8 (
 
).. 
• Circumference measurement of swelling on days 3, 5 and 8 which will be analysed using 
change from baseline in circumference of affected ankle and comparison to non-affected 
ankle by Figure of Eight method (CRF Page:Ankle swelling; Variables: FOEMINSC and 
FOEMCASC respectively.) (
 
).. 
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• Pain Intensity and Pain Relief (CRF Page: Subject Diary(Day 1/5) ; variables will used to 
calculate the Pain Intensity and Pain Relief are DPI and DPR respectively for each timepoint 
(DSTMPT)) 
• Pain Intensity (
).. 
• Pain intensity will be analysed based on the Sum of Pain Intensity Difference 
(SPID). SPID is defined as from 0 -24 hours post first dose corresponding to day 1 
and from 0-24 hours post first dose corresponding to day 5. 
• SPIDt=∑PIDt(timet-timet-1)(h), where, PIDt=pain intensity score (DPI from CRF 
page corresponding to day); timet=time in hours post first dose 
• Pain Relief (
)..: 
• Pain relief will be analysed based on the Total Pain Relief (TOTPAR). TOTPAR is 
defined as from 0-24 hours post first dose corresponding to day 1 and from 0-24 
hours post first dose corresponding to day 5. 
• TOTPAR=∑Rt(timet-timet-1), whert e Rt =pain relief score (DPR from CRF page 
corresponding to day) 
 
 
4.5.3 
Handling of Missing Values/Censoring/Discontinuations 
As a part of missing data analysis a Multiple Imputation (MI) simulation method for imputing 
missing data will be conducted on ANCOVA analysis for the primary efficacy endpoints on the 
ITT population. This will help to assess the impact of missing data on the primary analysis. 
 
Subjects who withdraw from the study prematurely will also be included in the statistical 
analyses up to the point of discontinuation. 
The SAS procedure MI will be used and the details of MI procedure will be stated in the dataset 
specification document. If the data is monotone missing, an imputation model with regression 
baseline parameters will be applied, otherwise Markov Chain Monte Carlo(MCMC) will be 
applied. All variables included in the analysis model which are used in the primary model will 
be used for imputation andvalues at day 3 for the primary endpoint (For Day 5) will be included 
in the imputation model. To reduce the sampling variability from the imputation process, 50 
datasets will be generated. 
In the estimation step, separate analysis will be performed using the model mentioned for the 
primary endpoint statistical analysis Section 4.5.1.2. 
After the completion of the estimation step SAS procedure MIANALYZE will be used to pool 
the estimates. 
Refer APPENDIX 4 for sample SAS codes. 
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No imputation is planned for missing diary card pain intensity and relief assessments. 
 
4.6 
Analysis of Secondary Objectives 
4.6.1 
Efficacy (Secondary) 
All the secondary endpoints POM at day 3 and 8, Karlsson score, tenderness, swelling and 
diary assessments (SPID and TOTPAR) will be analyzed using an ANCOVA model with 
treatment and center as fixed effect, baseline assessment for the corresponding endpoints as 
covariate. Treatment differences and two-sided 95% CI will be presented. 
The secondary efficacy analyses will be performed and also be listed on mITT and PP 
population. 
• Change from baseline of POM (CRF page: Pain on Movement; VAS score will be obtained 
from VASSCRL)on VAS on days 3 and 8 respectively (
). 
• Tenderness measured by pressure algometry on days 3, 5 and 8 which will be analysed using 
change from baseline and difference between the measurement in injured area (CRF page: 
Tenderness; measurement for study ankle : QS_INJA) and contralateral area (CRF page: 
Tenderness; measurement for study ankle : QS_CLTA) (
).. 
• Change from baseline Ankle Joint Function (Karlsson Scoring Scale; CRF page: Ankle Joint 
Function: Variable : Total Score KSSTS) on days 3, 5 and 8 (
 
).. 
• Circumference measurement of swelling on days 3, 5 8 which will be analysed using change 
from baseline in circumference of affected ankle and comparison to non-affected ankle by 
Figure of Eight method (CRF Page:Ankle swelling; Variables: FOEMINSC and 
FOEMCASC respectively.) (
;).. 
• Pain Intensity and Pain Relief (CRF Page: Subject Diary(Day 1/5) ; variables will used to 
calculate the Pain Intensity and Pain Relief are DPI and DPR respectively for each timepoint 
(DSTMPT)) 
• Pain Intensity (
) 
• Pain intensity will be analysed based on the Sum of Pain Intensity Difference 
(SPID). SPID is defined as from 0 -24 hours post first dose corresponding to day 1 
and from 0-24 hours post first dose corresponding to day 5. 
• SPIDt=∑PIDt(timet-timet-1)(h), where, PIDt=pain intensity score (DPI from CRF 
page corresponding to day); timet=time in hours post first dose 
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• Pain Relief (
) 
• Pain relief will be analysed based on the Total Pain Relief (TOTPAR). TOTPAR is 
defined as from 0-24 hours post first dose corresponding to day 1 and from 0-24 
hours post first dose corresponding to day 5. 
• TOTPAR=∑Rt(timet-timet-1), where Rt =pain relief score (DPR from CRF page 
corresponding to day) 
 
 
4.6.2 
Pharmacokinetic (Secondary) 
Not Applicable 
 
4.7 
Analysis of Safety 
4.7.1 
Adverse Events and Serious Adverse Events 
Adverse events (AE) recorded during the study will be mapped to a system organ class (SOC) 
and preferred term (PT) using the current medical dictionary for regulatory activities 
(MedDRA). 
Treatment emergent adverse events (TEAEs) are defined as new AEs that occur on or after the 
date/time of the first administration of study product or worsens if AE started prior to start of 
first administration. . 
Summary of all TEAE ( 
)will be presented with the following information – 
• Number and % of subjects with at least one TEAE 
• Time at risk in weeks (Patient-weeks [PW=YY.Y] = sum of the time on study in 
weeks=[(sum of the time on study in days) /7] 
• Number of adverse events (cases) 
• Exposure-Adj-TEAE in 100 weeks= 100*(number of patients with AE/sum of days at risk 
for AE) x 7days/weeks. It represents the number of events occurring in 100 Patient-Weeks 
• P-value (P-value will be obtained from Poisson regression model with number of subjects 
with AE as dependent variable, treatment and treatment as independent fixed effect. 
logarithm of time at risk will be considered as offset. Risk ratio and 95% confidence interval 
will also be presented along with the p-value.) 
Refer Appendix 4 for sample SAS code. 
All other TEAE will be presented with the following information – 
• Number of cases 
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• Number of subjects with AE 
• % of subjects with AE 
All the AE information will be taken from the Adverse Event CRF page. 
 
The following summary tables and listings will be presented by treatment group and overall for 
safety population: 
• Table of TEAEs by System Organ Class and Preferred Term (
) 
• Table of Serious TEAEs by System Organ Class and Preferred Term (
) 
• Treatment Emergent Adverse Events by System Organ Class, Preferred Term and Intensity 
(
) 
• Treatment Related Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term by Relationship status (
) 
• Treatment Emergent Adverse Events by Preferred Term leading to Drug Withdrawal (
 
) 
• Treatment Related Treatment Emergent Serious Adverse Events by Preferred Term (
 
) 
• Treatment Emergent Adverse Events Leading to Study Discontinuation by Preferred Term 
(
) 
• 
 All Treatment Emergent Adverse Events by Preferred Term 
• Listing of all AEs (including all subjects: 
) for all safety subjects. 
• Listing of all Serious Adverse Events (
) 
Additionally, all treatment-emergent adverse events will be listed (
). 
Deaths occurring during treatment (if any) will be listed by treatment, including the date and 
study day of death, and the principal cause of death (
). 
 
4.7.2 
Laboratory Tests 
Laboratory results will be summerised using safety population. Chemistry and hematology 
samples will be collected at Visit 1 (Screening/Baseline ) and Visit 4 (Early D/C ). The results 
will be summarized by visit and treatment. Descriptive statistics the mean, standard deviation, 
median, minimum and maximum values in each treatment group will be presented (
 
). Shifts in laboratory results for both chemistry and hematology will be 
presented in tables (
). Laboratory hematology, chemistry and Urine 
Pregnancy test parameters will be listed in 
 respectively. 
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As per the protocol following tests will be conducted for chemistry and hematology. 
Hematology related information should be mapped with Hematology CRF page and blood 
chemistry related information will be mapped with Chemistry CRF page. For other test Urine 
Pregnancy CRF page will be used. 
 
Table 4-2 
Laboratory Tests 
 
Chemistry 
Hematology 
Other 
BUN/Urea/Creatinine 
Hemoglobin 
Urine Pregnancy test 
Glucose (fasting) 
Hematocrit RBC count 
Calcium 
Platelet count 
Sodium 
WBC cont 
Magnesium 
Total Neutrophil (Abs) 
Potassium 
Eosinophil (Abs) 
Total CO2 (Bicarbonate) 
Monocytes (Abs) 
AST, ALT 
Basophils (Abs) 
Direct Bilirubin 
Lymphocytes (Abs) 
Indirect Bilirubin 
Total Bilirubin 
Alkaline Phophatase 
Uric acid 
Albumin 
Total Protein 
PT/INR 
Definitions: RBC= Red blood cell; WBC= White blood cells; BUN=Blood urea nitrogen; 
HIV= Humanimmunodeficiency virus; AST= transaminase; ALT= alanine transaminase; 
PT/INR= prothrombin time/international normalized ratio; 
Urine pregnancy test will be conducted at Visit 1 (Screening/Baseline ) and Visit 4(Early D/C ). 
Urine pregnancy test will be listed in 
. Unire pregnancy related information will 
be taken from urine pregnancy test pafe from CRF. 
All laboratory results will be listed including data from unscheduled visits. For lab summary 
and shift tables, the last available record/value for a particular lab test for a subject at a particular 
visit; will be considered for analysis. In case there are some unscheduled tests (irrespective of 
schedule visit or not) are conduted in any center due to some safety concerns then those tests 
will be listed. This information will be gathered from hematology and chemistry CRF page. 
 
4.7.3 
Vital Signs 
Vital sign parameters will be summarized using safety population. Vital signs parameters sitting 
systolic and diastolic blood pressure (mmHg), sitting pulserate (beats/minute), height (cm) and 
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weight (kg) will be recorded at Visit 1(Baseline) and at Visit 4(Early D/C) and will be 
summarized by the mean, standard deviation, median, minimum and maximum values by visit 
and treatment group (
). Change from baseline in vital signs parameters will also 
be summarized in the above table. Vital signs at each assessment will also be listed (
 
). All Vital sign related information will be taken from Vital Signs CRF page. 
 
4.7.4 
Findings on Physical Examination 
Physical examination (PE) performed at Visit 1 (Baseline) and Visit 4(Early D/C) will be listed 
(
) and the physical examination conditions (normal/abnormal/not examined) 
will be summerrized in 
. Physical examination will include general condition, 
dermatologic, eyes, ears, nose, throat, neck, thyroid, heart, respiratory system, abdomen, 
kidneys, skeletal system, extremities, lymphatic system, CNS and neurological condition. All 
the PE information will be taken from Physical Examination CRF page. 
 
4.7.5 
COVID-19 Assessment 
Covid-19 related assessment will be listed from COVID-19 Diagnosis CRF page using ITT 
population. If in case of any subject diagnosed with COVID-19 positive then the details of the 
diagnosis and treatment will be provided. ( 
) 
 
 
4.8 
Analysis of Other Variables 
Not Applicable. 
 
4.8.1 
Quality of Life 
Not Applicable 
 
4.8.2 
Patch Adhesion Performance 
Not Applicable. 
 
5 
Changes to the Protocol Defined Statistical Analysis Plan 
1. Rescue medication analysis has been performed considering time to event data. 
Whereas, protocol planned “Hodge Lehmann” analysis has not been performed. 
2. For Pain Intensity and Pain Relief, as per protocol for Day 1 it is “Sum of 0-24 hrs” and 
“Sum of 96-120 hrs”. Based on discussion and time consideration Day 5 will also be 
displayed as “Sum 0-24 hours”. 
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3. Compliance-Sensitivity analysis: Subjects with good compliance has been added in 
analysis to check if there is any change in variability in POM. 
4. There will be additional sensitivity analysis conducted for COVID 19 affected subjects 
for which protocol will not be updated. 
5. The definition of Per Protocol Population has been modified in the RAP. 
6. The protocol deviation criterion of compliance has been modified. 
Any changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 3. 
 
Table 3 
Changes to Protocol Defined Analysis Plan 
 
Protocol 
Reporting & Analysis Plan 
Statistical 
Analysis 
section 
Statistical 
Analysis Plan 
Rationale for Changes 
• Section 
12, 
Subsection 
12.2.6 
• Section 
4.4.3 
• Rescue medication can be clearly analysed defining 
time to event data. 
• Section 
12, 
Subsection 
12.2.6 
• Section 
4.5.2 
• Sine the “Day 5”, 96 hour is not actual 96th hour with 
respect to first treatment start time, so as per clinical 
consideration it’s start of Day 5 and consider as 0 hour 
of Day 5. 
• New 
addition 
• Section 
4.5.1 
• Compliance Sensitivity Analysis: This analysis has 
been done to check if there is any change in variability 
in POM based on good compliance.. 
• New 
addition 
• Section 
4.7.5 
• COVID analysis: As the pandemic started at the time 
of recruitment, as per regulatory requirement 
sensitivity analysis is planned for COVID patients, if 
any. 
• Section 
12.2. 
Subsection 
12.2.1 
• Section 
4.2.3 
• It was observed that most of the subjects has 50% ≤ 
weight compliance ≤ 80%. However these subjects 
has full and proper Pain on Movement measurements 
available. Based on these observations it has been 
decided to re look on the definition of PP Population. 
• New 
addition 
• Section 
4.2.2 
• For overdosed subjects the PP exclusion reason was 
updated       as 
 
“Other 
deviation-weight 
compliance 
>=143% 
or 
application 


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Protocol 
Reporting & Analysis Plan 
Statistical 
Analysis 
section 
Statistical 
Analysis Plan 
Rationale for Changes 
compliance >=143%" and for less dosed subjects, the 
PP exclusion reason was “Subjects with gel 
application compliance <= 80% or weight compliance 
<= 65% with study treatment”. 


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6 References 
1. Refer Protocol Section 14 of “Reference” 
2. Subject Case Report Forms 211206_Version 4.0_22JUN2020 – Unique 


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Appendix 1: Subgroups. 
Not Applicable 
 
Appendix 2: Center pools in multicenter studies. 
Not Applicable 
 
Appendix 3: Major Protocol Deviations Definitions. 
Protocol deviations are the deviations from the procedure outlined in the protocol. All the 
protocol deviations (PDs) will be summarized by ITT population and will be listed using ITT 
population as obtained from Clinical Trial Management System (CTMS) logs. PDs will be 
identified and discussed with the Investigator/Sponsor in PD review discussion to categorize 
them, and to finalize analysis set assignment. PDs may include COVID 19 related deviations 
as. COVID 19 related deviations will be listed separately. 
PDs will be grouped into the standardized terms, e.g., IP compliance deviation; Informed 
consent deviation; Study procedure deviation; or equivalent terms in the PD log will be used 
for reporting purpose in tables and listings. 
Any PD will be categorized into one of the following severity categories: 
 
 
Critical: A deviation from protocol-related procedure that threatens integrity of data, adversely 
affects subjects, and/or could invalidate acceptability of a project (or part of it). Such deviations 
require immediate action. 
Major: A deviation from protocol-related procedures that could affect integrity of the data or 
adversely affect subjects. Such deviations require timely action. 
Minor: A deviation from accepted procedures that will not adversely affect subjects or data 
integrity but should be dealt with appropriately. 


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Appendix 4: Sample SAS Code 
SAS code for primary End point Analysis 
Consider below mentioned SAS Code for primary model : 
1a) Subset for PP population and 
1b) Subset for mITT population 
 
 
 
 
 
 
 
 
*the variance-covariance matrix structure will be selected based data. 
 
SAS code for Supportive Analysis 
 
 
 
 
 
 
 
*The variance-covariance matrix structure will be selected based on data 
 
SAS code Repeated Measure Mixed Effect Model 
 
 
 
 
 
 
 
*The variance-covariance matrix structure will be selected based on data 
 
SAS code for Multiple Imputation 
Step1: Check on the missing patten of the data 
Step2: Based on the missing pattern decide on the method 
PPD
PPD
PPD


Di cl of e n a c Di et h yl a mi n e 2. 3 2 %  
2 1 1 2 0 6  
St ati sti c al R e p orti n g a n d A n al y si s pl a n Dr aft V 2. 0 2 0 J A N 2 0 2 1  
Gla x o S mit h Kli ne C o ns u mer Healt hcare C o nfi de ntial  
Pa ge 3 3  of 3 6  
 
 
 
Ste p 3: S A S c o de f or MI 
Ste p 4:t o get c o m bi ne d esti mate use f oll o wi n g c o d e: 
 
 
S A S c o d e f or R e s c u e M e di c ati o n A n al y si s:  
 
 
 
 
 
 
 
 
 
 
S A S c o d e f or P oi s s o n R e gr e s si o n f or A d v er s e E v e nt :  
 
 
 
 
 
 
 
 
  
 
 
w here,  
1.  n A E is n u m ber of patie nts wit h T E A E.  
P P D
P P D
P P D
P P D


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2. Logt=Logarithim (time to first AE or time at risk)( where time at risk = sum of (if a subject 
experienced an event it is time to first AE, if the subject did not experience event, it is time on 
study)) 


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Appendix 5: Prohibited Medication 
 
The following concomitant medications and/or therapies are prohibited: 
• Systemic or topical NSAIDs; 
• Steroids (injected or oral, except inhaled topical asthma and hayfever treatments and 
topical dermal treatments not applied to the sprained ankle); 
• Physiotherapy (including, but not exclusive to, transdermal electro neural stimulation 
(TENS), ultrasound, massage, and spinal manipulation) or any other kind of pain 
therapy throughout the course of the study; 
• Tranquilizers, anxiolytics, hypnotics, or sedatives, unless the subject’s prescribed daily 
dose has been unchanged for a month before the randomization visit; this regimen 
must continue unchanged for the entire study; 
• Amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamines, 
opiates,phencyclidine, and tetrahydrocannabinol; 
• Traditional, herbal or homeopathy treatments (oral and topical); 
• Adhesive and/or immobilizing casts, bandages, Aircast splints, treatment by rest, 
ice,compression, or elevation (RICE) are not allowed. 


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Attachment 1: List of Data Displays 
1. 
Work Sheet 1 is for CSR. 
 
Study_211206
 
 
PPD