Trial Outcomes & Findings for A Multicenter Efficacy Study of a Diclofenac+Menthol Gel in Subjects With Ankle Sprain (NCT NCT02100670)

Last Updated: 2018-01-12

Results Overview

AUC of PI on movement was measured by a numerical rating scale (NRS) during the 48 hour time interval from Day 1 to 3. AUC1-3 day was calculated based on trapezoidal method. Pain intensity was measured in NRS scale from 0 (no pain) to 10 (extreme pain). Participants assessed the severity of ankle pain using the NRS scale at baseline (prior to treatment) and at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

385 participants

Primary outcome timeframe

up to 72 hours

Results posted on

2018-01-12

Participant Flow

Participants were recruited at 16 centers in Germany.

A total of 388 participants were screened, out of which 385 were randomized, 3 did not meet the study criteria. Of the 385 participants randomized, 360 participants completed the study, 25 did not complete the study.

Participant milestones

Participant milestones
Measure	1% Diclofenac Sodium+3% Menthol 1% diclofenac sodium with 3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	1% Diclofenac Sodium 1% diclofenac sodium with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	3% Menthol 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Overall Study STARTED	118	113	78	76
Overall Study COMPLETED	105	106	74	75
Overall Study NOT COMPLETED	13	7	4	1

Reasons for withdrawal

Reasons for withdrawal
Measure	1% Diclofenac Sodium+3% Menthol 1% diclofenac sodium with 3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	1% Diclofenac Sodium 1% diclofenac sodium with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	3% Menthol 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Overall Study Adverse Event	10	3	3	0
Overall Study Lost to Follow-up	1	0	0	0
Overall Study Protocol Violation	0	1	0	1
Overall Study Withdrawal of Consent	0	1	1	0
Overall Study No swelling no pain	1	0	0	0
Overall Study Poor Efficacy	0	1	0	0
Overall Study Physician Decision	0	1	0	0
Overall Study Withdrawal by Subject	1	0	0	0

Baseline Characteristics

A Multicenter Efficacy Study of a Diclofenac+Menthol Gel in Subjects With Ankle Sprain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	1% Diclofenac Sodium+3% Menthol n=117 Participants 1% diclofenac sodium with 3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	1% Diclofenac Sodium n=112 Participants 1% diclofenac sodium with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Total n=381 Participants Total of all reporting groups
Age, Continuous	32.4 Years STANDARD_DEVIATION 11.83 • n=99 Participants	32.1 Years STANDARD_DEVIATION 11.40 • n=107 Participants	33.8 Years STANDARD_DEVIATION 12.15 • n=206 Participants	33.2 Years STANDARD_DEVIATION 11.63 • n=7 Participants	32.8 Years STANDARD_DEVIATION 11.70 • n=31 Participants
Sex: Female, Male Female	50 Participants n=99 Participants	41 Participants n=107 Participants	39 Participants n=206 Participants	35 Participants n=7 Participants	165 Participants n=31 Participants
Sex: Female, Male Male	67 Participants n=99 Participants	71 Participants n=107 Participants	38 Participants n=206 Participants	40 Participants n=7 Participants	216 Participants n=31 Participants

PRIMARY outcome

Timeframe: up to 72 hours

Population: Intent-to-Treat (ITT) population included all participants who fulfilled all the study entry criteria, received the study treatment and had at least one post-baseline efficacy assessment. This analysis was conducted on ITT population.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Area Under the Curve From Day 1 to Day 3 (AUC1-3 Days) of Pain Intensity(PI) on Movement for Diclofenac/Methanol Gel and Placebo Gel	276.97 NRS Score (0 - 10 scale) * hrs Standard Deviation 111.356	282.88 NRS Score (0 - 10 scale) * hrs Standard Deviation 100.958	—	—

SECONDARY outcome

Timeframe: up to 72 hours

Population: ITT population included all participants who fulfilled all the study entry criteria, received the study treatment and had at least one post-baseline efficacy assessment. This analysis was conducted on ITT population.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
AUC1-3 Days of PI on Movement for Diclofenac Sodium + Methanol, Diclofenac, Methanol and Placebo	276.97 NRS Score (0 - 10 scale) * hrs Standard Deviation 111.356	261.11 NRS Score (0 - 10 scale) * hrs Standard Deviation 96.791	272.65 NRS Score (0 - 10 scale) * hrs Standard Deviation 118.196	282.88 NRS Score (0 - 10 scale) * hrs Standard Deviation 100.958

SECONDARY outcome

Timeframe: Baseline to 10 days

PID on movement, calculated as PI at a given time 't' (after walking 5 steps on a flat surface) subtracted by the PI at baseline. Participants assessed the severity of ankle pain (PI) using the NRS scale from 0 (no pain) to 10 (extreme pain). PI was measured at baseline (prior to treatment) and at 10, 30 minutes (min.) and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Pain Intensity Difference (PID) on Movement PID at 72 hour (n=117, 112, 77, 75)	2.55 score on scale Standard Deviation 1.989	2.42 score on scale Standard Deviation 1.631	2.55 score on scale Standard Deviation 1.977	2.28 score on scale Standard Deviation 1.935
Pain Intensity Difference (PID) on Movement PID at 84 hour (n=113, 107, 75, 75)	2.84 score on scale Standard Deviation 1.883	2.68 score on scale Standard Deviation 1.686	3.08 score on scale Standard Deviation 1.916	2.68 score on scale Standard Deviation 2.008
Pain Intensity Difference (PID) on Movement PID at 96 hour (n=112, 107, 75, 74)	3.10 score on scale Standard Deviation 1.865	2.78 score on scale Standard Deviation 1.890	3.03 score on scale Standard Deviation 2.027	2.78 score on scale Standard Deviation 1.882
Pain Intensity Difference (PID) on Movement PID at 108 hour (n=112, 107, 75, 74)	3.34 score on scale Standard Deviation 1.980	3.01 score on scale Standard Deviation 1.751	3.48 score on scale Standard Deviation 1.989	3.18 score on scale Standard Deviation 1.996
Pain Intensity Difference (PID) on Movement PID at 120 hour (n=111, 107, 74, 74)	3.38 score on scale Standard Deviation 1.864	3.17 score on scale Standard Deviation 1.871	3.35 score on scale Standard Deviation 2.044	3.14 score on scale Standard Deviation 1.947
Pain Intensity Difference (PID) on Movement PID at 132 hour (n=110, 107, 74, 74)	3.70 score on scale Standard Deviation 1.961	3.53 score on scale Standard Deviation 1.824	3.72 score on scale Standard Deviation 1.913	3.47 score on scale Standard Deviation 2.042
Pain Intensity Difference (PID) on Movement PID at 144 hour (n=110, 107, 74, 74)	3.76 score on scale Standard Deviation 2.058	3.78 score on scale Standard Deviation 1.870	3.68 score on scale Standard Deviation 1.994	3.59 score on scale Standard Deviation 1.979
Pain Intensity Difference (PID) on Movement PID at 156 hour (n=109, 107, 74, 74)	4.17 score on scale Standard Deviation 2.115	4.05 score on scale Standard Deviation 1.870	3.95 score on scale Standard Deviation 1.999	3.88 score on scale Standard Deviation 2.158
Pain Intensity Difference (PID) on Movement PI at Baseline (n=117, 112, 77, 75)	7.8 score on scale Standard Deviation 1.55	7.4 score on scale Standard Deviation 1.44	7.8 score on scale Standard Deviation 1.60	7.7 score on scale Standard Deviation 1.47
Pain Intensity Difference (PID) on Movement PID at 10 min. (n=117, 112, 77, 75)	0.23 score on scale Standard Deviation 1.078	0.19 score on scale Standard Deviation 0.855	0.29 score on scale Standard Deviation 0.886	0.32 score on scale Standard Deviation 1.129
Pain Intensity Difference (PID) on Movement PID at 30 min. (n=117, 112, 77, 75)	0.44 score on scale Standard Deviation 1.302	0.36 score on scale Standard Deviation 0.967	0.49 score on scale Standard Deviation 0.868	0.55 score on scale Standard Deviation 1.464
Pain Intensity Difference (PID) on Movement PID at 1 hour (n=117, 112, 77, 75)	0.56 score on scale Standard Deviation 1.348	0.50 score on scale Standard Deviation 1.022	0.64 score on scale Standard Deviation 1.146	0.64 score on scale Standard Deviation 1.521
Pain Intensity Difference (PID) on Movement PID at 4 hour (n=117, 112, 77, 75)	0.71 score on scale Standard Deviation 1.640	0.48 score on scale Standard Deviation 1.057	0.79 score on scale Standard Deviation 1.128	0.69 score on scale Standard Deviation 1.414
Pain Intensity Difference (PID) on Movement PID at 6 hour (n=117, 112, 77, 75)	0.79 score on scale Standard Deviation 1.706	0.67 score on scale Standard Deviation 1.094	0.91 score on scale Standard Deviation 1.227	0.87 score on scale Standard Deviation 1.554
Pain Intensity Difference (PID) on Movement PID at 12 hour (n= 117, 112, 77, 75)	0.84 score on scale Standard Deviation 1.692	0.99 score on scale Standard Deviation 1.411	1.17 score on scale Standard Deviation 1.542	0.95 score on scale Standard Deviation 1.550
Pain Intensity Difference (PID) on Movement PID at 18 hour (n=117, 112, 77, 75)	1.19 score on scale Standard Deviation 1.707	1.32 score on scale Standard Deviation 1.409	1.44 score on scale Standard Deviation 1.751	1.16 score on scale Standard Deviation 1.661
Pain Intensity Difference (PID) on Movement PID at 24 hour (n=117, 112, 77, 75)	1.62 score on scale Standard Deviation 1.866	1.58 score on scale Standard Deviation 1.505	1.75 score on scale Standard Deviation 1.808	1.53 score on scale Standard Deviation 1.639
Pain Intensity Difference (PID) on Movement PID at 36 hour (n=117, 112, 77, 75)	1.59 score on scale Standard Deviation 1.899	1.65 score on scale Standard Deviation 1.592	1.55 score on scale Standard Deviation 1.818	1.32 score on scale Standard Deviation 1.702
Pain Intensity Difference (PID) on Movement PID at 48 hour (n=117, 112, 77, 75)	1.91 score on scale Standard Deviation 1.914	2.01 score on scale Standard Deviation 1.562	2.04 score on scale Standard Deviation 1.874	1.92 score on scale Standard Deviation 1.937
Pain Intensity Difference (PID) on Movement PID at 60 hour (n=117, 112, 77, 75)	2.41 score on scale Standard Deviation 1.917	2.26 score on scale Standard Deviation 1.659	2.56 score on scale Standard Deviation 1.963	2.05 score on scale Standard Deviation 1.888
Pain Intensity Difference (PID) on Movement PID at 168 hour (n=105, 104, 73, 74)	4.26 score on scale Standard Deviation 2.103	4.11 score on scale Standard Deviation 1.935	3.90 score on scale Standard Deviation 2.122	3.95 score on scale Standard Deviation 2.067
Pain Intensity Difference (PID) on Movement PID at 180 hour (n=105, 104, 73, 72)	4.58 score on scale Standard Deviation 2.065	4.45 score on scale Standard Deviation 1.980	4.37 score on scale Standard Deviation 1.933	4.08 score on scale Standard Deviation 2.121
Pain Intensity Difference (PID) on Movement PID at 192 hour (n=101, 102, 71, 72)	4.55 score on scale Standard Deviation 2.081	4.59 score on scale Standard Deviation 1.916	4.21 score on scale Standard Deviation 2.197	4.22 score on scale Standard Deviation 2.023
Pain Intensity Difference (PID) on Movement PID at 204 hour (n=101, 100, 71, 72)	5.17 score on scale Standard Deviation 2.020	4.94 score on scale Standard Deviation 1.984	4.87 score on scale Standard Deviation 1.999	4.56 score on scale Standard Deviation 2.122
Pain Intensity Difference (PID) on Movement PID at 216 hour (n=95, 100, 69, 72)	5.28 score on scale Standard Deviation 2.239	5.21 score on scale Standard Deviation 2.100	4.87 score on scale Standard Deviation 2.029	4.78 score on scale Standard Deviation 1.987
Pain Intensity Difference (PID) on Movement PID at 228 hour (n=95, 100, 69, 72)	5.71 score on scale Standard Deviation 2.292	5.62 score on scale Standard Deviation 2.068	5.28 score on scale Standard Deviation 2.071	5.01 score on scale Standard Deviation 2.113
Pain Intensity Difference (PID) on Movement PID at 240 hour (n=32, 43, 22, 42)	5.56 score on scale Standard Deviation 2.961	5.44 score on scale Standard Deviation 2.196	5.41 score on scale Standard Deviation 2.282	5.60 score on scale Standard Deviation 1.951

SECONDARY outcome

Timeframe: Baseline to 10 days

PID at rest was calculated as PI at a given time point't' (at rest) subtracted by the PI at baseline. Participants assessed the severity of ankle pain (PI) using the NRS scale from 0 (no pain) to 10 (extreme pain). PI was measured at baseline (prior to treatment) and at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after dosing.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
PID at Rest PI at Baseline (n=117, 112, 77, 75)	7.8 score on a scale Standard Deviation 1.55	7.4 score on a scale Standard Deviation 1.44	7.8 score on a scale Standard Deviation 1.60	7.7 score on a scale Standard Deviation 1.47
PID at Rest PID at 10 min. (n=117, 112, 77, 75)	0.34 score on a scale Standard Deviation 1.146	0.43 score on a scale Standard Deviation 1.145	0.17 score on a scale Standard Deviation 0.715	0.25 score on a scale Standard Deviation 1.175
PID at Rest PID at 30 min. (n=117, 112, 77, 75)	0.56 score on a scale Standard Deviation 1.185	0.45 score on a scale Standard Deviation 1.314	0.32 score on a scale Standard Deviation 0.818	0.44 score on a scale Standard Deviation 1.328
PID at Rest PID at 1 hour (n=117, 112, 77, 75)	0.64 score on a scale Standard Deviation 1.283	0.62 score on a scale Standard Deviation 1.187	0.48 score on a scale Standard Deviation 0.940	0.41 score on a scale Standard Deviation 1.620
PID at Rest PID at 4 hour (n=117, 112, 77, 75)	0.62 score on a scale Standard Deviation 1.413	0.53 score on a scale Standard Deviation 1.115	0.66 score on a scale Standard Deviation 1.071	0.43 score on a scale Standard Deviation 1.678
PID at Rest PID at 6 hour (n= 117, 112, 77, 75)	0.68 score on a scale Standard Deviation 1.473	0.62 score on a scale Standard Deviation 1.180	0.75 score on a scale Standard Deviation 1.183	0.53 score on a scale Standard Deviation 1.554
PID at Rest PID at 12 hour (n= 117, 112, 77, 75)	0.76 score on a scale Standard Deviation 1.501	0.86 score on a scale Standard Deviation 1.432	0.90 score on a scale Standard Deviation 1.429	0.68 score on a scale Standard Deviation 1.535
PID at Rest PID at 18 hour (n= 117, 112, 77, 75)	1.03 score on a scale Standard Deviation 1.597	1.14 score on a scale Standard Deviation 1.482	1.10 score on a scale Standard Deviation 1.594	0.85 score on a scale Standard Deviation 1.666
PID at Rest PID at 24 hour (n= 117, 112, 77, 75)	1.32 score on a scale Standard Deviation 1.579	1.39 score on a scale Standard Deviation 1.448	1.47 score on a scale Standard Deviation 1.535	1.13 score on a scale Standard Deviation 1.711
PID at Rest PID at 36 hour (n= 117, 112, 77, 75)	1.20 score on a scale Standard Deviation 1.549	1.32 score on a scale Standard Deviation 1.490	1.22 score on a scale Standard Deviation 1.635	1.09 score on a scale Standard Deviation 1.787
PID at Rest PID at 48 hour (n=117, 112, 77, 75)	1.43 score on a scale Standard Deviation 1.604	1.53 score on a scale Standard Deviation 1.464	1.51 score on a scale Standard Deviation 1.698	1.45 score on a scale Standard Deviation 1.840
PID at Rest PID at 60 hour (n= 117, 112, 77, 75)	1.91 score on a scale Standard Deviation 1.603	1.83 score on a scale Standard Deviation 1.593	1.88 score on a scale Standard Deviation 1.747	1.64 score on a scale Standard Deviation 1.893
PID at Rest PID at 72 hour (n= 117, 112, 77, 75)	1.91 score on a scale Standard Deviation 1.776	1.91 score on a scale Standard Deviation 1.545	1.86 score on a scale Standard Deviation 1.782	1.76 score on a scale Standard Deviation 1.972
PID at Rest PID at 84 hour (n= 113, 107, 75, 75)	2.11 score on a scale Standard Deviation 1.754	2.19 score on a scale Standard Deviation 1.655	2.19 score on a scale Standard Deviation 1.799	2.03 score on a scale Standard Deviation 1.931
PID at Rest PID at 96 hour (n= 112, 107, 75, 74)	2.26 score on a scale Standard Deviation 1.790	2.17 score on a scale Standard Deviation 1.707	2.23 score on a scale Standard Deviation 1.721	2.00 score on a scale Standard Deviation 1.720
PID at Rest PID at 108 hour (n=112, 107, 75, 74)	2.46 score on a scale Standard Deviation 1.795	2.43 score on a scale Standard Deviation 1.833	2.48 score on a scale Standard Deviation 1.743	2.27 score on a scale Standard Deviation 1.889
PID at Rest PID at 120 hour (n= 111, 107, 74, 74)	2.59 score on a scale Standard Deviation 1.836	2.48 score on a scale Standard Deviation 1.750	2.30 score on a scale Standard Deviation 1.856	2.09 score on a scale Standard Deviation 1.917
PID at Rest PID at 132 hour (n= 110, 107, 74, 74)	2.76 score on a scale Standard Deviation 1.877	2.78 score on a scale Standard Deviation 1.819	2.68 score on a scale Standard Deviation 1.873	2.49 score on a scale Standard Deviation 1.967
PID at Rest PID at 144 hour (n= 110, 107, 74, 74)	2.77 score on a scale Standard Deviation 1.989	2.77 score on a scale Standard Deviation 1.789	2.59 score on a scale Standard Deviation 1.965	2.49 score on a scale Standard Deviation 1.918
PID at Rest PID at 156 hour (n= 109, 107, 74, 74)	3.06 score on a scale Standard Deviation 2.011	3.11 score on a scale Standard Deviation 1.755	2.77 score on a scale Standard Deviation 1.884	2.65 score on a scale Standard Deviation 2.129
PID at Rest PID at 168 hour (n= 105, 104, 73, 74)	3.08 score on a scale Standard Deviation 2.037	3.15 score on a scale Standard Deviation 1.805	2.75 score on a scale Standard Deviation 1.869	2.64 score on a scale Standard Deviation 2.004
PID at Rest PID at 180 hour (n= 105, 104, 73, 72)	3.37 score on a scale Standard Deviation 2.100	3.38 score on a scale Standard Deviation 1.871	2.95 score on a scale Standard Deviation 1.747	2.88 score on a scale Standard Deviation 2.103
PID at Rest PID at 192 hour (n= 101, 102, 71, 72)	3.38 score on a scale Standard Deviation 2.240	3.30 score on a scale Standard Deviation 2.067	2.90 score on a scale Standard Deviation 1.928	3.00 score on a scale Standard Deviation 2.035
PID at Rest PID at 204 hour (n= 101, 100, 71, 72)	3.67 score on a scale Standard Deviation 2.250	3.61 score on a scale Standard Deviation 2.030	3.37 score on a scale Standard Deviation 1.853	3.21 score on a scale Standard Deviation 2.021
PID at Rest PID at 216 hour (n= 95, 100, 69, 72)	3.77 score on a scale Standard Deviation 2.372	3.87 score on a scale Standard Deviation 2.028	3.22 score on a scale Standard Deviation 2.306	3.26 score on a scale Standard Deviation 1.936
PID at Rest PID at 228 hour (n= 95, 100, 69, 72)	4.09 score on a scale Standard Deviation 2.348	4.02 score on a scale Standard Deviation 2.074	3.64 score on a scale Standard Deviation 2.000	3.53 score on a scale Standard Deviation 2.083
PID at Rest PID at 240 hour (n= 32, 43, 22, 42)	3.94 score on a scale Standard Deviation 2.862	4.23 score on a scale Standard Deviation 2.010	3.36 score on a scale Standard Deviation 2.610	3.67 score on a scale Standard Deviation 2.149

SECONDARY outcome

Timeframe: Day 1 to Day 7

Pain relief was measured at each time point using a 5-point Pain Relief Scale ranging from 0-4 while at rest (Where: 0- No pain relief; 1- A little or perceptible pain relief; 2- Meaningful pain relief; 3- A lot of relief; 4- Complete relief). Participants assessed the degree of ankle pain relief using the PRS scores at 10, 30 minutes and 1, 4, 6, 12, 18 and 24 hours after the first dose of treatment and twice daily after the first day of treatment.

Outcome measures

SECONDARY outcome

Timeframe: Baseline to Day 7

SPID was calculated as the time weighted sum of pain intensity differences (PID) from 0 to 7 Days. PID was calculated as PI at a given time point 't' subtracted by the PI at baseline. PI was measured on NRS scale from 0 (no pain) to 10 (extreme pain). The possible range of SPID for 0-6 hours was from -60 to 60, for 0-12 hours was from -120 to 120, for 0-1 day was from -240 to 240, for 0-3 days was from -720 to 720, for 0-7 days was from -1680 to 1680. A higher value of SPID indicates greater pain relief.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Sum of Pain Intensity Difference (SPID) At 0-6 hours	4.16 score on a scale Standard Deviation 9.299	3.19 score on a scale Standard Deviation 5.862	4.72 score on a scale Standard Deviation 6.306	4.37 score on a scale Standard Deviation 8.287
Sum of Pain Intensity Difference (SPID) At 0-12 hours	9.19 score on a scale Standard Deviation 18.788	9.13 score on a scale Standard Deviation 13.284	11.74 score on a scale Standard Deviation 14.675	10.05 score on a scale Standard Deviation 16.706
Sum of Pain Intensity Difference (SPID) At 0-1 days	26.01 score on a scale Standard Deviation 38.722	26.54 score on a scale Standard Deviation 28.497	30.91 score on a scale Standard Deviation 34.158	26.21 score on a scale Standard Deviation 34.877
Sum of Pain Intensity Difference (SPID) At 1 to 3 days	101.54 score on a scale Standard Deviation 87.184	100.07 score on a scale Standard Deviation 71.085	104.26 score on a scale Standard Deviation 83.689	90.88 score on a scale Standard Deviation 82.626
Sum of Pain Intensity Difference (SPID) At 0 to 7 days	451.12 score on a scale Standard Deviation 265.919	452.44 score on a scale Standard Deviation 244.488	464.96 score on a scale Standard Deviation 281.243	438.45 score on a scale Standard Deviation 287.369

SECONDARY outcome

Timeframe: Baseline to 10 days (end of study)

TOPR was measured by time when participants reported PRS ≥ 1, i.e. a "little" or "perceptible" pain relief'.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Time of Onset of Pain Relief (TOPR)	1.03 Hours Interval 0.2 to 157.0	4.00 Hours Interval 0.2 to 168.0	1.00 Hours Interval 0.2 to 94.3	4.00 Hours Interval 0.2 to 187.5

SECONDARY outcome

Timeframe: up to 10 days (end of study)

TOMR was measured by time when participants reported PRS ≥ 2, i.e. "some" or "meaningful" pain relief

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Time of Onset of Meaningful Pain Relief (TOMR)	92.50 Hours Interval 0.2 to 203.8	76.83 Hours Interval 0.2 to 184.1	72.00 Hours Interval 0.2 to 203.5	93.50 Hours Interval 0.2 to 203.0

SECONDARY outcome

Timeframe: up to 6 hours

Time of onset of cooling sensation measured by time when subjects reported to have a 'cooling effect as an enhancement of pain relief'. To assess this endpoint, participants were asked at 10, 30 minutes and at 1, 4, 6 hours post first dose "Do you feel a cooling sensation at the injured ankle from the study gel?

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Time of Onset of Cooling Sensation (TOCS)	0.17 Hours Interval 0.17 to 6.0	0.17 Hours Interval 0.17 to 6.0	0.17 Hours Interval 0.17 to 6.0	0.17 Hours Interval 0.17 to 6.0

SECONDARY outcome

Timeframe: Baseline to 168 hours

TOTPAR was calculated as sum of the products of PRS with time interval from one time point to the other. PRS was measured at each time point on a scale: 0= No pain relief, 1= A little or perceptible pain relief, 2= Meaningful pain relief, 3= A lot of relief, 4= Complete relief. The possible range of TOTPAR for 0-6 hours was from 0 to 24, for 0-12 hours was from 0 to 48, for 0-24 hours was from 0 to 96, for 0-72 hours was from 0 to 288, for 24-72 hours was from 0 to 192 and for 0-168 hours was from 0 to 672.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Total Pain Relief (TOTPAR) 0-6 hours	2.81 PRS Score (0 - 4 scale) Standard Deviation 3.162	2.64 PRS Score (0 - 4 scale) Standard Deviation 2.902	3.27 PRS Score (0 - 4 scale) Standard Deviation 3.176	2.75 PRS Score (0 - 4 scale) Standard Deviation 3.184
Total Pain Relief (TOTPAR) 0-12 hours	6.86 PRS Score (0 - 4 scale) Standard Deviation 6.125	6.81 PRS Score (0 - 4 scale) Standard Deviation 6.178	8.02 PRS Score (0 - 4 scale) Standard Deviation 7.045	6.35 PRS Score (0 - 4 scale) Standard Deviation 6.732
Total Pain Relief (TOTPAR) 0- 24 hours	16.04 PRS Score (0 - 4 scale) Standard Deviation 12.048	16.14 PRS Score (0 - 4 scale) Standard Deviation 12.479	18.85 PRS Score (0 - 4 scale) Standard Deviation 14.517	15.71 PRS Score (0 - 4 scale) Standard Deviation 13.146
Total Pain Relief (TOTPAR) 0-72 hours	60.14 PRS Score (0 - 4 scale) Standard Deviation 37.867	61.24 PRS Score (0 - 4 scale) Standard Deviation 35.877	66.69 PRS Score (0 - 4 scale) Standard Deviation 40.360	58.75 PRS Score (0 - 4 scale) Standard Deviation 41.724
Total Pain Relief (TOTPAR) 24-72 hours	44.10 PRS Score (0 - 4 scale) Standard Deviation 29.344	45.11 PRS Score (0 - 4 scale) Standard Deviation 26.431	47.84 PRS Score (0 - 4 scale) Standard Deviation 29.102	43.04 PRS Score (0 - 4 scale) Standard Deviation 31.570
Total Pain Relief (TOTPAR) 0-168 hours	172.97 PRS Score (0 - 4 scale) Standard Deviation 98.838	170.73 PRS Score (0 - 4 scale) Standard Deviation 97.187	184.17 PRS Score (0 - 4 scale) Standard Deviation 102.787	174.00 PRS Score (0 - 4 scale) Standard Deviation 94.917

SECONDARY outcome

Timeframe: At 10, 30, 60 minutes, 4 and 6 hours

Skin temperature was measured by thermal imaging.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=11 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=10 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=6 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=6 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Skin Temperature At 10 min.	27.69 degree celsius (°C) Standard Deviation 3.706	29.31 degree celsius (°C) Standard Deviation 2.610	29.92 degree celsius (°C) Standard Deviation 2.118	30.93 degree celsius (°C) Standard Deviation 2.842
Skin Temperature At 30 min.	28.26 degree celsius (°C) Standard Deviation 3.161	29.81 degree celsius (°C) Standard Deviation 2.595	30.50 degree celsius (°C) Standard Deviation 2.117	31.47 degree celsius (°C) Standard Deviation 3.386
Skin Temperature At 60 min.	28.64 degree celsius (°C) Standard Deviation 2.986	30.74 degree celsius (°C) Standard Deviation 2.781	30.22 degree celsius (°C) Standard Deviation 2.388	31.78 degree celsius (°C) Standard Deviation 3.213
Skin Temperature At 240 min.	30.52 degree celsius (°C) Standard Deviation 2.880	31.26 degree celsius (°C) Standard Deviation 2.981	31.15 degree celsius (°C) Standard Deviation 3.221	31.57 degree celsius (°C) Standard Deviation 2.700
Skin Temperature At 360 min.	31.02 degree celsius (°C) Standard Deviation 2.951	31.53 degree celsius (°C) Standard Deviation 3.299	31.27 degree celsius (°C) Standard Deviation 3.925	32.07 degree celsius (°C) Standard Deviation 3.482

SECONDARY outcome

Timeframe: Day 1 (baseline), 3, and 7

Ankle swelling measured by "figure of eight" method of injured ankle.

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Ankle Swelling At Day 3	566.2 Millimeters Standard Deviation 57.03	566.9 Millimeters Standard Deviation 49.55	567.0 Millimeters Standard Deviation 56.48	565.4 Millimeters Standard Deviation 52.67
Ankle Swelling At Day 1	573.9 Millimeters Standard Deviation 57.77	573.6 Millimeters Standard Deviation 50.20	577.1 Millimeters Standard Deviation 55.35	576.1 Millimeters Standard Deviation 50.19
Ankle Swelling At Day 7	558.3 Millimeters Standard Deviation 56.02	558.8 Millimeters Standard Deviation 46.37	558.4 Millimeters Standard Deviation 56.88	557.0 Millimeters Standard Deviation 50.85

SECONDARY outcome

Timeframe: up to 240 hours

Time to complete recovery measured as the day with complete relief of ankle pain (Participant-rated NRS scores were 0 for pain intensity at rest and pain) and swelling (Participants did not have any apparent swelling nor experience any pain or limitation of movement of the injured ankle as determined by the Principal Investigator or designee during the course of an ankle exam).

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Time to Complete Recovery	240.00 Hours Interval 17.0 to 240.0	240.00 Hours Interval 48.2 to 240.0	240.00 Hours Interval 53.2 to 240.0	240.00 Hours Interval 145.5 to 240.0

SECONDARY outcome

Timeframe: up to Day 10

PGART was measured at the end of study in a scale from 0-4 (Where: 0- Poor; 1- Fair; 2- Good; 3- Very Good; 4- Excellent)

Outcome measures

Outcome measures
Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=115 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=111 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=75 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Patient's Global Assessment in Response to Treatment (PGART) Poor=0	3 Participants 0.948	13 Participants 1.051	6 Participants 1.040	9 Participants 1.084
Patient's Global Assessment in Response to Treatment (PGART) Fair=1	24 Participants	20 Participants	12 Participants	14 Participants
Patient's Global Assessment in Response to Treatment (PGART) Good=2	44 Participants	46 Participants	26 Participants	27 Participants
Patient's Global Assessment in Response to Treatment (PGART) Very Good=3	35 Participants	26 Participants	26 Participants	21 Participants
Patient's Global Assessment in Response to Treatment (PGART) Excellent=4	9 Participants	6 Participants	5 Participants	4 Participants

Adverse Events

1% Diclofenac Sodium Plus 3% Menthol

Serious events: 0 serious events

Other events: 43 other events

Deaths: 0 deaths

1% Diclofenac Sodium Plus 0.09% Menthol

Serious events: 0 serious events

Other events: 26 other events

Deaths: 0 deaths

3% Menthol

Serious events: 0 serious events

Other events: 22 other events

Deaths: 0 deaths

Placebo With 0.09% Menthol Gel

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	1% Diclofenac Sodium Plus (+) 3% Menthol n=117 Participants 1% diclofenac sodium+3% menthol gel was supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=112 Participants Placebo gel was supplied in 30g tubes for each participant to apply 4g of gel topically to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 Participants 3% menthol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo n=75 Participants Placebo with 0.09% methanol gel was supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
Pain Relief Score (PRS) At 36 hour (n= 116, 112, 77, 74)	0.84 score on a scale Standard Deviation 0.709	0.84 score on a scale Standard Deviation 0.705	0.88 score on a scale Standard Deviation 0.760	0.78 score on a scale Standard Deviation 0.781
Pain Relief Score (PRS) At 10 min. (n= 117, 111, 77, 74)	0.33 score on a scale Standard Deviation 0.616	0.29 score on a scale Standard Deviation 0.609	0.32 score on a scale Standard Deviation 0.498	0.36 score on a scale Standard Deviation 0.610
Pain Relief Score (PRS) At 30 min. (n=117, 111, 77, 75)	0.44 score on a scale Standard Deviation 0.635	0.36 score on a scale Standard Deviation 0.585	0.49 score on a scale Standard Deviation 0.599	0.44 score on a scale Standard Deviation 0.683
Pain Relief Score (PRS) At 1 hour (n=116, 112, 77, 75)	0.48 score on a scale Standard Deviation 0.625	0.46 score on a scale Standard Deviation 0.599	0.57 score on a scale Standard Deviation 0.677	0.40 score on a scale Standard Deviation 0.717
Pain Relief Score (PRS) At 4 hour (n= 115, 110, 74, 71)	0.47 score on a scale Standard Deviation 0.626	0.45 score on a scale Standard Deviation 0.552	0.51 score on a scale Standard Deviation 0.579	0.49 score on a scale Standard Deviation 0.673
Pain Relief Score (PRS) At 6 hour (n= 109, 105, 70, 69)	0.50 score on a scale Standard Deviation 0.603	0.54 score on a scale Standard Deviation 0.605	0.63 score on a scale Standard Deviation 0.618	0.45 score on a scale Standard Deviation 0.607
Pain Relief Score (PRS) At 12 hour (n= 77, 89, 53, 58)	0.60 score on a scale Standard Deviation 0.591	0.72 score on a scale Standard Deviation 0.707	0.74 score on a scale Standard Deviation 0.684	0.62 score on a scale Standard Deviation 0.745
Pain Relief Score (PRS) At 18 hour (n= 76, 78, 53, 57)	0.71 score on a scale Standard Deviation 0.689	0.73 score on a scale Standard Deviation 0.715	0.83 score on a scale Standard Deviation 0.753	0.70 score on a scale Standard Deviation 0.680
Pain Relief Score (PRS) At 24 hour (n= 111, 105, 72, 72)	0.79 score on a scale Standard Deviation 0.662	0.74 score on a scale Standard Deviation 0.680	0.90 score on a scale Standard Deviation 0.754	0.81 score on a scale Standard Deviation 0.642
Pain Relief Score (PRS) At 48 hour (n= 116, 112, 77, 75)	0.90 score on a scale Standard Deviation 0.806	0.84 score on a scale Standard Deviation 0.651	0.99 score on a scale Standard Deviation 0.716	0.99 score on a scale Standard Deviation 0.846
Pain Relief Score (PRS) At 60 hour (n=115, 111, 77, 75)	1.07 score on a scale Standard Deviation 0.780	1.00 score on a scale Standard Deviation 0.714	1.16 score on a scale Standard Deviation 0.745	0.96 score on a scale Standard Deviation 0.779
Pain Relief Score (PRS) At 72 hour (n= 114, 109, 75, 74)	0.93 score on a scale Standard Deviation 0.784	1.06 score on a scale Standard Deviation 0.743	1.16 score on a scale Standard Deviation 0.806	0.97 score on a scale Standard Deviation 0.810
Pain Relief Score (PRS) At 84 hour (n= 113, 106, 75, 75)	1.07 score on a scale Standard Deviation 0.810	1.00 score on a scale Standard Deviation 0.756	1.25 score on a scale Standard Deviation 0.737	1.11 score on a scale Standard Deviation 0.746
Pain Relief Score (PRS) At 96 hour (n= 112, 106, 75, 74)	1.09 score on a scale Standard Deviation 0.823	1.03 score on a scale Standard Deviation 0.762	1.01 score on a scale Standard Deviation 0.830	1.09 score on a scale Standard Deviation 0.743
Pain Relief Score (PRS) At 108 hour (n= 111, 105, 75, 74)	1.18 score on a scale Standard Deviation 0.876	1.13 score on a scale Standard Deviation 0.809	1.28 score on a scale Standard Deviation 0.894	1.15 score on a scale Standard Deviation 0.734
Pain Relief Score (PRS) At 120 hour (n= 111, 107, 74, 72)	1.11 score on a scale Standard Deviation 0.918	1.14 score on a scale Standard Deviation 0.782	1.24 score on a scale Standard Deviation 0.904	1.10 score on a scale Standard Deviation 0.772
Pain Relief Score (PRS) At 132 hour (n= 110, 107, 73, 74)	1.34 score on a scale Standard Deviation 0.931	1.24 score on a scale Standard Deviation 0.878	1.34 score on a scale Standard Deviation 0.931	1.30 score on a scale Standard Deviation 0.887
Pain Relief Score (PRS) At 144 hour (n= 110, 107, 74, 73)	1.21 score on a scale Standard Deviation 1.015	1.21 score on a scale Standard Deviation 0.919	1.30 score on a scale Standard Deviation 0.947	1.27 score on a scale Standard Deviation 0.886
Pain Relief Score (PRS) At 156 hour (n= 109, 106, 74, 74)	1.41 score on a scale Standard Deviation 1.011	1.30 score on a scale Standard Deviation 1.053	1.47 score on a scale Standard Deviation 0.968	1.32 score on a scale Standard Deviation 0.952
Pain Relief Score (PRS) At 168 hour (n= 105, 103, 73, 73)	1.41 score on a scale Standard Deviation 1.026	1.31 score on a scale Standard Deviation 0.990	1.34 score on a scale Standard Deviation 1.003	1.40 score on a scale Standard Deviation 0.924

Measure	1% Diclofenac Sodium Plus 3% Menthol n=117 participants at risk 1% diclofenac sodium plus 3% menthol gel supplied in 30 gram (g) tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	1% Diclofenac Sodium Plus 0.09% Menthol n=112 participants at risk 1% diclofenac sodium plus 0.09% menthol gel supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	3% Menthol n=77 participants at risk 3% menthol gel supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.	Placebo With 0.09% Menthol Gel n=75 participants at risk Placebo with 0.09% menthol gel supplied in 30g tubes sufficient for each participant to apply 4g of gel to the injured ankle region four times daily for up to 10 days.
General disorders APPLICATION SITE DRYNESS	12.8% 15/117 • Up to 3 weeks of administration of investigational product	6.2% 7/112 • Up to 3 weeks of administration of investigational product	3.9% 3/77 • Up to 3 weeks of administration of investigational product	5.3% 4/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE PAIN	6.0% 7/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	2.6% 2/77 • Up to 3 weeks of administration of investigational product	1.3% 1/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE PRURITUS	4.3% 5/117 • Up to 3 weeks of administration of investigational product	2.7% 3/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	1.3% 1/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE ERYTHEMA	3.4% 4/117 • Up to 3 weeks of administration of investigational product	0.89% 1/112 • Up to 3 weeks of administration of investigational product	2.6% 2/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE ECZEMA	1.7% 2/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE DISCOLOURATION	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE RASH	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE REACTION	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE VESICLES	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders ASTHENIA	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders NECROSIS	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE BURN	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE HYPERSENSITIVITY	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.89% 1/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
General disorders APPLICATION SITE SWELLING	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders DRY SKIN	8.5% 10/117 • Up to 3 weeks of administration of investigational product	8.9% 10/112 • Up to 3 weeks of administration of investigational product	13.0% 10/77 • Up to 3 weeks of administration of investigational product	5.3% 4/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders PRURITUS	6.0% 7/117 • Up to 3 weeks of administration of investigational product	3.6% 4/112 • Up to 3 weeks of administration of investigational product	3.9% 3/77 • Up to 3 weeks of administration of investigational product	1.3% 1/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders ERYTHEMA	5.1% 6/117 • Up to 3 weeks of administration of investigational product	1.8% 2/112 • Up to 3 weeks of administration of investigational product	3.9% 3/77 • Up to 3 weeks of administration of investigational product	1.3% 1/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders BLISTER	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders DERMATITIS	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders DERMATITIS CONTACT	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders SKIN EXFOLIATION	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders SKIN WRINKLING	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders ECZEMA	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders RASH	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.89% 1/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders RASH VESICULAR	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	1.3% 1/75 • Up to 3 weeks of administration of investigational product
Skin and subcutaneous tissue disorders SKIN REACTION	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Nervous system disorders HEADACHE	3.4% 4/117 • Up to 3 weeks of administration of investigational product	1.8% 2/112 • Up to 3 weeks of administration of investigational product	5.2% 4/77 • Up to 3 weeks of administration of investigational product	4.0% 3/75 • Up to 3 weeks of administration of investigational product
Nervous system disorders BURNING SENSATION	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	1.3% 1/75 • Up to 3 weeks of administration of investigational product
Nervous system disorders HYPOAESTHESIA	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.89% 1/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Infections and infestations NASOPHARYNGITIS	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Infections and infestations PYODERMA	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Infections and infestations SINUSITIS	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Ear and labyrinth disorders VERTIGO	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Immune system disorders HYPERSENSITIVITY	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Injury, poisoning and procedural complications SKIN ABRASION	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Injury, poisoning and procedural complications ARTHROPOD STING	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.89% 1/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Injury, poisoning and procedural complications MUSCLE INJURY	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	1.3% 1/75 • Up to 3 weeks of administration of investigational product
Musculoskeletal and connective tissue disorders ARTHRALGIA	0.85% 1/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Musculoskeletal and connective tissue disorders BACK PAIN	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	2.7% 2/75 • Up to 3 weeks of administration of investigational product
Musculoskeletal and connective tissue disorders BONE SWELLING	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Musculoskeletal and connective tissue disorders EXOSTOSIS	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Musculoskeletal and connective tissue disorders OSTEOARTHRITIS	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Gastrointestinal disorders ABDOMINAL PAIN	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.89% 1/112 • Up to 3 weeks of administration of investigational product	0.00% 0/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Gastrointestinal disorders DIARRHOEA	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Gastrointestinal disorders NAUSEA	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product
Gastrointestinal disorders VOMITING	0.00% 0/117 • Up to 3 weeks of administration of investigational product	0.00% 0/112 • Up to 3 weeks of administration of investigational product	1.3% 1/77 • Up to 3 weeks of administration of investigational product	0.00% 0/75 • Up to 3 weeks of administration of investigational product