Topical Treatment Is Effective and Safe for Acute Ankle Sprains: The Multi-Center Double-Blind Randomized Placebo-Controlled TRAUMED Trial

Abstract

Background: Topical NSAIDs are widely used to treat ankle sprains. Traumed (Tr14) gel is a multicomponent formulation, demonstrating inflammation-resolution properties.

Methods: This multicenter, double-blind trial investigated the efficacy and safety of Tr14 gel versus placebo gel and non-inferiority versus 1% diclofenac gel, applied 3×/day for 7 days after acute lateral ankle sprain (EudraCT Number: 2016-004792-50). The primary outcome was AUC for pain on passive movement, assessed by VAS from baseline to Days 4 and 7.

Results: The trial population included 625 patients aged 18 to 78 years. The AUC scores were 187.88 and 200.75 on Day 4 (p = 0.02) and 294.14 and 353.42 on Day 7 (p < 0.001) for Tr14 and placebo, respectively. For Tr14 compared to diclofenac, the AUC scores were 187.50 and 197.19 on Day 4 (p = 0.3804) and 293.85 and 327.93 on Day 7 (p = 0.0017), respectively. On the FAAM-ADL subscale, Tr14 was superior to placebo and non-inferior to diclofenac at all time points. Time to 50% pain improvement was lowest for Tr14 (6.0 days), compared to placebo (7.1 days) and diclofenac (7.0 days). Adverse events were uncommon and minor.

Conclusions: Tr14 gel is effective and safe in acute ankle sprains, compared to placebo gel and diclofenac gel, and has faster pain resolution.

Trial registration: The trial was registered in clinicaltrialsregister.eu, EudraCT number 2016-004792-50 on 07.06.2017.

Keywords: TRAUMED; Tr14; ankle sprain; anti-inflammatory agents; diclofenac; injury; musculoskeletal pain; traumeel; treatment.

Figure 1

Participant flow.

Figure 2

Primary efficacy outcomes: pain on passive movement Tr14 vs. placebo (A) absolute values, (B) AUC. (A) Boxplot shows absolute pain scores on VAS for passive movement for all visits (median, Percentile 10–90, LOCF) for Tr14 vs. Placebo (FAS). Primary endpoints (Day 4 and Day 7) are shown in the box. p values for combined follow-up represent non-parametric repeated measurements analysis. p values at single visits represent a two-sided Wilcoxon-Mann-Whitney U-test analysis. (B) The effect size for primary endpoints shows AUC for pain on passive movement on Days 4 and 7 (two-sided Wilcoxon-Mann-Whitney U-test, FAS, 95% Cl) for Tr14 vs. Placebo. Abbreviations: AUC = Area under the curve; VAS = Visual analog scale, LOCF = Last observation carried forward, FAS = Full Analysis Set, MW = Mann-Whitney estimator, LB = Lower bound of the two-sided confidence interval, UB = Upper bound of the two-sided confidence interval, P = p-value of Wilcoxon-Mann-Whitney test, T = Valid number of test group, R = Valid number of reference group.

Figure 3

Primary efficacy outcomes: pain on passive movement Tr14 vs. diclofenac (A) absolute values, (B) AUC. (A) Boxplot shows absolute pain scores on VAS for passive movement for all visits (median, Percentile 10–90, LOCF) for Tr14 vs. diclofenac (PP). Primary endpoints (Day 4 and Day 7) are shown in the box. p values for combined follow-up represent non-parametric repeated measurements analysis. p values at single visits represent a two-sided Wilcoxon-Mann-Whitney U-test analysis. (B) The effect size for primary endpoints shows AUC for pain on passive movement on Days 4 and 7 (two-sided Wilcoxon-Mann-Whitney U-test, PP, 95% Cl) for Tr14 vs. Diclofenac. Abbreviations: AUC = Area under the curve; VAS = Visual analog scale, LOCF = Last observation carried forward, PP= Per Protocol set, MW = Mann-Whitney estimator, LB = Lower bound of the two-sided confidence interval, UB = Upper bound of the two-sided confidence interval, P = p-value of Wilcoxon-Mann-Whitney test, T = Valid number of test group, R = Valid number of reference group.

Figure 4

Secondary outcomes: pain at rest (all visits) Tr14 vs. placebo, (A) absolute values, (B) AUC. (A) Boxplot shows absolute pain scores on VAS for pain at rest for all visits (median, Percentile 10–90, LOCF) for Tr14 vs. Placebo (FAS). p values at single visits represent a two-sided Wilcoxon-Mann-Whitney U-test analysis. (B) The effect size for all visits shows AUC for pain at rest (two-sided Wilcoxon-Mann-Whitney U-test, FAS, 95% Cl) for Tr14 vs. Placebo. Abbreviations: AUC = Area under the curve; VAS = Visual analog scale, LOCF = Last observation carried forward, FAS = Full Analysis Set, MW = Mann-Whitney estimator, LB = Lower bound of the two-sided confidence interval, UB = Upper bound of the two-sided confidence interval, P = p-value of Wilcoxon-Mann-Whitney test, T = Valid number of test group, R = Valid number of reference group.

Figure 5

Secondary outcomes: pain at rest (all visits) Tr14 vs. diclofenac, (A) absolute values, (B) AUC. (A) Boxplot shows absolute pain scores on VAS at rest for all visits (median, Percentile 10–90, LOCF) for Tr14 vs. Diclofenac (PP). p values for combined follow-up represent non-parametric repeated measurements analysis. p values at single visits represent a two-sided Wilcoxon-Mann-Whitney U-test analysis. (B) Effect size shows AUC for pain at rest (two-sided Wilcoxon-Mann-Whitney U-test, PP, 95% Cl) for Tr14 vs. Diclofenac. Abbreviations: AUC = Area under the curve; VAS = Visual analog scale, LOCF = Last observation carried forward, PP = Per Protocol set, MW = Mann-Whitney estimator, LB = Lower bound of the two-sided confidence interval, UB = Upper bound of the two-sided confidence interval, P = p-value of Wilcoxon-Mann-Whitney test, T = Valid number of test group, R = Valid number of reference group.

Figure 6

Secondary outcome: FAAM-ADL (all visits), percent change from baseline, (A) Tr14 vs. placebo (FAS), (B) Tr14 vs. diclofenac (PP). Boxplot shows percent-change-from-baseline of absolute FAAM-ADL subscale values (normalized of mean, percentage negative score FAS, LOCF, P10/P90) for all visits (median, percentile 10–90, LOCF). p values for combined follow-up represent non-parametric repeated measurement analysis. p values at single visits represent a two-sided Wilcoxon-Mann-Whitney U-test analysis. Abbreviations: FAAM-ADL = Foot and Ankle Ability Measure-Activities of Daily Living; LOCF = Last observation carried forward.

Figure 6

Secondary outcome: FAAM-ADL (all visits), percent change from baseline, (A) Tr14 vs. placebo (FAS), (B) Tr14 vs. diclofenac (PP). Boxplot shows percent-change-from-baseline of absolute FAAM-ADL subscale values (normalized of mean, percentage negative score FAS, LOCF, P10/P90) for all visits (median, percentile 10–90, LOCF). p values for combined follow-up represent non-parametric repeated measurement analysis. p values at single visits represent a two-sided Wilcoxon-Mann-Whitney U-test analysis. Abbreviations: FAAM-ADL = Foot and Ankle Ability Measure-Activities of Daily Living; LOCF = Last observation carried forward.

Figure 7

Secondary outcomes: Time (days) to 50% reduction of pain on passive movement, absolute values, (A) Tr14 vs. placebo (FAS), (B) Tr14 vs. diclofenac (PP). Boxplots show absolute values in days for time to 50% reduction of pain on passive movement for all visits (Median, Percentile 10–90, LOCF). Abbreviations: LOCF = Last observation carried forward, FAS = Full Analysis Set; PP = Per Protocol set.