This multicentre, randomized, placebo-controlled, double-blind study was conducted across four clinical centres in Germany. The clinical trial was designed, implemented and reported in accordance with the ICH Guidelines for Good Clinical Practice, with applicable local regulations, and with the ethical principles laid down in the Declaration of Helsinki. Ethical approval for the study was granted by the Ethics Committee of the Landesärztekammer Nordrhein (three centres) and by the Ethics Committee of the Bayerischen Landesärztekammer (one centre). All patients provided written (signed) informed consent prior to participation in the study. The consent document informed patients that any scientific publication of results would be made in a form that does not allow any direct conclusions to be drawn about their person. Overall, 180 patients were enrolled, who, after signing of consent and confirmation of eligibility through initial clinical assessment, were assigned at random (ratio 2:1) to treatment with either the etofenamate 70 mg medicated plaster (Lixim 70 mg Patch) or a matching placebo plaster. In this outpatient study, participants returned for assessment after 12 h; further follow-up visits were scheduled at 24, 48, 72, 96 and 120 h with a final visit after 7 days of treatment. All study assessments as well as primary and secondary outcome measures were pre-specified in the study protocol.

Male or female patients presenting within 6 h of an acute strain, sprain or contusion of the soft tissues of an upper or lower limb sustained following blunt trauma were considered eligible. Patients aged ≥ 16 years could be included to allow for the collection of efficacy and safety data in older adolescents. To maximise the chance of demonstrating a clinically relevant difference between active and placebo treatments for these otherwise self-limiting injuries, pain on movement (POM) of the affected limb had to be ≥ 50 mm on a 100-mm visual analogue scale (VAS). Apart from the injury, patients were in satisfactory health as determined by the investigator on the basis of medical history and physical examination. Main exclusion criteria were serious injury to the limb (e.g. fracture, nerve injury, ligament disruption, tear of muscle or cartilage or open wound), a clinically significant concomitant illness, known allergy or contraindication to etofenamate, pregnancy or lactation, excessively hairy application site, a chronic skin disorder, or excessive sweating. Prior intake of NSAIDs or analgesics (36 h), opioids (7 days) or corticosteroids (60 days), or application of topical medication since the injury were also exclusion criteria.

A single plaster (etofenamate or placebo) was applied over the soft tissue injury every 24 h for 7 consecutive days. Placebo and active plasters, identical in every way apart from the presence of 70 mg etofenamate in the latter, were rectangular (10 cm × 14 cm) with rounded corners and consisted of an adhesive matrix layer and a backing layer of bi-elastic polyester fabric. Patients were instructed in correct application of the study treatment at the first visit (enrolment); subsequent plasters were self-administered at the study site monitored by the study personnel at each visit apart from the final plaster (144 h) which was applied at home. Patients with lower limb injuries were advised to limit weight-bearing and encouraged to use crutches where necessary. RICE (rest, ice, compression, elevation) therapy was permitted at the discretion of the investigator. Paracetamol 1 g was allowed as rescue medication up to four times daily in case of severe pain, but was to be avoided if possible in the 6 h prior to the 48-, 72-, 96- and 120-h visits.

To limit interference with healing of the injury, POM was assessed only once at each study visit, when the patient was asked to score POM in millimetres on a 100-mm VAS where 0 mm = ‘no pain’ and 100 mm = ‘extreme pain’. A standardised approach was used to assess POM: for the upper limb, pain was elicited by the patient actively flexing the elbow while holding a 3-kg barbell, while for the lower limb pain was elicited by the patient slowly walking 5 steps on an even surface. For injuries where these manoeuvres were considered unfeasible (e.g. ankle sprain) or insufficient to provoke pain, POM was elicited by the investigator performing an adequate passive movement of the joint nearest to the injured area.

POM data collected at each visit were used to generate additional variables, including area under the curve (AUC, calculated using the trapezoidal rule) of POM VAS pain scores over 0–48, 0–72, 0–96 and 0–120 h; time to achieve meaningful (30%), optimal (50%) and complete (100%) reduction of pain; responder rate, defined as the proportion of patients with at least 50% pain reduction at 72 h [1].

A 100-mm VAS was also used to assess pain at rest (PAR) at each visit. In addition, global efficacy was assessed at the 72-h and 168-h visits; for these assessments, patients and investigators were asked standardised questions about response to treatment, each graded on a 5-point Likert scale. Use of rescue medication (paracetamol) was recorded at each visit except visit 1 (baseline).

At each visit, adhesion of Lixim 70 mg Patch was assessed using the 5-point scale outlined in the 2023 US Food and Drug Administration (FDA) draft guidance ‘Assessing Adhesion with Transdermal Delivery Systems and Topical Patches for ANDAs’ (i.e. scores from 1, almost completely adhered [≥ 90%] to 5, completely detached).

The occurrence of adverse events (AE) after drug administration was recorded at each visit. In addition, at each visit, local tolerability was assessed using the 8-point dermal response scale outlined in the 2023 FDA draft guidance ‘Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs’ (i.e. scores ranging from 0 = ‘no evidence of irritation’ to 7 = ‘strong reaction spreading beyond test site’). Physical examination inclusive of vital signs was performed prior to randomisation and at the final visit.

Randomisation was implemented at the time of packaging and labelling in accordance with a code generated by a third party unconnected to the trial. Investigators assigned each patient the next available sequential treatment number at the time of enrolment. All persons involved in the conduct of the trial remained blind to treatment allocation throughout the study.

The sample size was calculated on the basis of the outcome of an earlier study with Lixim 70 mg Patch in patients with acute ankle sprain [11]. For the primary efficacy outcome of POM at 72 h after initiating treatment, a level of significance of α = 5% two-sided and a standard deviation of 16 mm, a sample size of 38 per group provides approximately 99% power to detect a difference of 10 mm between the two treatment groups. The final sample size was increased to N = 120 for the etofenamate group and N = 60 for placebo in order to obtain more precise results for the primary and secondary efficacy variables including for subgroup analyses, to increase the study power for secondary variables, and to allow for a drop-out rate of up to 20%.

The primary analysis was on the full analysis set (FAS). A per-protocol (PP) sensitivity analysis was planned; all enrolled patients were included in the safety analysis (SAF). Demographic and baseline values were analysed descriptively. For the primary endpoint, change of POM from baseline to 72 h, the null hypothesis was tested with an analysis of covariance (ANCOVA) model with baseline value as covariate and type of injury and centre as fixed factors with two-sided significance level α = 5%. For quantitative secondary efficacy outcomes assessed at the clinical trial site (POM, PAR) as well as derived outcomes (change from baseline, AUC), the ANCOVA model included baseline value as covariate and centre as fixed factor. The AUC analyses were based on actual rather than scheduled timings and were calculated using the trapezoidal rule.

For comparisons using the specified ANCOVA models above, the least square mean for each treatment and the corresponding difference between least square means (verum plaster − placebo) with the p value and 95% confidence interval were derived from the model.

For ordered categorical outcomes (Global efficacy assessments), differences between treatments were tested with the Cochran–Mantel–Haenszel (CMH) test, stratified by centre. Qualitative variables were presented per treatment through descriptive statistics. AEs were listed and evaluated descriptively with regard to frequency and intensity, relationship to study treatment, action taken, outcome, and seriousness as well as treatment group.