Evaluation of the Safety and Efficacy of Esflurbiprofen Topical System and Paracetamol in Acute Limb Contusion Pain Management

The primary objective of this clinical trial is the **characterization of safety** during treatment with the Esflurbiprofen Topical System (EFTS) in patients experiencing pain due to acute contusions of the upper or lower limbs. This objective is clinically relevant as it aims to ensure that the treatment does not pose undue risk to patients, thereby supporting its potential use in managing contusion-related pain.

Secondary objectives include: - Characterization of local tolerability during treatment, which is important for understanding the patient's comfort and potential side effects at the site of application. - Characterization of adhesion, which assesses the patch's ability to remain in place, ensuring consistent delivery of the active substance. - Characterization of efficacy in patients with acute contusions, which evaluates the treatment's effectiveness in alleviating pain, thereby providing insights into its therapeutic value.

The clinical trial focuses on adult **patients** aged 18 to 64 years, both male and female, who have experienced an **acute contusion** of the upper or lower limbs. Participants are required to have a pain-on-movement (POM) elicited on active standardized movement, with a baseline Visual Analogue Scale (VAS) score for POM of the injured extremity greater than 50 mm on a 100 mm VAS. The injury size must be between 25 cm² and 120 cm², as assessed by the Investigator. Enrollment must occur within 6 hours of the injury. Participants are expected to be in satisfactory health, as determined by the Investigator based on medical history and physical examination. The trial population includes both genders and is not limited to any specific lifestyle considerations such as diet or physical activity. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the safety and efficacy of the **Esflurbiprofen Topical System (EFTS)** in the treatment of pain associated with acute contusions of the upper or lower limbs. This is an open-label, multi-centric trial, which will involve adult participants aged 18 to 64 years who have sustained an acute contusion. The trial will be conducted over a period of approximately eight months, with recruitment expected to start on January 1, 2025, and the estimated end date being August 31, 2025. Participants will be enrolled within six hours of sustaining the injury, provided they meet the inclusion criteria, which include a baseline Visual Analog Scale (VAS) score for pain-on-movement (POM) of greater than 50 mm on a 100 mm scale and an injury size between 25 cm² and 120 cm².

The trial will follow a structured sequence of study visits. The initial visit will serve as the screening and inclusion visit, where eligibility will be confirmed, and informed consent will be obtained. Participants will then undergo a series of follow-up visits to monitor safety and efficacy outcomes. These visits will occur at specified intervals, including assessments at 24, 48, 72, 96, 120, and 168 hours post-treatment initiation. The primary endpoint of the trial is the occurrence of adverse events, while secondary endpoints include changes in VAS scores for POM and pain-at-rest (PAR), time to meaningful and optimal pain reduction, and the resolution of contusions. The end-of-study visit will conclude the trial, where final assessments will be conducted, and data will be collected for analysis.

Participant involvement is expected to last for a maximum of seven days, corresponding to the treatment period with the **Esflurbiprofen Topical System**. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or withdrawal of consent by the participant. The trial will also assess the use of rescue medication, local tolerability, and the adhesive power of the EFTS. The trial is categorized as a Phase III therapeutic and confirmatory clinical trial, aiming to confirm the therapeutic benefits and safety profile of the EFTS in a real-world setting.

The clinical trial involves the use of the **Esflurbiprofen Topical System (EFTS)**, a transdermal patch designed for the local symptomatic and short-term treatment of pain in contusions. The active substance in this experimental medication is **esflurbiprofen**, a chemical compound. The patch is applied topically, allowing for direct delivery of the medication to the affected area. The maximum daily dose of esflurbiprofen is 165 mg, with a total maximum dose of 1155 mg over a treatment period of up to 7 days. The patch is manufactured by TEIKOKU SEIYAKU CO., LTD. and is not formulated for pediatric use. Participant compliance with the dosing schedule is monitored throughout the trial to ensure accurate assessment of the treatment's safety and efficacy.

In addition to the experimental treatment, **paracetamol** is used as a non-experimental, auxiliary treatment in the study. Paracetamol is administered in tablet form and taken orally. The maximum daily dose is 3000 mg, with a total maximum dose of 21000 mg over a 7-day treatment period. This standard-of-care therapy serves as a comparator to evaluate the effectiveness of the Esflurbiprofen Topical System. The use of paracetamol is intended to provide a baseline for assessing the pain relief provided by the experimental treatment. Compliance with the paracetamol dosing schedule is also monitored to ensure the integrity of the trial results.

The efficacy of the Esflurbiprofen Topical System (EFTS) in the treatment of pain associated with contusions will be assessed using several parameters. The primary endpoint for efficacy evaluation is the occurrence of **Adverse Events (AEs)**. Secondary endpoints include the Visual Analog Scale (VAS) scores for pain-on-movement (POM) and pain-at-rest (PAR) at specified time points: before bedtime on Day 1, and at 24, 48, 72, 96, 120, and 168 hours. These scores will be used to calculate Pain Intensity Differences (PIDs) and Summed Pain Intensity Differences (SPIDs).

Additional secondary endpoints include the time to meaningful and optimal reduction of pain, defined as a 30% and 50% reduction in VAS scores for POM, respectively. The time to complete resolution of pain, both on movement and at rest, is also measured, with a VAS value of 0 mm indicating complete resolution. Responder rates will be calculated, with Responder Rate 1 defined as the number of patients achieving at least a 50% reduction in VAS score for POM at 48 hours, and Responder Rate 2 as the number of patients able to resume normal physical activity by 168 hours.

Global efficacy assessments will be conducted by both physicians and patients using a 5-point scale at 48, 72, and 168 hours. The use of rescue medication will be monitored at every visit except the first. Local tolerability will be assessed at Visit 6 using an 8-point scale for skin damage or reaction. The adhesive power of the EFTS will be visually assessed by site staff and subjects using a 5-point scale at various time points, including 24 hours after application and before/after bedtime.