Efficacy and Safety Evaluation of Esflurbiprofen Topical System in Acute Ankle Sprains: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this randomized, controlled, double-blind, multi-center trial is to demonstrate that the **Esflurbiprofen Topical System (EFTS)** is superior in reducing pain compared to a matching placebo in patients with acute ankle sprains. This is assessed based on the Sum of Pain Intensity Difference (SPID) of the Visual Analogue Scale (VAS) score for pain-on-movement (POM) over a 0-48 hour period. The clinical relevance of this objective lies in providing an effective local symptomatic treatment for pain associated with acute ankle sprains, potentially improving patient outcomes and recovery times.

Secondary objectives include: - Demonstrating that the EFTS is superior in pain reduction compared to a placebo based on pain-on-movement (POM) and pain-at-rest (PAR) assessments, as well as global efficacy assessments during a 7-day observation period. - Characterization of tolerability during treatment. - Characterization of local tolerability during treatment. - Characterization of adhesion.

The clinical trial focuses on evaluating the efficacy of EFTS in reducing pain for patients with **acute ankle sprains grade I**. The study population comprises adult male and female participants aged 18 to 64 years, who are in satisfactory health as determined by medical history and physical examination. Participants were required to enroll within 6 hours of sustaining the injury, with a baseline Visual Analogue Scale (VAS) score for pain-on-movement (POM) of the injured extremity greater than 50 mm on a 100 mm scale. The trial includes individuals who have provided written informed consent. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific criteria, including the location of injury eliciting POM on active standardized movement. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, although specific details about this group are not disclosed.

The clinical trial is designed as a **randomized**, **controlled**, **double-blind**, multi-center study to evaluate the efficacy and safety of the **Esflurbiprofen Topical System (EFTS)** compared to a placebo in the treatment of pain associated with **acute ankle sprains grade I**. The primary objective is to demonstrate the superiority of EFTS in reducing pain, as measured by the Sum of Pain Intensity Difference (SPID) on the Visual Analogue Scale (VAS) for pain-on-movement (POM) over a 48-hour period. The trial is expected to commence on January 1, 2025, and conclude by August 31, 2025.

Participants will be involved in the study for a maximum of 7 days, with the trial consisting of several key visits. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on criteria such as age (18-64 years), recent injury (within 6 hours), and a baseline VAS score for POM greater than 50 mm. Following the screening, participants will be randomly assigned to receive either the EFTS or a placebo patch, which is indistinguishable from the investigational drug but lacks the active ingredient.

Subsequent follow-up visits will occur at specified intervals to assess pain levels, the use of rescue medication, and any adverse events. These visits will also include evaluations of the adhesive power of the EFTS and local tolerability. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted. Conditions that may lead to early termination from the study include significant adverse events or withdrawal of consent by the participant.

The trial's methodology ensures rigorous assessment through its double-blind design, where neither participants nor investigators are aware of the treatment allocations. This approach minimizes bias and enhances the reliability of the results. The study's endpoints include both primary and secondary measures, such as the time to meaningful pain reduction and global efficacy assessments by both physicians and patients. The trial's comprehensive design aims to provide robust data on the therapeutic potential of EFTS in managing pain from acute ankle sprains.

The clinical trial involves the evaluation of the **Esflurbiprofen Topical System (EFTS)**, a transdermal patch designed for the local symptomatic and short-term treatment of pain in ankle sprains. The active substance in this investigational product is **esflurbiprofen**, a chemical compound. The patch is applied via **topical application** and is intended for use over a maximum treatment period of 7 days. The maximum daily dose of esflurbiprofen is 165 mg, with a total maximum dose of 1155 mg over the treatment period. The product is manufactured by TEIKOKU SEIYAKU CO., LTD. and is identified by the sponsor product code TK-254RX.

In addition to the investigational product, the trial includes a **placebo patch** that is indistinguishable from the EFTS but does not contain the active ingredient. This placebo serves as a comparator to evaluate the efficacy of the EFTS in reducing pain. The placebo patch is used under the same conditions as the EFTS, ensuring that any observed effects can be attributed to the active substance in the investigational product.

As an auxiliary treatment, **paracetamol** is included in the study. Paracetamol is administered in tablet form via the **oral** route. The maximum daily dose of paracetamol is 3000 mg, with a total maximum dose of 21000 mg over a 7-day period. This auxiliary treatment is provided to manage pain as part of the standard-of-care therapy, ensuring that participants receive adequate pain relief during the trial. Compliance with the dosing schedule is monitored to ensure adherence to the treatment protocol.

The efficacy of the Esflurbiprofen Topical System (EFTS) in the treatment of pain associated with acute ankle sprains will be assessed using the **Sum of Pain Intensity Difference (SPID)** of the Visual Analogue Scale (VAS) score on pain-on-movement (POM) over a 0-48 hour period. This primary endpoint will provide a quantitative measure of pain reduction, comparing the EFTS to a placebo. Secondary endpoints include various VAS scores on POM and pain-at-rest (PAR) at multiple timepoints, such as 6 hours, before bedtime on Day 1, and at 12-hour intervals up to 168 hours. These scores will be used to calculate related Pain Intensity Differences (PIDs) and SPIDs.

Additional secondary endpoints involve the time to meaningful and optimal pain reduction, defined as a 30% and 50% reduction from baseline VAS scores, respectively. The time to complete resolution of pain, both on movement and at rest, will also be evaluated. Responder rates will be determined by the percentage of patients achieving at least a 50% reduction in VAS scores for POM at 48 hours and those able to resume normal physical activity by 168 hours. The resolution of the ankle sprain will be assessed by the percentage of patients with POM and PAR scores of 0 at 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, adverse events (AEs), serious adverse events (SAEs), and local tolerability will be monitored throughout the trial. The adhesive power of the EFTS will be visually assessed by site staff and subjects using a 5-point score at specified visits and timepoints. These comprehensive assessments will provide a robust evaluation of the EFTS's efficacy in managing pain from acute ankle sprains.