Non-Inferiority Trial of Compression Therapy Versus Phenoxymethylpenicillin and Compression Therapy in Recurrent Erysipelas of the Lower Limbs

The primary objective of this clinical trial is to evaluate whether **supervised compression therapy** alone is non-inferior to supervised compression therapy combined with antibiotics in controlling the relapse of recurrent erysipelas in the lower limbs. This is clinically relevant as it may offer a less complex treatment option with potentially fewer side effects and lower costs, while maintaining efficacy in preventing recurrences.

Secondary objectives include:

• Assessing the time to the first confirmed recurrence of erysipelas.
• Evaluating the severity of the recurrence.
• Assessing the safety of interventions.
• Evaluating the quality of life during the prophylaxis phase.
• Assessing patient adherence to interventions.
• Determining, in a joint analysis, that supervised compression therapy is both not inferior in terms of quality-adjusted life years (QALY) and not more expensive at 1 year than supervised compression therapy combined with antibiotics.

The clinical trial focuses on individuals with **recurrent erysipelas** in the lower limbs. The study population includes both male and female participants who are 18 years of age or older. Participants must have experienced at least two episodes of recurrent erysipelas in the same leg within the previous 52 weeks, with no more than five episodes in the same areas of the lower limbs during the year before randomization. The last episode must have been diagnosed within the previous three months. Participants are required to have a body mass index (BMI) of less than 40 kg/m², indicating no morbid obesity, and must be capable of applying compression therapy independently or with assistance. All participants must be affiliated with a social security regimen and able to provide written informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the efficacy of **supervised compression therapy** alone compared to the combination of supervised compression therapy and **antibiotics** in preventing the recurrence of **recurrent erysipelas** in the lower limbs. This is a non-inferiority, randomized, multicenter clinical trial. The trial will employ a double-blind, controlled methodology to ensure unbiased results. The estimated duration of the trial is from October 2025 to October 2029, with a total participant involvement period of 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, history of erysipelas, and ability to comply with study requirements. Following successful screening, participants will be randomized into one of the two study arms. Regular follow-up visits will be scheduled throughout the 12-month prophylaxis phase to monitor the recurrence of erysipelas, adherence to treatment, and any adverse effects. The primary endpoint is the proportion of patients experiencing at least one recurrence of erysipelas during the study period, assessed by a blinded evaluator. Secondary endpoints include time to first recurrence, severity of recurrence, and quality of life assessments.

The end-of-study visit will occur at the conclusion of the 12-month period, where final assessments will be conducted, including a comprehensive evaluation of the participant's health status and any long-term effects of the treatment. Participants may be withdrawn from the study early if they experience severe adverse effects, are unable to comply with the study protocol, or choose to withdraw consent. The trial aims to provide valuable insights into the management of recurrent erysipelas, potentially influencing future clinical practices.

The clinical trial involves the use of **PHENOXYMETHYLPENICILLIN**, an antibiotic administered in tablet form. The active substance, **phenoxymethylpenicillin**, is of chemical origin. The medication is intended for **oral use**. In the context of this trial, the experimental treatment does not specify a maximum daily dose, indicating a flexible dosing regimen tailored to the study's requirements. The treatment period is set for a maximum of 12 months. The role of this medication in the trial is categorized as a test product, and it is not a pediatric formulation.

In addition to the experimental treatment, a comparator treatment is also utilized in the study. This involves the administration of **PHENOXYMETHYLPENICILLIN** in a similar tablet form, with a specified maximum daily dose of 2,000,000 IU. The route of administration remains **oral use**, and the treatment duration is also capped at 12 months. This comparator serves to evaluate the efficacy of the experimental treatment against a standard antibiotic regimen. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The efficacy of the clinical trial titled "PRESENT - Prophylaxis of Recurrent Erysipelas in lower limbs: compreSsion thErapy vs aNTibiotics and compression therapy" will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of patients experiencing at least one recurrence of **erysipelas** during the 1-year prophylaxis phase, evaluated by an assessor who is blinded to the treatment allocation. This endpoint will provide a direct measure of the trial's main objective, which is to determine if supervised compression therapy alone is non-inferior to the combination of supervised compression therapy and antibiotics in preventing erysipelas relapse.

Secondary endpoints include several parameters: the time to the first confirmed recurrence of erysipelas, the severity of recurrence measured by the number of nights hospitalized for cellulitis, and the presence of skin necrosis or ulceration. Additionally, the trial will assess adverse and serious adverse effects during the prophylaxis phase, quality of life using the Dermatology Life Quality Index and EQ-5D-5L, and adherence to treatment by tracking the number of days per week compression was worn and antibiotics were taken, as recorded in a patient book. Oedema will be assessed through circumferential measurements and the truncated cone formula. A health-economic evaluation will also be conducted to determine the probability that the experimental strategy is clinically and economically non-inferior to the control strategy, considering different values of economic non-inferiority margin and a constant clinical non-inferiority margin of 15%.