Efficacy of Levobupivacaine Hydrochloride for Post-Endoscopic Submucosal Dissection Pain in Esophageal Lesions: A Randomized Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of local injection of **levobupivacaine** during esophageal endoscopic submucosal dissection (ESD) for direct post-procedural pain relief within 90 minutes after the procedure. This is clinically relevant as effective pain management can significantly improve patient comfort and recovery outcomes following ESD for visible esophageal lesions, including precancerous conditions.

Secondary objectives include: - Evaluating the effect of local levobupivacaine on the severity and duration of pain in the first 14 days post-procedure. - Assessing the safety of levobupivacaine administration. - Determining the effect of levobupivacaine on the length of hospital stay. These objectives aim to provide a comprehensive understanding of the benefits and risks associated with levobupivacaine use in this clinical setting.

The clinical trial involves participants with **visible esophageal lesions**, specifically (pre)cancerous conditions, who are scheduled for esophageal endoscopic submucosal dissection (ESD). The study population includes both male and female subjects aged 18 years and older. The trial does not involve a vulnerable population. Participants were selected based on the presence of a visible lesion in the esophagus with a minimum diameter of 20 mm, and all participants provided informed consent. The sponsor did not provide information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **levobupivacaine hydrochloride** for pain relief following endoscopic submucosal dissection (ESD) for visible esophageal lesions, which may be precancerous or cancerous. This study is a **randomized controlled trial** with a double-blind design to ensure unbiased results. The trial is categorized as a low-intervention study, as the investigational drug is used in accordance with its marketing authorization, and additional procedures are limited to a brief daily questionnaire over 14 days, posing minimal risk to participants. The trial is expected to commence recruitment on October 1, 2024, and conclude by October 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (≥18 years), presence of a visible esophageal lesion with a minimum diameter of 20 mm, and scheduled ESD. Informed consent is required. The primary endpoint is the proportion of patients experiencing major pain, defined as a score of four or higher on a 0-10 numerical rating scale (NRS), within 90 minutes post-procedure. Secondary endpoints include pain scores at various intervals up to 14 days, cumulative pain assessment, duration of pain, analgesic use, and incidence of adverse events related to the drug.

Participants will be involved in the study for a maximum of 14 days post-procedure, during which they will complete daily pain assessments and record analgesic use. Follow-up visits will occur at predefined intervals to monitor pain levels and any adverse events. The end-of-study visit will assess the overall outcomes and gather final data. Conditions for early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial aims to provide valuable insights into the pain management of patients undergoing ESD for esophageal lesions.

The clinical trial involves the administration of **Paracetamol Fresenius Kabi 10 mg/ml**, a **solution for infusion**. This medication contains the active substance **paracetamol** and is provided by Fresenius Kabi Nederland B.V. The pharmaceutical form is a solution specifically designed for infusion, with a maximum daily dose of 4000 mg. The administration route is via infusion, and the treatment period is limited to a maximum of one day. The solution is not a pediatric formulation and is used as an auxiliary treatment in the trial.

Another treatment used in the trial is **Levobupivacaine Fresenius Kabi 2.5 mg/ml**, which is a **solution for injection/infusion**. The active substance is **levobupivacaine hydrochloride**, also supplied by Fresenius Kabi Nederland B.V. This medication is administered through injection, with a maximum daily dose of 75 mg and a total dose not exceeding 2 mg/kg. The treatment period is restricted to one day. This solution is not formulated for pediatric use and serves as the primary test treatment in the study, focusing on pain relief after esophageal endoscopic submucosal dissection.

The trial also includes the use of **Diclofenac Na CF 25 mg/ml**, a **solution for injection**. The active ingredient is **diclofenac sodium**, provided by Centrafarm B.V. This medication is administered via infusion, with a maximum daily dose of 150 mg. The treatment duration is limited to one day. Similar to the other treatments, this solution is not intended for pediatric use and is utilized as an auxiliary treatment in the trial.

The efficacy of the clinical trial titled "Local Levobupivacaine for pain relief after Endoscopic Submucosal Dissection for esophageal lesions: a Randomized Controlled Trial" will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of patients experiencing major pain within 90 minutes post-procedure, comparing the group receiving **levobupivacaine** (LB) to the non-LB group. Major pain is defined as a score of four or higher on a 0-10 Numeric Rating Scale (NRS), with the peak pain score being recorded at one of the three predefined time points: 30, 60, and 90 minutes after the procedure.

Secondary endpoints include several measures: pain scores based on a 0-10 NRS within 90 minutes post-procedure, at 6 hours post-procedure, and daily up to day 14; cumulative pain over 14 days calculated as the area under the curve of a pain versus time plot; duration of pain, defined as the number of days until pain scores are reported as 0 on all subsequent days; daily and overall use of analgesics up to day 14, recorded in a patient diary; incidence of adverse events and serious adverse events related to LB administration, including allergic reactions; and the length of hospital stay in days.