Efficacy of Intrapapillary Clostridium Botulinum Neurotoxin Type A Injection in Preventing Postoperative Pancreatic Fistula Following Distal Pancreatectomy

The primary objective of this study is to evaluate the **efficacy** of intrapapillary botulinum toxin injection for the prevention of postoperative pancreatic fistula (POPF) of grade B and C within three months following distal pancreatectomy. This is clinically relevant as POPF is a significant complication after pancreatic surgery, leading to increased morbidity and healthcare costs.

Secondary objectives include assessing the efficacy of the injection on various postoperative outcomes during a 3-month follow-up period:

• Effect on each grade of severity of POPF (B and C).
• Impact on the risk of biochemical leak, defined as a drain output with an amylase content greater than three times the serum amylase activity but without clinical impact, in patients without pancreatic fistula.
• Influence on the risk of other postoperative complications such as intra-abdominal fluid collection, delayed gastric emptying, post-pancreatectomy hemorrhage, pancreatitis, wound infection, and other infectious complications.
• Effect on the Clavien-Dindo classification for post-surgical morbidity.
• Impact on the duration of hospital stay and the risk of readmission.
• Influence on the risk of transfer to the Intensive Care Unit and the duration of these stays.
• Effect on the risk of postoperative invasive procedures for managing pancreatic fistula.
• Impact on the reduction of overall costs and quality of life.
• Effect on post-surgical mortality at 30 and 90 days.
• Assessment of whether BMI modifies the efficacy of the injection in preventing POPF (grade B and C) after distal pancreatectomy.
• Evaluation of the safety of the injection during the 3-month and 6-month postoperative follow-up.

The clinical trial focuses on patients diagnosed with **pancreatic fistula** and aims to evaluate the efficacy of intrapapillary botulinum toxin injection in preventing postoperative pancreatic fistula following distal pancreatectomy. The study population includes both male and female participants aged 18 years and older. Participants are those scheduled for distal pancreatectomy, either open or minimally invasive, with or without splenectomy. The trial does not specifically target a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **intrapapillary botulinum toxin injection** for the prevention of postoperative pancreatic fistula following distal pancreatectomy. This study is a randomized, double-blind, controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to span from March 2023 to August 2026, with participant involvement lasting approximately three months post-surgery.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as undergoing distal pancreatectomy and being aged 18 years or older. Follow-up visits will occur at regular intervals to monitor the primary endpoint, which is the incidence of clinically relevant postoperative pancreatic fistula (grade B and C) within three months post-surgery. Secondary endpoints include the assessment of postoperative complications, quality of life, and health economics outcomes. The end-of-study visit will conclude the participant's involvement, where final assessments are conducted.

Participants may be withdrawn from the study if they experience adverse events that compromise their safety or if they fail to adhere to the study protocol. The trial's design and procedures are structured to ensure the collection of robust data while maintaining participant safety and scientific integrity.

The clinical trial involves the use of **XEOMIN 100 unités**, a **poudre pour solution injectable** containing **Clostridium botulinum neurotoxin type A (150kD), free of complexing proteins**. This experimental medication is administered as a **solution for injection**. The pharmaceutical form is a powder that is reconstituted into a solution prior to administration. The maximum daily dose is 100 units, with a total maximum dose of 100 units over the treatment period. The route of administration is **intestinal use**, specifically targeting the intrapapillary region. The treatment period is limited to a single day, and the medication is classified as a biological product. The active substance is a protein derived from **Clostridium botulinum** and is free from complexing proteins, ensuring a high degree of purity and specificity in its action.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of the intrapapillary injection of the botulinum toxin for the prevention of postoperative pancreatic fistula following distal pancreatectomy. Participant compliance with the dosing schedule is monitored through standard clinical trial procedures, ensuring adherence to the protocol and accurate assessment of the treatment's efficacy.

The efficacy of the intrapapillary botulinum toxin injection for the prevention of postoperative pancreatic fistula (POPF) will be assessed in this clinical trial. The primary endpoint for evaluating efficacy is the occurrence of clinically relevant POPF, specifically grades B and C, within three months following distal pancreatectomy (DP). Secondary endpoints include the grade of postoperative pancreatic fistulas based on the ISGPF 2016 update, biochemical leaks post-surgery, and various postoperative complications such as intra-abdominal fluid collection, delayed gastric emptying, hemorrhage, pancreatitis, wound infection, and other infectious complications. Additionally, the Clavien-Dindo classification will be used to assess post-surgical morbidity.

Health economics endpoints will also be evaluated, including the duration of hospital stay, hospital readmissions, transfers to intensive care units, and the duration of these stays. The trial will assess fistula-related postoperative invasive procedures, overall costs, the incremental cost utility ratio, and the incremental cost-effectiveness ratio based on clinical endpoints such as mortality and post-surgical complications, including pancreatic fistula. Quality of life will be measured using the EQ5D5L questionnaire, and postsurgical mortality will be recorded at 30 and 90 days. Side effects related to the endoscopic botulinum toxin injection will also be monitored. The trial is designed to provide comprehensive data on the efficacy and safety of the intervention in preventing POPF after DP.