A Double-Blind Randomized Controlled Trial of Clostridium Botulinum Neurotoxin Type A Injection in Preoperative Management of Large Incisional Hernia

The primary objective of this study is to demonstrate that preoperative **botulinum toxin A** (BTA) injection in the lateral abdominal wall muscles reduces the rate of postoperative morbi-mortality following the repair of large incisional hernia (IH) with a width of 10 cm or more, using mesh, compared to a placebo injection. This is clinically relevant as it aims to improve surgical outcomes and reduce complications associated with large IH repair, which can significantly impact patient recovery and healthcare resources.

Secondary objectives include assessing the impact of preoperative BTA injection on various clinical parameters:

• Length of hospital stay
• Severity of surgical complications
• Surgical difficulty, including abdominal wall closure and the need for bridge prosthetic repair
• Radiological response, such as lateral muscle elongation, muscular defect reduction, and hernia sac volume on CT-scan
• Intra-abdominal pressure until bladder catheter removal
• Consequences of repair on pain evolution and analgesic consumption up to 12 months post-surgery
• Repair results, including post-operative abdominal wall disruption, clinical and radiological recurrence of IH, and reoperation for recurrence at 1 year postoperatively
• Evolution of quality of life from inclusion to 90 days, 6 months, and 1 year postoperatively

The clinical trial involves participants diagnosed with **incisional hernia**, specifically targeting individuals with a hernia width of 10 cm or greater. The study population includes both male and female subjects, aged between 18 and 79 years, who are in general good health with a body mass index (BMI) of less than 35 kg/m². Participants are required to have a midline anterior primary or recurrent incisional hernia, without loss of domain, as confirmed by an abdominopelvic CT scan conducted within six months prior to inclusion. The trial does not involve a vulnerable population. Participants must have scheduled surgery for an open incisional hernia repair and, for females of childbearing potential, the use of highly effective contraception is mandatory. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of preoperative **botulinum toxin A** injection in reducing postoperative complications in patients undergoing surgical repair of large **incisional hernia**. The trial aims to demonstrate that the injection into the lateral abdominal wall muscles decreases the rate of postoperative morbi-mortality compared to a placebo. The study will involve participants aged 18 to 79 years with a body mass index (BMI) of less than 35 kg/m², who have a midline anterior primary or recurrent incisional hernia of at least 10 cm in width, as confirmed by abdominopelvic CT scans performed within six months prior to inclusion. The trial is expected to commence recruitment on June 1, 2024, and conclude by January 15, 2028.

Participants will be involved in the study for a period that includes preoperative assessments, the surgical procedure, and a follow-up period extending up to 12 months post-surgery. The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are confirmed, and informed consent is obtained. This is followed by the administration of the investigational product or placebo prior to the scheduled surgery. Postoperative follow-up visits will occur at regular intervals, including assessments at 1, 3, 6, and 12 months after surgery. These visits will evaluate primary and secondary endpoints, such as the occurrence of Clavien-Dindo classification grade II or higher postoperative complications within 90 days, length of hospital stay, and quality of life measures using the EQ-5D-5L scale.

The expected length of participant involvement is approximately 18 months, accounting for preoperative assessments, the surgical procedure, and the follow-up period. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the integrity and validity of the collected data.

The clinical trial involves the administration of **XEOMIN**, a pharmaceutical product containing **Clostridium botulinum neurotoxin type A (150kD), free of complexing proteins**. This experimental medication is provided in the form of a powder for solution for injection. The product is manufactured by Merz Pharmaceuticals GmbH and is authorized under the marketing authorization number 34009 571 886 0 3. The medication is administered via **intramuscular injection**. The maximum daily dose is 288 IU, with the same amount being the maximum total dose allowed during the treatment period, which is limited to one day. The administration of XEOMIN is intended to reduce postoperative morbi-mortality in patients undergoing surgical repair of large incisional hernias.

The study also includes a **placebo** treatment, which is a powder for injection designed to mimic the appearance and administration route of XEOMIN. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of which treatment is being administered. The placebo does not contain any active substances and is not associated with any specific pharmaceutical form or marketing authorization number. The use of a placebo allows for a controlled comparison to evaluate the efficacy of the experimental medication.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the occurrence of Clavien-Dindo classification grade II or higher post-operative complications during the 90-day postoperative period. This endpoint will provide a direct measure of the impact of preoperative **botulinum toxin A** injection on postoperative outcomes.

Secondary endpoints include a variety of parameters to further evaluate efficacy. These include the length of hospital stay, severity of complications according to the Clavien-Dindo classification, and the occurrence of CST and incomplete wall closure during incisional hernia repair. Additionally, changes in the length and width of lateral muscles, as well as variations in the muscular defect and peritoneal sac volume, will be measured between pre-inclusion CT and CT performed 4 weeks after the injection. Intravesical pressure will be monitored daily until bladder catheter removal.

Pain will be assessed using the Analogical Visual Scale at multiple timepoints: at inclusion, from the 1st to the 7th postoperative day, and at 1, 3, 6, and 12 months post-surgery. The prescription of type 3 analgesics during the 90-day postoperative period will also be recorded. The occurrence of postoperative abdominal wall disruption, clinical and radiological recurrence of the incisional hernia, and reoperation for recurrence will be tracked over a year. Quality of life will be evaluated using the EQ-5D-5L scale at inclusion and at 90 days, 6 months, and 12 months post-surgery.