Surgery with Botulinum Toxin a for Incisional Hernia (INCISOX)

Surgical Treatment of Large Incisional Hernia with Botulinum Toxin a Injection: a Double-blind Randomized Controlled Trial

After laparotomy, treating large incisional hernias (width >= 10cm) proves challenging due to the progressive retraction of lateral abdominal muscles and the separation of rectus muscles. This width is a significant risk factor for repair failure and recurrence. High rates of severe postoperative morbidity, up to 50%, are reported, linked to dissection extent, increased muscular tension, and abdominal pressure. Reconstructing normal anatomy by bringing muscles together may be impossible, leading to the use of complex procedures like component separation techniques (CST), involving large aponeurotomy for muscle relaxation. Intramuscular injection of botulinum toxin A (BTA) induces reversible flaccid paralysis, with potential benefits in hernia closure, known as "chemical CST." Retrospective studies suggest reduced muscle retraction and facilitated closure without specific morbidity. Prehabilitation with BTA aims to reduce surgical morbidity compared to repair and CST. The prospective evaluation of BTA's clinical benefits, including reduced postoperative morbidity, pain, successful abdominal closure, and decreased IH recurrence risk, is lacking. A prospective randomized double-blind placebo-controlled trial is proposed to demonstrate BTA's efficacy. The hypothesis is that BTA injection before IH repair is more effective than a placebo in reducing postoperative morbimortality. Secondary expectations include a significant reduction in complete closure of the abdominal wall without CST.

Study Overview

• Status: Recruiting
• Conditions: Incisional Hernia
• Intervention / Treatment: Drug: BTA group; Drug: Placebo group

Detailed Description

Almost 20% of patients will develop an incisional hernia (IH) after laparotomy. Each year in France, around 30,000 patients undergo IH repair with mesh [PMSI, 2017]. The treatment of large IH (width>=10cm) is difficult due to the progressive retraction of the lateral abdominal muscles associated with the separation of the rectus muscles. The IH width is a major risk factor of failure of the repair and recurrence. Furthermore, high rates of severe postoperative morbidity, up to 50%, have been reported and related to the extent of dissection and increase of muscular tension and abdominal pressure. Thus, bringing the muscles together to reconstruct the normal anatomy may be impossible and lead the surgeon to use complex and morbid technical procedures, such as component separation techniques (CST), consisting in large aponeurotomy for relaxation of the lateral muscles. The intramuscular injection of botulinum toxin A (BTA) makes it possible to obtain a reversible flaccid paralysis of the striated muscle fibers and its advantage has been demonstrated for the treatment of neurological spasticity. Its use to obtain a relaxation of the lateral muscles of the abdomen, so-called "chemical CST", reduce their retraction and facilitate hernia closure, as studied in retrospective studies, without specific morbidity. In particular, prehabilitation with BTA injection, is supposed to reduce surgical morbidity in comparison with surgical repair and CST. The expected clinical benefit, in terms of reduction of postoperative morbidity and pain, successful closure of the abdomen, and reduction of the risk of recurrence of the IH, has never been evaluated prospectively. Thus, a prospective randomized double-blind placebo-controlled trial would be the best method to demonstrate the benefit of BTA injection. The investigators hypothesize that BTA injection in the lateral muscles before IH repair is more effective than placebo injection in reducing postoperative morbimortality. Secondarily, the investigators expect that BTA injection is associated with a significant reduction of complete closure of the abdominal wall without CST.

• Study Type: Interventional
• Enrollment (Estimated): 260
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: David MOSZKOWICZ, MD-PhD; Phone Number: +33 (0)1 47 60 66 02; Email: david.moszkowicz@aphp.fr

Study Locations

• France
  • Colombes, France
    • Recruiting
    • David Moszkowicz
    • Contact: David Moszkowicz, Pr; Phone Number: 01 47 60 63 84; Email: david.moszkowicz@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients between 18 and 79 years;
2. BMI < 35 kg/m²;
3. Midline anterior primary or recurrent IH (subxiphoidal to suprapubic), of width >= 10 cm, on the abdominopelvic CT without injection of contrast agent, performed in the 6 months before inclusion (EHS W3);
4. IH without loss of domain, defined by the ratio: (volume of the peritoneal sac) / (total peritoneal volume) < 25%, on the abdominal CT without injection of contrast agent, performed in the 6 months before inclusion;
5. Written informed consent;
6. Scheduled surgery for an open IH repair;
7. For female of childbearing potential: using highly effective contraception.

Exclusion Criteria:

1. Other types of IH (lateral, groin, para-stomal, portsite);
2. VHWG grades 3 or 4 for the risk of surgical site infection;
3. Ongoing skin infection or inflammation at the IH site or at the BTA injection site;
4. Planned IH repair with slowly absorbable mesh;
5. IH with loss of domain (volumetric ratio > 25%);
6. Emergency IH surgery;
7. ASA score > 3;
8. Pregnancy or breastfeeding;
9. Ongoing treatment with aminoglycosides;
10. Severe hemostasis disorder or non-weaning treatment with curative dose anticoagulant;
11. Active tobacco use (or cessation inferior to 3 months);
12. Use of another investigational product within 6 months or 5 half-lives (whichever is longer), or currently participating in a prospective study with an investigational product, whether it concerns an experimental drug or a medical device;
13. Patient not covered by social insurance;
14. Patient under legal guardianship;
15. Hypersensitivity to the active substance (Clostridium Botulinum neurotoxin type A) or to any of the excipients (Human albumin, sucrose);
16. Generalized disorders of muscle activity (e.g. myasthenia gravis, Lambert-Eaton syndrome, peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis or motor neuropathy), facial nerve disorders, underlying neurological disorders) and history of dysphagia and aspiration);
17. Patient with ongoing treatment with medicinal products that interfere with the transfer of an impulse from a nerve to a muscle, e.g. tubocurarine-type muscle relaxants that weaken the muscles;
18. Patient with severe and uncontrolled cardiovascular diseases;
19. Patient has received BTA within 12 weeks;
20. Patients with a history of seizures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BTA group; This arm corresponds to patients presenting with midline anterior primary or recurrent IH (subxiphoidal to suprapubic) of width >= 10 cm, without loss of domain, scheduled for IH repair with mesh. Patients will be injected with 288 IU of BTA (XEOMIN® 100U) into the lateral muscles (18 injection sites, 16UI/8mL/injection site), 4 to 6 weeks before the treatment of the IH.	Drug: BTA group; It consists of a blind injection of 288 IU (/144mL) of BTA (XEOMIN®) into the lateral muscles (18 injection sites, 16UI/8mL/injection site), 4 to 6 weeks before the treatment of a large anterior IH (width ≥ 10 cm) with open non absorbable mesh repair. The injection of BTA (XEOMIN®) will be done during an outpatient hospitalization, in each of the 3 lateral muscles of the abdomen on each side. To do this in the BTA group, 3 vials of 100 equivalent IU of BTA (XEOMIN® 100U), diluted to 2 IU/mL with 0.9% saline will be distributed in 3 syringes of 50 mL equipped with a 21G needle. A total of 72 mL of BTA solution (144 IU) will be injected on each side, at 3 injection points between the costal rim and iliac crest, under ultrasound control.
Placebo Comparator: Placebo group; This arm corresponds to patients presenting with midline anterior primary or recurrent IH (subxiphoidal to suprapubic) of width >= 10 cm, without loss of domain, scheduled for IH repair with mesh. Patients will be injected with placebo of BTA (XEOMIN® 100U matching placebo) into the lateral muscles (18 injection sites, 8mL/injection site), 4 to 6 weeks before the treatment of the IH.	Drug: Placebo group; It consists of a blind injection of placebo of BTA (XEOMIN® 100U matching placebo) into the lateral muscles (18 injection sites, 8mL/injection site), 4 to 6 weeks before the treatment of a large IH (width >= 10 cm) with open non absorbable mesh repair. The injection of placebo of BTA (XEOMIN® 100U matching placebo) will be done during an outpatient hospitalization, in each of the 3 lateral muscles of the abdomen on each side. To do this in the control group, 3 vials of placebo of BTA (XEOMIN® 100U matching placebo), diluted with 0.9% saline will be distributed in 3 syringes of 50 mL equipped with a 21G needle. A total of 72 mL of placebo of BTA solution will be injected on each side, at 3 injection points between the costal rim and iliac crest, under ultrasound control.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Demonstrate the efficacy of preoperative BTA injection in the lateral abdominal wall muscles reduces the rate of postoperative morbimortality after large IH (width >= 10cm) repair with mesh, compared with placebo injection.	Occurrence of Clavien-Dindo classification grade II or higher post-operative complication	During the 90-day postoperative period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the impact of preoperative BTA injection on length of stay.	Length of hospital stay in days	From surgery until hospital discharge, average 5 days
Assessment of the impact of preoperative BTA injection on severity of surgical complications	Severity of complications according to the Clavien-Dindo classification	During the 90-day postoperative period
Assessment of the impact of preoperative BTA injection on surgical difficulty: abdominal wall closure with CST; incomplete closure of the wall with need of bridge prosthetic repair	Occurrence of CST and occurrence of incomplete wall closure (bridge closure)	During IH repair surgery
Assessment of the impact of preoperative BTA injection on radiological response:lateral muscles elongation	Sum of the length variation of the left and right lateral muscles (cm)	Between the pre-inclusion CT-scan and the CT-scan 4 weeks after BTA injection
Assessment of the impact of preoperative BTA injection on radiological response:lateral muscles elongation	Sum of the width variation of the left and right lateral muscles (cm)	Between the pre-inclusion CT-scan and the CT-scan 4 weeks after BTA injection
Assessment of the impact of preoperative BTA injection on radiological response: muscular defect reduction	Width (cm) variation of the muscular defect	Between the pre-inclusion CT-scan and the CT-scan 4 weeks after BTA injection
Assessment of the impact of preoperative BTA injection on radiological response: muscular defect reduction	Surface(cm²) variation of the muscular defect	Between the pre-inclusion CT-scan and the CT-scan 4 weeks after BTA injection
Assessment of the impact of preoperative BTA injection on radiological response: hernia sac volume	Volume (cm3) variation of the peritonial sac	Between the pre-inclusion CT-scan and the CT-scan 4 weeks after BTA injection
Assessment of the impact of preoperative BTA injection on intra-abdominal pressure, monitored until bladder catheter removal	Measurement of intravesical pressure	From catheter insertion to removal
Assessment of the impact of preoperative BTA injection on consequences of repair on pain evolution and consumption of analgesics	Pain on Analogical Visual Scale, prescription of type 3 analgesics	From 1st to 7th postoperative day and at 1, 3 , 6, and 12 months after surgery
Assessment of the impact of preoperative BTA injection repair results: post-operative abdominal wall disruption , clinical and radiological recurrence of the IH	Occurrence of post-operative abdominal wall disruption during a 90 days period after surgery, defined as early postoperative abdominal content herniation with or without skin coverage, identified clinically or at CT-scan; Occurrence of clinical recurrence of the IH during the first year after surgery, defined as any fascial defect that was palpable and was located within 7 cm of the site of hernia repair while the patient was in the supine position with legs extended and raised. Occurrence of radiological recurrence of the IH at 12 months post-surgery; radiologic hernia is defined as any protrusion of abdominal contents including the anterior parietal peritoneum through a discontinuity of the fascial layers on CT performed during follow-up without Valsalva maneuver postoperative occurrence of clinical and radiological recurrence of the IH, or reoperation for recurrence.	90 days and 12 months after surgery
Assessment of the impact of preoperative BTA injection on evolution of quality of life	EQ-5D-5L scale	90 days, 6, and 12 months after surgery

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: David MOSZKOWICZ, APHP

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2025
• Primary Completion (Estimated): August 4, 2028
• Study Completion (Estimated): March 4, 2029

Study Registration Dates

• First Submitted: May 31, 2024
• First Submitted That Met QC Criteria: July 11, 2024
• First Posted (Actual): July 12, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 20, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Botulinum toxin A; Incisional Hernia; Incisional Hernia repair; Laparatomy
• Additional Relevant MeSH Terms: Postoperative Complications; Pathologic Processes; Pathological Conditions, Anatomical; Incisional Hernia; Hernia
• Other Study ID Numbers: APHP220805

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No