Effectiveness, Appropriateness and Safety of GLUTACK-Glubran Tiss 2 Surgical Glue Compared to GLUTACK-Glubran 2 Device System for Mesh Fastening in Laparoscopic and Robotic Hernia Surgery

This pre-market, prospective, randomized, non-inferiority clinical study was designed to evaluate the safety and performance/effectiveness of Glutack-Glubran® Tiss 2 system compared to Glutack-Glubran® used for mesh fixation in laparoscopic and robotic hernia surgery to obtain the indication and upgrade the medical device Glubran® Tiss 2 to class IIb.Cyanoacrylate is the generic name of a group of fast-acting adhesives such as ethyl-2-cyanoacrylate, n-butyl cyanoacrylate, 2-octy1 cyanoacrylate sold under various trade names and blend. Cyanoacrylate is a liquid acrylate monomer that polymerizes exothermically in the presence of water, especially with hydroxide ions, joining the bonded surfaces in 4-5 s and reaching the final stage in 60-90 s . It bonds body tissue excellently and shows bacteriostatic effects . The film of glue is eliminated by hydrolytic breakdown, a process whose duration varies according to tissue type and quantity .

In contrast to most cyanoacrylate glues used only for external applications as skin wound closure, Glubran® 2 is a modified n-butyl-cyanoacrylate (Glubran® 2 - N-Butyl 2 Cyanoaciylate \[NBCA\]+ Methacryloxysulfolane \[MS\]), class III medical device, CE-certified for both external and internal use .

Glubran® 2 effectiveness in repairing hernias with less post-operative pain, less complications, less hernia recurrences and a greater cost-effectiveness is largely documented . Other cyanoacrylate-based glues are authorized to fix hernia meshes, i.e.: Histoacryl (pure NBCA; classified as class IIb medical device), Liquibond FIX8 (pure NBCA; classified as class III medical device) and Ifabond (n-hexyl-cyanoacrylate; classified as class III medical device). Others are authorized to be used for specific internal indication like Omnex (2-Octyl-CyanoAcrylate \[OCA\] + Butyl-Lactoyl-Cyanoacrylate), which is indicated for use in vascular reconstructions. Sometimes, abroad, also some cyanoacrylate-based glues are applied for internal uses even if not authorized .

The present prospective and randomized study was aimed at comparing the effectiveness and safety of another cyanoacrylate-based glue called Glubran® Tiss 2 (NBCA + OCA), classified as class IIa surgical medical device, CE-marked (under the European Union \[EU\] Directive 93/42 EEC), being already authorized for use as atraumatic fixation system: Glubran® 2. Both medical devices have previously demonstrated to be well-tolerated and safe.

Glubran® 2 and Glubran® Tiss 2 were to be applied by Glutack®, a CE-marked medical device system for glue application in the surgical field. Glutack® is the related Glubran® 2/ Glubran® Tiss 2 applicator device for laparoscopic mesh fixation procedures was fabricated to offer a precise and controlled delivery of Glubran® glues .

Glubran® Tiss 2 fulfils the requirements of EU Medical Device Regulation (MDR) 2017/745 (confirmation letter received by the relative Notified Body). The composition of Glubran® Tiss 2 is obtained by mixing two different monomers of cyanoacrylate (NBCA + OCA); this gives the product a better elasticity, while maintaining high levels of tensile strength. In fact, international scientific literature has shown that the common NBCA is the cyanoacrylate molecule with the greatest tensile strength (34.27 N), low elasticity, while OCA has a lower resistance (11.27 N) but has good elastic properties. Glubran® Tiss 2 glue has a tensile strength of 27.34 N and thanks to the presence of OCA, also excellent elasticity . Among its characteristics, this formulation has haemostatic, sealing, bacteriostatic and adhesive properties. Polymerization begins 1-2 seconds after application and completes within 60 seconds. The polymerization reaction generates a temperature of approximately 45°C, which is lower than that of pure cyanoacrylates .

Glubran® Tiss 2, indicated also for use in paediatrics, is a sterile, ready for use, blended cyanacrylate adhesive to be used on the skin and mucosal tissues, which is approved as class IIa medical device, effective even in patients anticoagulated and with congenital coagulopathies .

This was a pre-market, prospective, randomized, non-inferiority, clinical study aimed at evaluating the safety and performance/effectiveness of Glutack-Glubran® Tiss 2 system compared to Glutack-Glubran® 2 applied for mesh fastening in laparoscopic and robotic hernia surgery to get the indication and upgrade Glubran® Tiss 2 to class IIb. The study was conducted in seven centres in Italy and was to enroll 100 patients. Patients were to be followed for 6 months. The global duration of the trial was approximately 32 months.

According to the CIP, 6 Visits were planned over the perioperative/post operative period for each patient (after 24 hours,7, 14, 90, and 180 days).

At Visit 1 (V1, day 0, Baseline visit), patients were requested to sign the written informed consent before any procedure was performed. Patients were screened for eligibility for the study ascertaining that all inclusion criteria and no exclusion criteria were met. At V1, the Investigator recorded demographic and medical history, basal clinical assessment data and performed full physical examination and evaluation of clinical signs/symptoms.

Patients were randomly assigned (1:1 allocation ratio) to one of the two treatment groups: Glutack-Glubran® system (Group 1) or Glutack-Glubran® Tiss 2 (Group 2). The application of Glutack-Glubran® system or Glutack-Glubran® Tiss 2 was performed by the investigator, after a previous appropriate training on how to assemble/use each device.

Technical success of glue fastening was evaluated intra-operatively, the investigator registered whether mesh fixation system achieved technical success or not. Technical success was to be defined as successful hernia repair as intended, but actually defined in the present analysis as a surgical procedure with no complications within the first 24 hours after surgery and a surgeon's rating for Efficacy and Control greater than or equal to 4.At specific intervals, at V2 (24 hours), V3 (7 days), V4 (14 days), V5 (90 days) and V6 (180 days), patients were requested to return to the centre for the clinical assessments of safety, quality of life and effectiveness. As regards effectiveness, at each Visit, the area of the mesh implant was evaluated for recurrence through a specific abdominal clinical examination. In case of any suspicion of recurrence, an ultrasound or MRI was to be performed according to hospital practice to distinguish true hernia recurrences from bulging. At V6 cost effectiveness was also to be evaluated.The primary objective of the study was to assess the effectiveness of Glutack-Glubran® Tiss 2 mesh fastening in comparison with mesh fixation by Glutack-Glubran® 2 evaluated in terms of hernia recurrence rate after surgery and technical success of glue fastening (evaluated intra-operatively).

The secondary objectives were aimed at investigating the following:

1. Safety in terms of side effects
2. Cost effectiveness in terms of direct costs of intervention, operating and hospitalization times, times of return to normal activity
3. The adequacy of Glutack® medical device for the application of surgical glue for fixing the prosthesis (mesh) in terms of ease of use and satisfaction of the surgeon.

This study enrolled 107 adult patients submitted to surgical treatment for laparoceles (incisional hernia) or monolateral or bilateral inguinal hernia.

6.3.1 Inclusion Criteria

Patients could be enrolled in the investigation if they met all the following inclusion criteria:

1. No significant cardiopulmonary, hepatic, or renal impairment, and no contraindications for surgery;
2. Clinical diagnosis of:

   1. bilateral inguinal hernia eligible for minimally invasive repair (TAPP-TEP VLS/ROB)
   2. recurrent monoliteral inguinal hernia (TAPP-TEP VLS/ROB)
   3. large inguinoscrotal hernias (TAPP-TEP ROB)
   4. primary ventral hernia with defects size ≤ 7cm (IPOM-TARUP-COSTA-THT-MILOS-eMILOS VLS/ROB)
   5. primary abdominal border hernia (idem VLS/ROB)
   6. post-incisional hernia with defect size ≤ 7cm (idem VLS)
   7. post-incisional hernia and complex abdomen (RIVES-RIVES+TAR ROB)
   8. Swiss-cheese defects multiple small defects if treatable with only one mesh; if the total width of the defect is ≤ 5cm will be repaired by IPOM VLSM; if it is \> 5cm will be repaired by RIVES-RIVES+TAR ROB;
3. Age \> 18 years, male and Female;
4. Obese patient (BMI\>35);
5. Patients with ASA grade from I to III;
6. Patients must sign and date the informed consent form prior to treatment. 6.3.2 Exclusion Criteria

Patients could not be enrolled in the investigation if they met any of the following exclusion criteria:

1. Incarcerated hernia;
2. Allergy to multiple classes of drugs, recent allergic disease, or use of drugs that are known harmful to vital organs during the 4 weeks before surgery;
3. Patients with ASA IV or V;
4. Participations in other clinical studies in the 3 months before surgery;
5. Atopic allergy history;
6. Mental illness history;
7. Diseases that may significantly increase Intra-Abdominal Pressure (IAP) and cannot be effectively controlled such as severe ascites, severe asthma caused by bronchitis, pulmonary emphysema, or urine retention caused by significant Benign Prostatic Hyperplasia (BPH);
8. Infection located at the surgical site or bacteraemia;
9. Patients with collagenopathies;
10. Relevant other concurrent diseases;
11. Patient with neurological disorders and/or mood disorders;
12. Hyperemotional patients;
13. Pregnant women.

Eligibility Criteria:
Inclusion criteria:

1. No significant cardiopulmonary, hepatic, or renal impairment, and no contraindications for surgery;
2. Clinical diagnosis of:

   1. bilateral inguinal hernia eligible for minimally invasive repair (TAPP-TEP VLS/ROB)
   2. recurrent monoliteral inguinal hernia (TAPP-TEP VLS/ROB)
   3. large inguinoscrotal hernias (TAPP-TEP ROB)
   4. primary ventral hernia with defects size ≤ 7cm (IPOM-TARUP-COSTA-THT-MILOS-eMILOS VLS/ROB)
   5. primary abdominal border hernia (idem VLS/ROB)
   6. post-incisional hernia with defect size ≤ 7cm (idem VLS)
   7. post-incisional hernia and complex abdomen (RIVES-RIVES+TAR ROB)
   8. swiss-cheese defects multiple small defects if treatable with only one mesh; if the total width of the defect is ≤ 5cm will be repaired by IPOM VLSM; if it is \> 5cm will be repaired by RIVES-RIVES+TAR ROB;
3. Age \> 18 years, male and female;
4. Obese patient (BMI\>35);
5. Patients with ASA grade from I to III;
6. Patients must sign and date the informed consent form prior to treatment.

Exclusion criteria:

1. Incarcerated hernia;
2. Allergy to multiple classes of drugs, recent allergic disease, or use of drugs that are known harmful to vital organs during the 4 weeks before surgery;
3. Patients with ASA IV or V;
4. Participations in other clinical studies in the 3 months before surgery;
5. Atopic allergy history;
6. Mental illness history;
7. Diseases that may significantly increase Intra-Abdominal Pressure (IAP) and cannot be effectively controlled such as severe ascites, severe asthma caused by bronchitis, pulmonary emphysema, or urine retention caused by significant Benign Prostatic Hyperplasia (BPH);
8. Infection located at the surgical site or bacteraemia;
9. Patients with collagenopathies;
10. Relevant other concurrent diseases;
11. Patient with neurological disorders and/or mood disorders;
12. Hyperemotional patients;
13. Pregnant women.