Prevention of Anastomotic Leak in Colorectal Surgery by Glue Reinforcement. A Prospective Randomized Trial.
Phase: NA
Conditions: Rectal Cancer
Sponsor: Societa Italiana di Chirurgia ColoRettale

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ReAL trial (Rectal Anastomosic seaL)  
PROTOCOL 
 
 
Full title: 
Prevention of anastomotic leak in colorectal surgery by glue 
reinforcement. A prospective randomized trial. 
 
Developed by Department of Emergency and Organ Transplantation (DETO), 
University of Bari, Italy 
 
 
 
 
Clinicaltrial.gov ID number:   NCT03941938 
Date of protocol: 09/01/2019 
 
 
 
 
 
 

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ReAL Trial Management Group 
 
 

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Surgery 
Prof. Donato F. Altomare, MD, Arcangelo Picciariello, MD 
Dept of Emergency and Organ Transplantation, University of Bari, Italy,  
c/o Azienda Ospedaliero-Universitaria Policlinico di Bari, piazza G Cesare, 11 – 70124 Bari, Italy 
Phone +39.0805478764 Mobile phone:+39.3397593066 
Fax:  +39.0805478735 
e-mail: donatofrancesco.altomare@uniba.it 
 
 
 
Randomization 
 
Simple randomization will be centralized and carried out by assigning the 2 treatment options to 
consecutive computer generated random number obtained through the website 
http://www.randomizer.at 
 
The randomization code will be obtained by contacting the number or the Tel number +39 3287586007 / 
+39 3397593066 or by the e-mail address arcangelopicciariello@gmail.com , or  
donatofrancesco.altomare@uniba.it 
Clinical queries during office hours should be directed to one of the clinical coordinators or to an 
appropriate member of the ReAL trial Management Group 
 
Data Monitoring and Ethics Committee 
 
Clinical data monitoring will be carried out by Ms Angela Accettura: Dept of Emergency and Organ 
transplantation, University of Bari e-mail: angela.accettura@uniba.it  
Tel +39.0805592235 
Independent Ethics Committee of the Azienda Ospedaliero Universitaria Policlinico Consorziale Bari 
piazza Giulio Cesare, 11 70124 Bari, Italy   
Tel +39.0805593399 fax +39. 0805575716 e-mail: comitatoetico@policlinico.ba.it 
Protocol approval n. 4555/2014  
Trial Sponsor: University of Bari, Department of Emergency and Organ Transplantation, DETO, Section of 
Surgery, Bari, Italy, Tel: +39 5592107 – +390805478764 
 
 
 

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ReAL Study Office 
For general queries, supply of trial materials, and collection of data: 
Trial Coordinator: Prof. Donato F. Altomare,  mobile phone +39.3397593066 – office 
+39.0805478764 e-mail donatofrancesco.altomare@uniba.it 
 
Computing: Dr Arcangelo Picciariello, MD – mobile phone +393492185104 – e-mail: 
arcangelopicciariello@gmail.com 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Background 
 

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Colorectal cancer (CRC) is the second most common cause of cancer-related death in male and the third in 
females in Western Countries accounting for more than 500,000 deaths in 2013 worldwide(1). 
One of the most worring postoperative complication in colorectal surgery is the anastomotic leak which can 
occurr in about 10-15% of the cases(2). 
This complication severely impact clinical outcomes with increased risk of death or permanent stoma, 
higher risk of local recurrence) and relevant increase in hospital costs (length of hospital stay, admission 
to intensive care, re-interventions)(3). 
The problem of anastomotic leak is particularly relevant in rectal surgery. The more distal the 
anastomosis, the higher the likelihood of failure, with resection of a distal rectal cancer having almost a 
five-fold increased risk of anastomotic leak compared with resection for colon cancer(4). 
In fact, anastomotic Leakage (AL) is the most severe complication after Low anterior resection of rectum 
for cancer, occurring between 3 and 24 % of patients(5). 
Many risk factors have been recognized in the onset of this complication(6), including gender (male 
patient have  a higher anastomotic leak rate)(7), malnutrition, obesity an diabet, ASA score, tobacco use, 
cardiovascular disease, immunosoppression, use of NSAID(8), preoperative pelvis radiation. 
Other intraoperative risk factors considered are the splenic flexure mobilization with proximal ligation of 
the IMA(9), positive intraoperative Air-Leak Test(10) and the perfusion of the anastomosis (11). 
Temporary fecal diversion  has also been suggested (although a diverting stoma mitigates the clinical 
consequences of an anastomotic leak but does not prevent it(12). 
Other intraoperative technical factors include the use of single or double stapled anastomotic 
techniques, with or without transanal reinforcing sutures(13). 
Therefore, preventing the anastomotic leak can bring benefits to the patient and the health system. 
All the risk factors described above rapresent the rationale that justifies the use of intraoperative 
procedures to prevent the anastomotic leak, such as additional manual stiches to the mechanical suture 
and / or patches of collagen (proper reinforcement or buttressing) or of sealants. 
Several attempts have been proposed to reduce the risk of AL in low rectal cancer surgery including 

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suture protection with omental flap and external suture reinforcement by biological glue or mesh (14-
16). 
Some Authors have reported good results of reinforcement of the colon anastomosis with cyanoacrylate 
glue. in a porcine model(17, 18).  
Cyanoacrilate is a synthetic glue with sealing, adhesive and hemostatic properties widely used in surgery. 
Furthermore the sealing effect creates an antiseptic barrier against bacteria (19). 
Several clinical studies have described the utility of cyanoacrylate glue mainly in vascular surgery,  
urology(20, 21) and bariatric surgery (22). 
Considering its mechanical, physical, biological properties and its safety, cyanoacrylate glue could 
facilitate the healing of the colorectal anastomosis reducing leak rate, without negative effects 
on  perfusion(23).  
 
 
2. Study hypothesis  
The hypothesis is that the application of nebulized cyanoacrylate to the colo-rectal anastomosis in open or 
laparoscopic/robotic rectal surgery can prevent the leakage  
 
 
3.1 General Design  
Prospective, multi-centre, parallel-arm randomized controlled superiority trial. Eligible patients will be 
randomized to cyanoacrylate reinforcement arm and no reinforcement arm, following rectal anastomosis. 
 
 
3.2 Endpoints  
3.2.1 Primary  

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The aim of the trial is to observe a significantly lower number of anastomotic leak of a colorectal 
anastomosis in the group of patients treated with cyanoacrylate glue  
3.2.2 Secondary 
SAFETY: Demonstration that the new treatment will not add related morbidity  
EFFICACY: Demonstrate that anastomotic reinforcement with cyanoacrylate decrease the rate of 
anastomotic leakage  
 
3.2.3 SWOT analysis 
 
 
STRENGHTS 
 
- Applicable to anastomosis located over 7 cm 
from the anal verge 
- High risk of stoma-related complications 
- Psychological impact of a stoma 
- Possibility to improve patient’s outcome and 
reduce hospital costs 
- Low cost of the  new treatment 
 
WEAKNESS 
 
- 
High number of patients to be recruited 
- 
Variability of the techniques  
 
 
OPPORTUNITIES 
 
- 
Applicable to a relevant proportion of 
patients affected by Rectal cancer which is 
one of the most frequent human cancer. 
- 
Reduce number of stomas, stoma related 
complications and new operations for stoma 
closure 
- 
Reduce hospital costs  
- 
Improvement of the patients QoL 
 
 
THREATS 
 
- 
Risk of sepsis for anastomotic leakage (?)   
 
 
 
3.3 Randomization 

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Written informed consent will be obtained prior to surgery by the operating surgeon.  Computer-generated 
randomization will be used to create an allocation sequence to assign patients to the different study arms. 
Randomization will be computer generated and centrally controlled by an operator not involved in the 
study.  Patients will be randomized only after completion of neoadjuvant chemo radiation (when indicated) 
and before surgery.  
3.4. Subject Recruitment and Screening 
Each patient referred for elective resection found eligible per stated inclusion and exclusion criteria will be 
approached by the operating surgeon.  The patient will be informed about the study as per IRB protocol 
and consent.  Patients will be given information about the risks, discomforts, and potential benefits of both 
treatments.  The randomization protocol will be explained to the patient before consent is obtained. 
 
3.5 Participating Institution and Surgeons  
This multicenter trial is opened to the contribution of surgeons across Europe in order to achieve the 
required number of patient recruitment in the shortest period. 
• 
All surgeons must have prior experience in performing colorectal cancer surgery either in open or 
laparoscopic route. 
• 
All participating institutions must have IRB (Institutional Review Board)/Ethics Committee approval 
in order to enroll patients in the trial. 
• 
As part of educational interventions, all participating surgeons will preview a video of the surgical 
technique of the application of nebulised cyanoacrilate glue.   
• 
Recruitment of Centers will be by direct invitation or spontaneous proposal of Colorectal Units 
interested in the study.  
 
3.6 Definition of Outcome Measures 

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Please use the following definitions: 
• 
estimated blood loss (ml) recorded by the anaesthesiologist (not by the surgeon)    
 
• 
duration of hospital stay (defined as from beginning of surgery to time of discharge, measured in 
days) 
• 
Anastomotic leak will be confirmed by one or more that the following conditions 
• 
fecal discharge from the pelvic drainage at any time after surgery 
• 
rectovaginal fistula defined as fecal or mucus discharge from the vagina 
• 
pelvic sepsis as defined by the collection of pus/ fecal material in the pelvis documented by 
CTscan 
• 
Two sides X- Ray proctography performed by introducing 100 ml of hydro soluble liquid 
contrast medium (Gastrographin NOT barium solphate) through the anus over the 
anastomotic line, by a Foley catheter (with an empty balloon) with the patient in standing 
position. The Foley catheter must be withdrawn after injection of the contrast medium and 
before the X Rays in order to prevent false-negative results. 
 
Classification of the anastomotic leak: Grade A anastomotic leakage results in no change in patients' 
management, whereas grade B leakage requires active therapeutic intervention but is manageable without 
re-laparotomy. Grade C anastomotic leakage requires re-laparotomy (according to Rahbari NN, et al. 
Surgery 2010) 
 
 
3.6.1 Definition of Adverse Events 
• 
Primary ileus will be defined as bowel dysfunction occurring after surgery for a duration greater 
than 10 days and that requires intervention including nil per os (NPO) status, naso-gastric tube, 
medication, or surgery. 

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• 
Secondary ileus will be defined as bowel dysfunction that occurs after the patient has resumed oral 
nutrition after surgery, and that requires intervention including NPO status, naso-gastric tube, 
medication, or surgery. 
• 
Urinary tract infection (UTI)  
• 
Symptomatic urinary tract infection must meet at least 1 of the following criteria:  
§ fever (>38°C), urgency, frequency, dysuria, or suprapubic tenderness and patient 
has a positive urine culture, that is, ≥105 microorganisms per cc of urine with no 
more than 2 species of microorganisms. 
• 
Urinary retention will be defined as the condition of urinary dysfunction that occurs following 
surgery and requires intervention, including placement of urinary catheter. 
• 
Pyrexia will be defined as any documented patient temperatures >38.0 C that require any 
treatment intervention such as antipyretics or that result in an increase in hospital stay.   
• 
Wound dehiscence is defined as a delayed opening of the abdominal scar, without evidence of 
infection. 
• 
Rectovaginal fistula defined as fecal or mucus discharge from the vagina 
• 
Surgical site infection purulent discharge from the wound with positive culture 
• 
Pulmonary infection documented by Chest X Ray 
 
 
3.6.2 Classification of the postoperative complications 
• 
The Clavien Dindo Classification for postoperative complications will be adopted (see 
attached form 9.2) 
• 
The Comprehensive Complication Index 
 
3.7 ELIGIBILITY CRITERIA 
3.7.1 Inclusion Criteria 

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• 
Resectable, histologically proven primary adenocarcinoma of the High-medium rectum without 
internal and/or external sphincter muscle involvement. 
• 
 Distal margin of the tumor at least 8 cm form the anal verge 
• 
Staged as follows prior to neoadjuvant chemoradiation: 
o Stage T2 - T4 at MRI 
• 
Patient classified T3-T4 will undergo neoadjuvant chemoradiation if the cancer is located in the 
extraperitoneal rectum 
3.7.2 Exclusion Criteria 
• 
Squamous cell carcinoma 
• 
Adenocarcinoma Stage T1,  
• 
T4 with one of the following: 
o with pelvic side wall involvement 
o requiring sacrectomy 
o requiring prostatectomy (partial or total) 
• 
Unresectable primary rectal cancer or Inability to complete R0 resection. 
• 
Rectal cancer under 8 cm from the anal verge requiring colo-anal or ultra low rectal anastomosis 
• 
Recurrent rectal cancer 
• 
Previous pelvic malignancy 
• 
Inability to sign the informed consent 
 
3.8 Withdrawal Criteria  
Study participants will be informed of their ability to withdraw from the study or refuse initial enrollment at 
any time. Patients may withdraw without explanation. 
 
 

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4 STUDY INTERVENTION 
4.1 Preoperative work-up 
Patients will be seen for preoperative evaluation within 2 weeks prior to surgery.  All tests and evaluations 
should be completed prior to surgery. 
• 
All subjects will receive bowel prep per institutional routine. 
• 
The entire colon should be investigated by a colonoscopy.  
• 
Proctoscopy should be performed to assess the localization of the tumor and the distance from the 
anal verge.  
• 
Histological confirmation of the tumor prior to surgery is mandatory. 
Preoperative Tumor and nodal staging should be done by MRI and /or endorectal ultrasonography  
 
4.1.1 Timing of surgery after Neoadjuvant Chemoradiation 
Surgery must occur within 8-12 weeks (56-84 days) after completion of neoadjuvant therapy when 
indicated 
 
4.2 Operative protocol 
• 
Anesthetic care will include general endotracheal anesthesia with gastric and bladder 
catheterization. 
• 
Epidural catheter may be used for post-operative pain control. 
4.2.1 Technique  
Patient preparation to rectal surgery will follows the general Rules for Good Clinical Practice. Mechanical 
bowel preparation using oral PEG solution will be used according to surgeon preference, antibiotic and 
antithrombotic prophylaxis will start immediately before surgery. 
Patient Position: Lithotomy position for abdominal and perineal procedures.  

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Abdominal procedure (open or laparoscopic) will be carried out according the oncological guidelines 
included total mesorectal excision with adequate lymph-node retrieval, at least 1 cm of distal clearance. A 
termino-terminal, latero-terminal, colorectal knight-Griffen anastomosis.  
Both groups of patients will have a pneumo-hydraulic test after the completion of the anastomosis. 
  
4.2.1.1 NO CYANOACRYLATE GROUP 
Patients selected in the no cyanoacrylate glue arm will not have anastomotic reinforcements   
 
4.2.1.2 CYANOACRYLATE GROUP 
Patients selected in this group will receive the anastomotic reinforcement with nebulized cyanoacylic glue 
using the special short catheter device for open surgery or the laparoscopic catheter.  
 
4.3 Post-Operative Management 
Postoperative care will be according to current standards as directed by the operative surgeon. 
• Pain control will initially be provided using parenteral (intramuscular, intravenous or epidural) 
administration of narcotics or analgesics. 
• Oral analgesics will be offered ad lib when the patient has resumed oral intake. 
• The initiation of oral intake and dietary advances will be made according to individual patient 
tolerance. 
• Intravenous fluids will consist of maintenance crystalloid solution in addition to blood products as 
needed until the patient is able to sustain oral intake. 
• Hospital discharge will occur only after the patient has shown diet tolerance, return of bowel 
function and ability to resume self-care with minimal assistance. 
Subjects will return to the PIs ambulatory clinic for a post-op 30-day follow-up visit in order to collect the 
post-operative data and the post-operative proctography to document the integrity of the anastomosis.  If 

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the subject does not come for the follow-up, the research nurse will contact him/her by all means available 
(phone, email, mail) to ascertain whether the patient had any complications and/or adverse events that 
were treated at another institution.  If the research nurse is unsuccessful in contacting the patient, this 
subject will be considered ‘lost to follow-up”.   
 
5. DATA MANAGEMENT: Data will be collected by a combination of the study investigators, nurse research 
coordinators, and trained residents and fellows. Baseline characteristics and clinical data, procedural data, 
and postprocedure outcomes will prospectively entered into a secure database available to each 
participating center.  
 
6 STATISTICAL ANALYSIS 
6.1 Sample Size Determination:  
The mean percentage of anastomotic leak after rectal cancer is 16% and its reduction to 10% is considered 
to be clinically significant. Therefore, the interval of confidence calculated is 12. A sample size calculation 
shows that 67 subjects per arm will suffice for accepting of the hypothesis with a power of 0.8 and a type I 
error probability of 0.05, with a Confidence level of 95% (sample size calculated by R Studio 
Version 1.1.419 – © 2009-2018 RStudio, Inc.). Accounting for a predicted 5% estimated loss to follow-up, a 
total of 138 (134+4) patients will be included in the study. 
 
5.2 Statistical Methods: 
All statistical analysis will be done in an intention-to-treat fashion. No interim analyses are planned. For all 
statistical tests, a P value of .05 will be considered significant. A Student t-test will provide an unadjusted 
estimate of the difference between treatment arms. Analysis of covariance, a more robust method that 
allows control for key differences in baseline characteristics, will be used to provide adjusted comparisons. 

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Like the primary outcome, continuous secondary outcomes (such as safety and efficacy) will be modeled by 
t-tests and analysis of co-variance. 
Any relationship of the anastomotic leakage with other possible adverse factors will be evaluated by 
univariate and multivariate regression analysis 
When the complete case analysis will exclude more than 5% of patients due to missing data, exploratory 
analyses to investigate the effect of missing data will be performed. In order to explore the mechanism of 
the missing data and the validity of a complete case analysis for each end point, patient characteristics will 
be compared between those with and without missing data and multilevel logistic regression models will be 
used to identify any associations between prognostic variables and to inform if data are missing at random. 
Multilevel logistic regression will be used to estimate the odds ratios (ORs) for conversion to laparotomy, 
intraoperative complications, and postoperative complications between treatment groups. 
 
 
5.3 Subject Population for Analysis 
Data analysis will be performed in accordance with the intention to treat principle. If a violation of 
randomization occurs, all patients will be analyzed according to the original allocation. 
The following information will be prospectively collected and reported: 
• All-randomized population:  Any subject randomized into the study, regardless of whether they 
receive the intervention. 
• Protocol-compliant population:  Any subject who was randomized and received both the study 
intervention and received the required protocol processing. 
 
6. ETHICS 

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6.1 Risks of Participation 
Patients in both study arms will be informed of standard risks of anterior resection surgery, such as ileus, 
surgical site infections, thrombotic complications, cardiac, or pulmonary complications. In addition, the risk 
of anastomotic dehiscence will be discussed and the two randomized options to prevent them (suture 
reinforcement or not) will be carefully described  
6.2 Institutional Review Boards 
This study will be conducted in accordance to the principles of the Declaration of Helsinki and good clinical 
practice guidelines. The study protocol will be approved by the Ethics committee of all participating 
institutions. Prior to randomization, written informed consent will be obtained from all patients.  
6.3 Data Safety Monitoring Committee 
A data safety monitoring board (DSMB) will be established with experts independent of the authors. The 
chairman of the DSMB will receive the clinical data forms continuously from the coordinating center and 
will review data.  The DSMB chair may at any time suggest to the Study Chair to terminate the study in case 
of ethical concerns such as unacceptable complication rates and others. 
 
7. AUTHORSHIP AND PUBLICATION 
The rules described herein apply to any presentation of this study. Members of the Protocol Writing 
Committee as well as Study Chairs qualify for authorship of this study. Vancouver Authorship Guidelines 
rules shall apply (for full document please see full article at http://www.icmje.org/index.html).  Surgeons 
that include patients will attain authorship through a group authorship where names of surgeons will be 
mentioned. The order of the authors in the group authorship according their active contribution to the trial. 
The study results may only be published and/or presented as final analyses after the completion of the 
study, and needs authorization by the study chairs. Publication and/or presentation are defined as any 

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article, podium presentation, poster, abstract, or any other public presentation of this research. As is 
generally accepted, members of the DSMB should be independent and not involved in the study in any way 
including authorship. 
 
 
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