2-octyl cyanoacrylate sealing of the pancreatic remnant after distal pancreatectomy – A prospective pilot study

Background Postoperative pancreatic fistula (POPF) remains a frequent problem especially after distal pancreatectomy. The application of 2-octyl cyanoacrylate showed promising results in the reduction of POPF after pancreatoduodenectomy prompting an expansion of this technique to distal pancreatectomy. Thus, the objective of the current study was to assess safety, feasibility and preliminary efficacy of an intraoperative 2-octyl cyanoacrylate application after distal pancreatectomy. Methods Between April 2015 and June 2016 adult patients scheduled for elective distal pancreatectomy were considered eligible for the study. It was planned to include a total of 35 patients. After distal pancreatectomy with hand-sewn closure of the pancreatic remnant, a 2-octyl cyanoacrylate surgical glue was applied to the cut surface of the pancreas. Patients were followed up for three months with main focus on safety in terms of (serious) adverse events. Further endpoints included POPF, other pancreas-specific and surgical complications. Results 15 patients were included in the study because the manufacturer stopped production and distribution of the investigational device thereafter. There was a total of ten serious adverse events but no device-related events and no mortality. The serious adverse events depicted a typical safety profile after distal pancreatectomy. POPF occurred in five cases (33.3%), delayed gastric emptying and post-pancreatectomy haemorrhage in two cases respectively (13.3%). Conclusions Application of 2-octyl cyanoacrylate to the pancreatic remnant after distal pancreatectomy seems feasible and safe. The planned evaluation of preliminary efficacy was not possible due to the inadvertent early termination and subsequent small sample size of the study. Novel techniques for prevention and therapy of POPF should be evaluated in future trials.


Key inclusion and exclusion criteria
Key inclusion criteria:  Patients scheduled for elective distal pancreatic resection (DP)  ≥ 18 years of age  Written informed consent Key exclusion criteria:  Haemoglobin< 10 g/dl  Bilirubin > 3 times ULN  AST or ALT > 4 ULN  INR > 1.7  Creatinine clearance < 30 ml/min (estimated by Cockcroft-Gault)  Serious cardiovascular disease (e.g. myocardial infarction in the last 12 months, congestive heart failure NYHA III/IV, unstable angina pectoris)  Liver cirrhosis (of any Child-Pugh grade)  ASA score > III  Immunosuppressive therapy (cortison ≥ 40 mg/d or equivalent; azathioprin)  Pregnancy or lactation  Drug trial participation within 30 days before screening visit  Understanding or language problems  Inability to comply with study and/or follow-up procedures  Allergy or known intolerability to 2-octyl cyanoacrylate, butyl-lactoylcyanoacrylate or formaldehyde  Any condition which could result in an undue risk for the patient in the opinion of the investigator o Perioperative lung embolism  30-day mortality  Operation time  Intraoperative blood loss  Postoperative hospital stay Assessment of safety: Patients will be closely monitored for the occurrence of any (serious) adverse events. Adverse events will be categorized in surgical, cardiovascular, pulmonary, urinary and others. Furthermore it will be defined if adverse events are device-related or not.

Study type
A monocenter open label prospective proof of concept trial in a single arm study design at the development stage (according to the IDEAL recommendations [4])

Statistical analysis
Descriptive statistical analysis will be conducted.

Sample size
To be assessed for eligibility:(n = 50 ) To be allocated to trial: (n = 35) To be analyzed: (n = 30)

Trial duration
First patient in to last patient out (months): 12 months Duration of the entire trial (months): 24 months Recruitment period (months): 6 months Trial report completed (months): 6 months after last-patient-out

Participating centers
Dept. of General, Visceral, and Transplantation Surgery, University of Heidelberg BOND Protocol version 3. 2 12.11.2014 Study Center of the German Surgical Society (SDGC) page 10 of 67

Assessment of baseline data
Intervention/Operation

INTRODUCTION
In Germany there are about 15,000 newly diagnosed neoplasms of the pancreas each year. [5] Exact numbers for benign or borderline lesions do not exist. In 2011 aproximately 11,800 partial resections of the pancreas were performed in German hospitals. [6] Pancreatic surgery is complex from a diagnostic, surgical and perioperative point of view.
Centralization of pancreatic surgery in specialized institutions has led to acceptable mortality rates below 5%. [7][8][9] Moreover, standardization of surgical and perioperative care in these centers of expertise is a prerequisite for low morbidity rates. [7] Postoperative pancreatic fistula (POPF) still represents the most common postoperative morbidity in pancreatic surgery and can profoundly affect patient recovery and outcome. The incidence of POPF reported in the literature varies widely with overall rates between 0% and 24%. [10] After pancreaticoduodenectomy (PD) POPF rates range from 10% to 15% in different studies, and usually occur at a higher rate of about 10% to 30% after DP respectively. [11] In a large multicenter RCT conducted by the SDGC comparing stapler vs.
hand-sewn closure of the pancreas after DP, the overall POPF rate was 30% in 352 analyzed patients, coinciding well with the rates in the literature. [12] In-hospital mortality due to POPF or subsequent complications occur in up to 14%, [13] reaching up to 33% in high-risk subgroups. [14] Pancreatic surgeons still lack an effective strategy to reduce the rates of POPF. Therefore, further research on the prevention of POPF is obligatory.

SCIENTIFIC BACKGROUND
In current routine practice, after DP the pancreatic remnant is usually closed by either the use of a stapler or by hand-suture with conventional surgical sutures without any further measures. Several surgical techniques and technical modifications have been proposed in an attempt to reduce fistula rates in pancreatic surgery. [15] For instance, different types of fibrin sealants have been evaluated in their potential to reduce the occurrence of POPF, but none of them has been proven effective so far. [16,17] A recent systematic review and metaanalysis of Orci et al. [18] concluded that "fibrin sealants cannot be recommended for routine clinical use in the setting of pancreatic surgery". Also, mesh reinforcements of the pancreaticojejunal anastomosis have provided no significant benefit in the reduction of POPF. [19] Compared to fibrin sealants, the medical glue 2-OCA is also easily applicable to the resection surface and will not be degraded by aggressive pancreatic enzymes due to its long-lasting tissue bonds. Cyanoacrylate is an acrylic resin that rapidly polymerizes in the In 2013,Barakat et al. [21] have published their first results on the topical application of 2-OCA to the pancreaticojejunal anastomosis after PD. They reported a highly significant reduction of POPF for the 2-OCA group compared to patients without 2-OCA application.
The rate of POPF in the 2-OCA group was 3.5% compared to 36% in the group without 2-OCA application. Currently, no further evidence on the application of 2-OCA in pancreatic surgery is available in the literature.

TRIAL RATIONALE
Based on the results of Barakat et al. [21], topical 2-OCA application promises a substantial benefit in the prevention of POPF. Currently, there are only data available on the topical application to the pancreaticojejunal anastomosis after PD. Therefore, we intend to expand this promising technique to further pancreatic interventions. DP shows even higher rates of POPF compared to PD, thus, there may be a larger benefit for prevention of POPF in this indication.
Based on these facts, we conduct this trial in a proof-of-concept design to further develop the technique and to evaluate safety and preliminary efficacy in these indications.

OBJECTIVES
The main objective of this study is to evaluate the safety of a 2-OCA application to the pancreatic remnant after distal pancreatectomy. Therefore all serious adverse events will be closely monitored. If the intervention proofs to be safe under these conditions, a multicenter RCT will be planned to evaluate the efficacy of this new and promising technique.
As primary efficacy parameter, the rate of POPF will be assessed.

TRIAL DESIGN
BOND is amonocenter open label prospective proof of concept and safety trial in a single arm study design at the development stage (according to the IDEAL recommendations [4]) The duration of the trial for each patient is planned to be 3 months. The duration of the overall trial is expected to be 2 years, including prearrangement and analysis.  Serious cardiovascular disease (e.g. myocardial infarction in the last 12 months, congestive heart failure NYHA III/IV, unstable angina pectoris)  Liver cirrhosis (of any Child-Pugh grade)  ASA score > III  Immunosuppressive therapy (cortison ≥ 40 mg/d or equivalent; azathioprin)  Pregnancy or lactation  Drug trial participation within 30 days before screening visit  Understanding or language problems  Inability to comply with study and/or follow-up procedures  Allergy or known intolerability to 2-OCA, butyl-lactoyl cyanoacrylate or formaldehyde  Any condition which could result in an undue risk for the patient in the opinion of the investigator 2.1.1 Number of patients and trial centers BOND will be conducted as a monocenter proof-of-concept and safety trial, therefore no actual sample size calculation was performed. A total of 35 patients is planned to be included into the trial. From our previous RCT on DP and from a review of the literature, there is good evidence that the rate of POPF after conventional DP is 30%. [12] Thus, we would expect the occurrence of about 10 cases of POPF without application of the sealant which should be reduced by the application of the 2-OCA sealant. Therefore, a number of 35 was judged sufficient for a preliminary evaluation of safety and applicability by the investigators in this early phase of the new technique. BOND will be conducted as a monocenter trial at the Department of General, Visceral, and Transplantation Surgery at the University of Heidelberg, Heidelberg, Germany. If the trial intervention proofs to be safe, a multicenter RCT is planned with a sample size calculation based on the preliminary efficacy results (frequency of POPF).

Criteria for withdrawal of patients
Patients are free to leave the trial at any time and without giving reasons for their decision.
Subjects may be withdrawn from the trial for the following reasons: (a) At their own request or (b) If, in the investigator's opinion, continuation of the trial would be detrimental to the subject's well-being. In case of (b), the reason for withdrawal must be recorded in the CRF and in the patient's medical records.
Patients that were included into the trial but the designated intervention could not be performed due to any reason (e.g. DP was not feasible upon abdominal exploration) will be replaced by consecutive patients until the planned sample size is reached.

Investigational Device
The The sterile, non-pyrogenic device is provided as a packaged single-use applicator and stored at room temperature.
ETHICON™ OMNEX™ is a CE marked and certified device. It conforms to the essential requirements of the Medical Device Directive 93/42/EEG and was tested in conformity to the ISO 10993 series for biocompatibility of a long-term implantable medical device.
Further information about the investigational device including a summary of preclinical and clinical testing can be found in the investigator's brochure ("Handbuch des klinischen Prüfers"), provided by the SDGC.

Description of trial interventions
2-OCA in DP: After routine resection of the pancreatic tail and/or body the remnant will be closed according to local standards [22] by direct suture of the pancreatic duct with a nonreabsorbable surgical suture (e.g. Novafil 4-0) and closure of the pancreatic tissue with absorbable sutures (e.g. PDS 5-0) in fish-mouth technique. After the conventional closure, a thin layer of the 2-OCA surgical sealant will be applied to the sutured surface of the pancreatic remnant (not exceeding 4 ampoules). The surrounding area will be covered with sterile surgical gauzes to avoid contact of the sealant to other tissue not intended to get in contact with the sealant. Before application, the surface of the pancreatic remnant will be patted dry with a sterile gauze, to assure direct contact of the sealant to the tissue as described in the directions for use of the product. No additional covering of the pancreatic remnant will be conducted. Additional sutures of the cut surface for reasons of hemostasis will be allowed. After polymerization of at least 2-3 minutes the operation will be continued in a routine manner. [22] Perioperative treatment will not be changed by the trial intervention and will be conducted according to local standards.

Benefits and risks of trial interventions
ETHICON™ OMNEX™ has been tested extensively for biocompatibility, cytotoxicity, intracutaneous reactivity, dermal sensitization, acute toxicity, pyrogenicity, hemolysis, mutagenicity, etc. Furthermore, various animal studies including implantation studies up to 24 months have been performed. The tests were in accordance with ISO 10993 series and were appropriate for an implant device that is in permanent contact with tissue (>30 days). All the results indicated that the materials and processes used to manufacture ETHICON™ OMNEX™ Surgical Sealant and the delivery system are biocompatible and suitable for their intended use. The FDA's "Summary of Safety and Effectiveness Data" is provided in the appendix.
In addition to the preclinical testing, ETHICON™ OMNEX™ has been examined in a clinical feasibility study, [23] a RCT [24] and a prospective, single-arm, multicenter trial [25] of vascular surgery prior to its approval. The clinical trials showed no unanticipated adverse device effects. The complication profile was typical for patients undergoing vascular surgical procedures and did not raise any safety concerns. Furthermore, the number of patients with at least one vascular or bleeding complication was significantly reduced in the group treated with ETHICON™ OMNEX™, although the study was not powered for this analysis. The (safety) results of the clinical trials are also given in the "Summary of Safety and Effectiveness Data" in the appendix.
Moreover, there are several reports on observed beneficial effects in "internal" use of 2-OCA sealants: e.g. heart surgery: ventricular wall ruptures; [26]   complications possibly related to intra-corporal 2-OCA application were identified in 119 patients (see Table 2).  The intended benefit is an effective sealing of the pancreatic remnant after routine closure by sutures and/or staples. The aim of this sealing is to reduce the rate of POPF, which represents one of the most frequent and potentially most hazardous complications after DP.
A conceivable adverse event could be unintended adhesions of other tissues (e.g. bowels) due to unintended contact of the surgical sealant to these tissues. This will be avoided through covering of the surrounding area with sterile gauzes during the application and polymerization process. The sterile gauzes will be removed after the sealant has fully polymerized.

Procedures for minimization of risks
For minimization of potential risks, study specific handling instructions for the investigational device have been defined in the investigator's brochure. All investigators are obliged to read the investigator's brochure ("Handbuch des klinischen Prüfers") as well as the study protocol prior to trial start. Furthermore, investigators will be trained at a pre-trial study visit.
The study will be monitored to ensure the identification, documentation and analysis of all adverse events and compliance with the protocol. Furthermore, it will be ascertained, that the terms of the IEC to protect safety and rights of all subjects, and all other applicable regulations will be followed.
A Data Safety and Monitoring Board will be implemented for ongoing safety monitoring of the study.

Assignment of intervention and blinding
The primary aim of the BOND-trial is the evaluation of safety of the intervention. All participants will receive treatment with the 2-OCA surgical sealant and will be closely monitored for potential serious adverse events. Therefore patients and outcome assessors will not be blinded in this setting.

OUTCOMES/ENDPOINTS
Safety objectives: The incidence of all adverse events (AE) and serious adverse events (SAE) will be closely monitored and evaluated. All (S)AE and intervention related side effects will be documented on the specific forms (CRF, SAE-form).

Description of trial visits
Before acquisition of any data, patients will be informed about the trial and all trial-specific procedures (including data handling and data protection) by one of the investigators.

Visit 1
Baseline data: If a patient has given informed consent and all eligibility criteria are fulfilled, then the following baseline data will be documented. Pre-existing exocrine insufficiency Sampling of 20 ml of blood for translational research in the context of a routine blood sample Visit 2: The following operative data are documented:  Performed surgical intervention in detail: o DP o Additional resections like lymphadenectomy, splenectomy or extrapancreatic resections normally not included in the above mentioned techniques o Operation time defined as the interval from first incision of the skin until last knot of the skin suture, last skin staple respectively o Intraoperative blood loss as estimate from the anaesthesia protocol o Exact description of the application of 2-OCA (one layer, two layers, application problems, etc.) o Description of any problems during the application process (e.g. adhesive did not stick to the intended area, contact of the adhesive with other tissue, etc.) o Consistency of the pancreas: soft, medium, hard If any sealants or other procedures not mentioned in the study protocol are used, this has to be documented in the CRF.  (Serious) adverse events

Visit 3, 4 and 5
On day 3, 7 and 14 after operation, the patients will be visited by study personnel. Furthermore, medical records of the patients will be checked to assess the primary and secondary endpoints. If the patients are dismissed before day 14 after the initial operation, Visit 5 will be performed within 36 hours prior to discharge.

Visit 6
On day 30 after the initial operation patients will be contacted by telephone and asked for the occurrence of further complications in a standardized interview. In case, further information is required, the treating physician will be contacted, if patients gave their consent to this. The following data are documented:  Postoperative occurrence of pancreatic fistula (anamnestic)  Assessment of the following perioperative secondary endpoints: o Delayed gastric emptying (according to ISGPS definition) [2] o Postpancreatectomy hemorrhage ( according to the ISGPS definition) [ 3 months after the index operation, the patients will be contacted again by telephone to evaluate the occurrence of further complications. A standardized telephone interview like detailed above (Visit 6) will be conducted.

PLAN FOR FURTHER TREATMENT OF THE PATIENTS AFTER TERMINATION OF THE TRIAL
After termination of the trial, the trial subjects will be further treated and followed-up in regular intervals in the pancreatic consultation at the Department of General, Visceral, and Transplantation Surgery at the University of Heidelberg. In this consultation, all patients operated on the pancreas at the Department of General, Visceral, and Transplantation Surgery at the University of Heidelberg, are regularly assessed by specialists in the field of pancreatic surgery.

DATA MANAGEMENT
All protocol-required information collected during the trial must be entered by the investigator, or designated representative, in the CRF. The investigator, or designated representative, should complete the CRF pages as soon as possible after information is collected, preferably on the same day that a trial subject is seen for an examination, treatment, or any other trial procedure. Any outstanding entries must be completed immediately after the final examination. An explanation should be given for all missing data.
The completed CRF must be reviewed and signed by the investigator named in the trial protocol or by a designated sub-investigator. After keeping a copy at the trial center, the original CRF is sent to the SDGC (staff not included in trial conduct) for data entry.
In order to ensure that the database reproduces the CRFs correctly, the SDGC accomplishes a double entry of data. The completeness, validity and plausibility of data are examined by validating programs, which thereby generate queries. The investigator or the designated representatives are obliged to clarify or explain the queries. At the end of the trial the principal investigator will retain the originals of all CRFs.
The data will be managed and analyzed in accordance with the appropriate Standard Operating Procedures (SOPs) valid in the SDGC.

SAMPLE SIZE CALCULATION
A total of 35 patients will be recruited to the trial and treated by the application of the 2-OCA surgical sealant to the surface of the pancreatic remnant after DP. This sample size is judged sufficient for the evaluation of safety and applicability in this setting. If the trial proves safety of the intervention, a multicenter efficacy RCT will be conducted consecutively.

ANALYSIS VARIABLES AND STATISTICAL METHODS
All patients treated with the trial intervention will be considered in the final analysis.
The empirical distribution of all endpoints will be calculated, including mean, standard deviation and quartiles in case of continuous variables and scores, and with absolute and relative frequencies in case of categorical data. 95% confidence intervals will be calculated.
Whenever appropriate, statistical graphics will be used to visualize the findings.
Missing data will be minimized by consequent documentation and all other reasonable methods. No interpolation of missing data will be performed.
(Serious) adverse events will be summarized using descriptive statistics. The adverse events will be categorized as surgical, cardiovascular, pulmonary, urinary and other complications.
Furthermore, it will be defined if events were device-related or not. Device-related and not device-related (serious) adverse events will be reported seperately. Proportions and frequencies of adverse events will be presented. Specific focus will be placed on potential device-related adverse events.
Because the BOND-Trial is designed as a proof-of-concept trial no formal analyses will be conducted. In case of safety and feasibility, the results will serve as a basis for sample size calculation (set into relation to the results from previous RCTs) for a succeding randomized controlled trial.

CLINICAL DATA MONITORING
During the clinical trial, quality control and quality assurance will be ensured via monitoring, final report can be drawn from the source data. This includes controlling of data filing and organisation of the study center as well as controlling of third parties and original documents.

Definition and Documentation of Adverse Events
According to ISO 14155 an adverse event is any untoward medical occurrence, unintended disease or injury, or untoward clinical sign (including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the investigational medical device. Note: This definition includes events related to the investigational medical device or the comparator.
This definition includes events related to the procedures involved.
For users or other persons, this definition is restricted to events related to investigational medical devices.
An AE may be: A pre-existing disease or symptom will not be considered an adverse event unless there will be an untoward change in its intensity, frequency or quality. This change will be documented by an investigator.
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that require surgery. The condition for which the surgery is required may be an AE. All AEs (including SAEs) will be documented on an AE-form. AEs are classified as "non-serious" or "serious".

Serious Adverse Event (SAE)
According to the Ordinance on Medical Devices Vigilance (Medizinprodukte-Sicherheitsplanverordnung, MPSV), a serious adverse event (SAE) is defined as follows: Any untoward event in a clinical trial which is subject to approval that indirectly or directly led, Planned hospitalization for a pre-existing condition, or a procedure required by the protocol, without serious deterioration in health, is not considered a serious adverse event.
Adverse Device Effect (ADE) An adverse device effect is an adverse event related to the use of an investigational medical device.

Serious Adverse Device Effect (SADE)
A serious adverse device effect is a device effect that has resulted in any of the consequences characteristic of a serious adverse event.

Unanticipated Serious Adverse Device Effect (USADE)
An unanticipated serious adverse device effect (USADE) is a serious adverse device effect which by its nature, incidence, severity or outcome has not been identified in the current version of the risk analysis report, as contained in the investigator's brochure ("Handbuch des klinischen Prüfers").
In contrast, an anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity or outcome has been identified in the risk analysis report.
All adverse events occuring during the period between the application of the medical device and the last follow-up visit must be documented on an "Adverse Event Form" in the CRF. All untoward medical occurrences appearing prior to the application of the medical device will be recorded as medical history.

Classification of Intensity
The intensity of a SAE will be classified as follows:

Mild:
Temporary event which is tolerated well by the subject

Moderate:
Event which results in discomfort for the subject and impairs his/her normal activity Severe: Event which results in substantial impairment of normal activities of subject

Classification of Outcome
The outcome of a SAE at the time of last contact with the subject is classified.

Ongoing:
Signs and symptoms of the SAE still exist.

Recovered completely:
All signs and symptoms of SAE have disappeared.
Recovered with sequelae: Acute signs and symptoms of SAE have disappeared, sequelae caused by the SAE still exist.

Death:
The SAE has caused the death of the patient. If a subject has suffered from more than one SAE, only the outcome for the SAE directly responsible for death is classified as 'death', the other SAEs are classified according to their specific outcome. Unknown: The outcome is not known or is implausible and there is no possibility to complete or verify the information.

Classification of Causality
The causality will be classified in a binary order: Reasonable possibility that the trial intervention caused the SAE? YES/NO If causality is "not assessable" it will be classified as NO.

Classification of Countermeasures
The countermeasures will be documented according to the following rules:

None: No action taken
Drug treatment: Newly-prescribed medication or change in dose of a medication

Others:
Other countermeasures, e.g. an operative procedure

Reporting of Serious Adverse Events
Immediate Reporting

Periodic Reporting
All SAEs which do not fulfill the criteria for immediate reporting will be documented completely by the sponsor and summarized. They will be reported quarterly to the BfArM or upon request using the SAE reporting table form provided on the EC website (http://ec.europa.eu/health/medical-devices/documents/guidelines/index_en.htm).

Actions of Sponsor
The sponsor has to assure, that every SAE will be reported by all investigators participating in this trial. Serious adverse events have to be reported by the attending physician to the principal investigator within 24 hours after the incident. The initial report must be as complete

Emergency treatment
During and following a subject's participation in the trial, the investigator must ensure that adequate medical care is provided. The subject must receive adequate treatment in any clinical situation including emergencies and outcome of the patient must be controlled.

Data safety and monitoring board (DSMB)
In case of any irregularities for example concerning the frequency or type of SAE reported the principal investigator will inform the members of the independent Data Safety Monitoring Board (DSMB) without delay. At least once every 3 months, the DSMB will receive a written safety report. After reception of the semestral report, the members of the DSMB will discuss the safety report in a telephone conference. The members of the DSMB then report the result of the benefit/risk assessment to the steering committee and will give appropriate recommendations concerning the continuation of the trial.
The Members of the DSMB are stated above (see "ROLES AND RESPONSIBILITIES").

STEERING COMMITTEE
A steering committee will be established (see Roles and Responsibilities). The steering committee will supervise the conduct of the trial and will issue recommendations for early termination, modifications or continuation of the trial, if necessary. Regular meetings of the steering committee will be held during the whole course of the trial.

RECORD RETENTION AND DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The SDGC will maintain the records of the study consisting of all correspondence with the relevant authorities and ethics committee, study protocol with any amendments, investigator's brochure, the patients' signed informed consent forms, investigational device accountability records, and individual subject records. All source data and relevant Study Center of the German Surgical Society (SDGC) page 29 of 67 documents will be kept for at least 2 years after this clinical trial is terminated. Thereafter, documents will be archived for at least 10 years after termination of the trial as required by the MPKPV. Other regulations for the storage of medical records stay unaffected by this procedure.
According to the MPKPV the investigators must provide direct access to source data for trial related monitoring, audits and regulatory inspections. Each subject has consented -via written informed consent -to direct access to his/her original medical recrds for trial-related monitoring, audit and regulatory inspection.
All data and documents will be made available if requested by the relevant authorities.

DEVICE ACCOUNTABILITY
The surgical sealant will be provided to the study site by the SDGC after all required regulatory documentation has been received. A label stating "Exclusively for clinical investigation" will be applied and the device will be stored in a locked area at the appropriate storage conditions. Access will be limited to designated study staff. A device accountability log will be provided. Every disposition of the device will be documented referring to the individual study subject (including units used per patient).
In the device accountability log, potential product deficiencies will be documented. In case of SAEs a potential connection between device deficiencies and SAE can be assessed by review of the documentation.

ETHICAL AND LEGAL ASPECTS
As described in the sections 1.1 and 2.2.3 above, 2-OCA is a surgical glue which promises benefit in the prevention of POPF. From the available results in the literature, 2-OCA seems to be safe and has already been approved for the intracorporal use.
Distal pancreatic resection is a standard operative technique for pancreatic lesions in the body or tail of the gland, which is used on a day-to-day basis at the surgical department of the University Hospital Heidelberg.
Nevertheless, we will closely monitor the occurrence of all (serious) adverse events.
Before the acquisition of any data, patients will be informed about the trial and the data handling and have to provide written informed consent. All data will be handled according to the German Data Protection Law. Data will be pseudonymized and access to data will only be given to authorized persons, e.g. monitors and the competent authorities (BfArM). The insurance company has to be informed about all amendments that could affect patients' safety.

PREMATURE TERMINATION OF THE TRIAL
The trial may be closed prematurely by the principal investigator in consultation with the steering committee and the responsible biometrician.
If the termination of the trial becomes necessary, the steering committee of the trial will discuss this issue with the independent Data Safety Monitoring Board (DSMB). Reasons that may necessitate a termination of the trial include the following: -The incidence or severity of serious adverse events/morbidity in this trial indicates a potential health hazard caused by the trial intervention.
-It appears that patients' enrolment is unsatisfactory with respect to quality and/or quantity or data recording is severely inaccurate and/or incomplete.
-External evidence demanding a termination of the trial.
The independent ethics committee (IEC) and the corresponding authorities (BfArM) will then be informed.

PROTOCOL APPROVAL AND AMENDMENTS
Study Center of the German Surgical Society (SDGC) page 31 of 67 Before the start of the trial, the trial protocol, informed consent document, and any other appropriate documents will be submitted to the independent EC and the corresponding authorities (BfArM). Also all amendments will be submitted to the ECs and the corresponding authorities. Formal approval by the EC should preferably mention the title of the trial, the trial code, the trial site, and any other documents reviewed. Changes will not be implemented until approval of the IEC and the BfArM have been given.

RESPONSIBILITIES OF INVESTIGATOR
The principal investigator should ensure that all persons assisting in the trial are adequately informed about the protocol, any amendments to the protocol, the investigator's brochure, the medical device, the trial treatments, and their trial-related duties and functions.
The investigator should maintain a list of sub-investigators and other appropriately qualified persons to whom he or she has delegated significant trial-related duties.

FINAL REPORT
In accordance with §23a of the MPG the final report of the trial will be submitted to the BfArM within 12 months after the end of the clinical phase (LPO).

FINANCING OF THE TRIAL
The trial was partially funded by a grant of the Heidelberger Stiftung Chirurgie, Im Neuenheimer Feld 110, 69120 Heidelberg.

DISSEMINATION
The trial will be registered in an international trial registry (e.g. www.clinicaltrials.gov).
Simultaneously to trial start, the protocol will be published.
Results of the BOND trial will be presented to the national and international surgical community at (inter-)national surgical conferences. Furthermore, the final report will be published in an international peer-reviewed journal.
After completion of the trial and if the trial intervention proves to be safe, a multicenter RCT will be set up for the evaluation of efficacy.
The Department of General, Visceral, and Transplantation Surgery of the University of Heidelberg in its role as the European Pancreas Center has an exemplary function for the treatment of pancreatic diseases worldwide.
Besides that, the SDGC promotes evidence-based surgery and evidence-based patient information on a national and international level, via publications, scientific presentations, internet presence, the German Surgical Research Network, CHIR-Net, and with training programs and educational courses for surgeons.

TRANSLATIONAL RESEARCH
The basic and clinical research aims to identify parameters which influence the clinical outcome and may be useful for prognostic or therapeutical decision making in future with main focus on POPF. Serum parameters (20 ml blood) are investigated in a standardised fashion. A proteomic screening is planned for potential factors influencing the occurrence of POPF. The alterations are analysed in detail and assessed for their clinical implications. The main focus will be an explorative evaluation of potential risk factors for POPF, which can be assessed preoperatively. So in the future, potential individual treatment decisions can be made on the preoperative assessment of these factors.
Potential markers include the type I/III-collagen ratio, MMPs, TIMPs etc., which are related to cell adhesions and the integrity of connective tissues. All investigations will be performed centralised and all data stored in a separate database. This will be linked to the clinical database to answer the above mentioned questions.

DECLARATION OF INVESTIGATOR
I have read the above trial protocol and I confirm that it contains all information to accordingly conduct the clinical trial. I pledge to conduct the clinical trial according to the protocol. I will enroll the first subject only after all ethical and regulatory requirements are fulfilled. I pledge to obtain written consent for trial participation from all subjects.
I know the requirements for accurate notification of serious adverse events and I pledge to document and notify such events as described in the protocol.
I pledge to retain all trial-related documents and source data as described. I will provide a curriculumvitae (CV) before trial start.