Use of Hemopatch as a Sealant at the Pancreaticojejunostomy After Pancreatoduodenectomy to Prevent Postoperative Pancreatic Fistula
Phase: PHASE3
Conditions: Pancreatic Fistula
Sponsor: Hospital Miguel Servet

Study protocol - Use of Hemopatch as a sealant in pancreaticojejunostomy after PD. 
Version 2.0. 
 
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STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
Use of Hemopatch as a sealant in the pancreaticojejunostomy after 
pancreatoduodenectomy to prevent postoperative pancreatic fistula  
 
 
Mario Serradilla Martín 
Division of Hepato-Pancreato-Biliary Surgery  
Department of Surgery 
Miguel Servet University Hospital 
Zaragoza, Spain 
 
 
 
 
 
 
 
 
Version 3.0 
25/01/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This document is confidential and can not be circulated without the written 
authorization of the principal investigators. 
 
 
 

Study protocol - Use of Hemopatch as a sealant in pancreaticojejunostomy after PD. 
Version 2.0. 
 
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Content 
 
1. Synopsis of the study..………………………………………………………………...3 
2. Visit and evaluation...…………………………………………………………………5 
3. Structure of the organization …………………………………………………………5 
3.1. Sponsor…..……………………………………………….…………………5 
3.2. Principal investigators…..…………………………...……………………...5 
4. Summary………………………………………………………………………………7 
5. Hypotheses / objectives ………………………………………………………..……..9 
6. Study design……….………………………………………………………………….9 
6.1. Type of study …………..…………………………………………………...9 
6.2. Primary objective and secondary objectives ……………………………….9 
6.3. Duration of study ...………………………………………………………..10 
7. Patients..……………………………………………………………………………..10 
7.1. Criteria..……………………………………………………………………10 
7.2. Recruitment………………………………………………………………...11 
7.3. Inclusion and exclusion criteria ..………………………………………….11 
7.4. Surgical techniques and materials of intervention  ……...………………...11 
7.5. Postoperative period ..……………………………………………………..12 
7.6. Complications / failure of the intervention ……..…………………………13 
7.7. Termination conditions / Adverse events ……..…………………………..13 
8. Data..…………………………………………………………………………………14 
 
8.1. Calculation of sample size ……...…………………………………………14 
 
8.2. Randomization and groups...………………………………………………14 
8.3. Evaluation of efficacy……………………………………………………...14 
8.4. Patient data sheet………..…………………………………………………15 
 
8.5. Statistical methods and data analysis ……………………………………...15 
9. Patient safety…….….……………………………………………………………….16 
10. Impact on practice …………………………………………………………………16 
11. Ethics and legal requirements ……………………………………………………...16 
12. Registry……………………………………………………………………………..16 
13. Publication.…………………………………………………………………………16 
14. References.…………………………………………………………………………17 
 
 

Study protocol - Use of Hemopatch as a sealant in pancreaticojejunostomy after PD. 
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1. SYNOPSIS OF THE STUDY. 
 
Principal investigator 
Mario Serradilla Martín, MD, FACS 
Associate Professor at University of Zaragoza  
Attending Surgeon in General Surgery  
Division of Hepato-Pancreato-Biliary Surgery 
Miguel Servet University Hospital  
Paseo Isabel La Católica, 1-3 
50009 Zaragoza, Spain 
Tel.: +34 636 006 184 
Fax: +34 976 765 509 
E-mail: 
marioserradilla@hotmail.com 
/ 
mserradilla@salud.aragon.es 
Title of the study 
Use 
of 
Hemopatch 
as 
a 
sealant 
in 
the 
pancreaticojejunostomy after pancreatoduodenectomy to 
prevent postoperative pancreatic fistula  
 
Population 
Patients undergoing pancreatoduodenectomy (PD) (due to 
benign or malignant tumors or chronic pancreatitis) with 
duct-to-mucosa pancreaticojejunostomy reconstruction 
Objetives 
Primary objective: 
• To demonstrate the effectiveness of Hemopatch in the 
prevention of postoperative pancreatic fistula after PD 
with duct-to-mucosa reconstruction against ductomucosal 
reconstruction without Hemopatch 
Secondary objectives: 
• To assess the safety and tolerance of Hemopatch in 
patients undergoing PD 
Interventions 
Performing duct-to-mucosa anastomosis with or without 
Hemopatch reinforcement after PD 
Inclusion and exclusion 
criteria 
Inclusion criteria: patients submitted to PD by 
laparoscopic or open approach for benign / malignant 
tumors or chronic pancreatitis; ASA < 4; men and women 
≥ 18 and ≤ 80 years of age. 
Exclusion criteria: patients under 18 and over 80 years 
old; ASA score ≥ 4; subjected to multivisceral resections 
different from PD; patients with acute necrotizing 
pancreatitis; immunosuppressed patients; patients who 
have not signed the informed consent; patient with 
contraindication of PD performance 
Results 
Primary point: 
Type B and C postoperative pancreatic fistula defined 
according to the criteria of the International Study Group 
on Pancreatic Fistula (ISGPF) 
Secondary endpoints: 
1) Duration of postoperative hospital stay. 
2) Length of stay in intensive care unit. 
3) Measurement of drainage debit. 
4) Reinterventions including interventional radiology. 
5) Infection of the surgical site and / or dehiscence of the 

Study protocol - Use of Hemopatch as a sealant in pancreaticojejunostomy after PD. 
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wound; complications in the deep organ space up to 30 
days postoperatively. 
6) Delayed gastric emptying. 
7) Biliary fistula. 
8) Postoperative hemorrhage. 
9) Death, regardless of the cause. 
Type of study 
Prospective randomized double blind unicentric clinical 
trial 
Statistic analysis  
For the evaluation of the primary endpoint patients will be 
dichotomized by the presence or absence of the sealant 
reinforcement. Further, patients will be categorized by the 
type of pancreatic fistula rate defined according to the 
International Study Group of Pancreatic Fistula (ISGPF). 
Next, a contingency table will be created to calculate 
positive predictive value, specificity, sensitivity, and c-
index. Association between sealant reinforcement and 
POPF rate will be expressed as odds ratio calculated by 
logistic regression models with the appropriate covariates. 
The strength of association between categorical variables 
will be tested with a chi-square test with Yate’s 
correction.  
Secondary end points will be analyzed descriptively by 
tabulation. Chi-square tests will be used to test 
associations among categorical variables, while Student's 
t-test or Mann-Whitney U-test will be used to compare 
continuous normal or non-normal data, respectively. Time 
dependent variables will be tested by Kaplan-Meier 
analysis and Cox regression. Statistical analysis will be 
performed with R. 
 
Sample size 
64 patients, 32 in each group 
Ethical approval 
This study is approved by the Clinical Research Ethics 
Committee of Aragon (CEICA) 
Duration of the study 
The study will begin on February 1, 2018. It is estimated a 
duration of 1.5 years, according to the PD rate of our 
center (40-50 year). Estimated end date: July 31, 2019. 
Participating centers 
Division 
of 
Hepato-Pancreato-Biliary 
Surgery, 
Department of Surgery, Miguel Servet University 
Hospital 
 
 
 

Study protocol - Use of Hemopatch as a sealant in pancreaticojejunostomy after PD. 
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2. PATIENT VISIT AND EVALUATION. 
 
There will be a first visit in an outpatient clinic where the patient will be informed about 
the study in detail and will be offered to participate in it as long as it meets the selection 
criteria. Two copies of the informed consent will be signed, one of them for the patient 
and the other will be kept together with the study documentation. A first evaluation of 
the patient will be carried out as it appears in the data collection notebook. 
 
 
3. STRUCTURE OF THE ORGANIZATION. 
 
3.1. Sponsor. 
 
Investigator Initiated Research Grant from Baxter S.L., Chicago, Illinois, United States, 
convened on March 24, 2017. 
 
3.2. Principal investigators. 
 
Principal investigator: 
 
Mario Serradilla Martín, MD, FACS 
Associate Professor at University of Zaragoza 
Attending Surgeon in General Surgery 
Division of Hepato-Pancreato-Biliary Surgery  
Miguel Servet University Hospital 
Paseo Isabel La Católica, 1-3 
50009 Zaragoza, Spain 
Tel .: +34 636 006 184 
Fax: +34 976 765 509 
E-mail: marioserradilla@hotmail.com / mserradilla@salud.aragon.es 
 
Collaborating researchers: 
 
Alejandro Serrablo Requejo, MD, PhD, FACS 
Associate Professor at University of Zaragoza 
Head of Division, Division of Hepato-Pancreato-Biliary Surgery  
Department of Surgery 
Miguel Servet University Hospital 
Paseo Isabel La Católica, 1-3 
50009 Zaragoza, Spain 
Tel .: +34 629 675 491 
Fax: +34 976 765 509 
E-mail: almaley@telefonica.net 
 
Sandra Paterna López, MD 
Attending Surgeon in General Surgery  
Division of Hepato-Pancreato-Biliary Surgery  
Miguel Servet University Hospital 
Paseo Isabel La Católica, 1-3 
50009 Zaragoza, Spain 

Study protocol - Use of Hemopatch as a sealant in pancreaticojejunostomy after PD. 
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Tel .: +34 619 520 628 
Fax: +34 976 765 509 
E-mail: pichicatos@yahoo.es 
 
Methodological, Statistical and Documentation Consultant: 
 
José Miguel Arbonés Mainar, PhD 
Aragonese Institute of Health Sciences 
Translational Research Unit 
Miguel Servet University Hospital 
Paseo Isabel La Católica, 1-3 
50009 Zaragoza, Spain 
Tel .: +34 976 769 565 
Fax: +34 976 769 566 
E-mail: jmarbones.iacs@aragon.es 
Web: www.adipofat.com 
 
 
 

Study protocol - Use of Hemopatch as a sealant in pancreaticojejunostomy after PD. 
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4. SUMMARY. 
 
Pancreatoduodenectomy (PD) is a common surgical procedure to treat carcinoma of the 
head of the pancreas and other tumors of the periampullary region. Recent advances in 
surgical techniques and perioperative treatments have reduced the perioperative 
mortality below 10% in high volume centers [1–4]. However, PD is associated with 
considerable morbidity in 40–58.5% of patients manifesting postoperative pancreatic 
fistula (POPF), delayed gastric emptying (DGE), postpancreatectomy hemorrhage 
(PPH), and postoperative pulmonary complications [2, 5, 6]. 
 
Several surgical techniques and perioperative care have been studied in order to prevent 
or decrease the incidence of POPF after PD, including digestive tract reconstruction 
with 
pancreaticogastrostomy 
[7], 
duct-to-mucosa 
(DTM) 
or 
invagination 
pancreaticojejunostomy (PJ) [8], prophylactic somatostatin or somatostatin analogues 
[9], and pancreatic duct stents [10].  
 
Probably the reasons why the pancreaticojejunal anastomosis has greater diffusion are 
different, starting from the first descriptions of the surgical technique with subsequent 
inertia, until it is feasible to use 3 anastomosis reconstruction after PD with the same 
jejunal handle. Currently, there is a growing pancreatic reconstruction trend by 
pancreaticogastrostomy technique. However, the results of prospective randomized 
studies as well as meta-analyzes conclude that both techniques are safe and that the rate 
of fistula is similar in both cases. Despite this, with the pancreaticogastrostomy 
technique, there is a higher rate of postoperative bleeding and a higher rate of DGE [11-
12]. There is another factor in the choice of the technique, which is the consistency of 
pancreatic remnant. A soft pancreas will always be an added risk for the onset of the 
fistula. In these cases, many surgeons choose a PJ according Peng’s technique [13]. 
 
Although perioperative morbidity and mortality associated with a PD has improved 
significantly over the years, even in high-volume centers, the incidence of POPF is still 
in the range of 9.9–28.5% [14–16]. Therefore, an ideal pancreatic reconstruction 
technique or perioperative treatment, which prevents POPF, is still unavailable. 
 
The use of sealants has been one of the approaches performed in order to try to reduce 
the POPF (Table 1). Some non-controlled or non-randomized studies have shown that 
the use of fibrin glue based sealants in combinations with patches of felts may lead to a 
POPF grade B/C of 0-10% [18-21]. Only 2 randomized control trials have been 
performed with fibrin glue, with opposite results in terms of significant reduction of 
POPF [17, 22]. 
 
 
 

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Table 1. Studies with the use of sealants in PD and rates of pancreatic fistula. 
 
Author 
Year 
Study type 
Patients / 
Surgery 
N 
CONTROL 
TREATMENT 
P 
Technique 
POPF 
Technique 
POPF 
Lillemoe 
[17] 
2004 
RCT 
High risk 
(soft 
panc/small 
duct) 
125 
Ø (66) 
30%1 
Fibrin glue: 
Hemaseel (59) 
26%1 
NS 
Ochiai 
[18] 
2010 
Retrospective 
- 
54 
Ø (36) 
38.9%2 
PGA felt + 
Fibirnogen/ 
thrombin 
patch (18) 
5.6%2 
0.016 
Pozzo 
[19] 
2010 
Retrospective 
non-
controlled 
- 
27 
- 
- 
Tachosil 
0%2 
- 
Mita [20] 
2011 
Retrospective 
non-
controlled 
Duct-to-
mucosa 
40 
- 
- 
Tachocomb 
7,5%2 
- 
Satoi [21] 
2011 
Prospective 
(historical 
control) 
- 
128 
Ø (78) 
14%2 
PGA felt + 
Fibrin glue: 
Bolheal (50) 
10%2 
NS 
Martin 
[22] 
2013 
RCT 
- 
57 
Ø (32) 
43.8%1 
Fibrin glue: 
TISSEEL (59) 
40%1 
NS 
1- Fistula grade A, B & C; 2- Fistula grade B & C 
 
 
 
Hemopatch is an NHS-PEG patch that consists of a soft, thin, pliable, flexible pad of 
collagen derived from bovine dermis, coated with NHS-PEG (pentaerythritol 
polyethylene glycol ether tetra-succinimidyl glutarate). It is intended as a surgical 
sealant for procedures in which control of leakage by conventional surgical techniques 
is either ineffective or impractical [23], making it a plausible option to use during PD 
surgical technique in order to decrease POPF. 
 
Preliminary experience with Hemopatch: case serie 
 
In our center we have been using this NHS-PEG patch envolving the 
pancreaticojejunostomy as a new way to decrease POPF after PD. The results of more 
than a year of experience have been submitted as an abstract communication to the E-
AHPBA congress in Mainz, Germany (May, 2017), and are the following: 
 
Sealing with NHS-PEG patch to prevent postoperative pancreatic fistula after 
pancreaticojejunostomy 
 
Mario Serradilla, Ana Palomares, Sandra Paterna, José Manuel Ramia, Alejandro 
Serrablo 
 
Background. Postoperative pancreatic fistula (POPF) is a common and most severe 
complication following pancreatoduodenectomy (PD) (9.8% to 34.2%). POPF not only 
prolongs hospital stay and increases healthcare costs, but also plays a central role in the 
development of life-threatening events such as intra-abdominal abscess and 

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postoperative hemorrhage. We present a new way to decrease POPF after PD using a 
NHS-PEG patch envolving duct-to-mucosa (DTM) pancreaticojejunostomy. 
Materials and methods. 26 consecutive PD were performed  from July 2015 to October 
2016, using the same technique, 13 of them sealing with NHS-PEG patch after DTM. 
Both groups were statistically homogeneous. Demographic data were collected (age, 
gender, diagnosis, date of intervention), and rates of postoperative complications 
(pancreatic fistula, biliary fistula, delayed gastric emptying –DGE-, hemorrhage, exitus, 
Clavien-Dindo classification, readmission and mean stay). 
Results.  Postoperative complication rates were (with NHS-PEG patch/without NHS-
PEG patch): pancreatic fistula (A: 7.7%/7.7%; B: 0%/7.7%; C: 0%/15.5%); biliary 
fistula: 7.7%/15.4%; DGE: 7.7%/7.7%; hemorrhage: 7.7%/15.5%; exitus: 0%/7.7%; 
readmission: 7.7%/46%; mean stay: 21.3/26.1 days; other complications: 61.5%/46.2%.  
Discussion. Sealing with NHS-PEG patch to prevent postoperative pancreatic fistula 
after DTM pancreaticojejunostomy can offer a new possibility to decrease POPF, with 
less fistula rate B and C, less hospital stay an less healthcare costs. Randomized 
controlled trials with larger number of patients should be performed to support this 
theory. 
 
Therefore, we have design the following randomized controlled trial in order to validate 
our positive experience with Hemopatch in PD. 
 
 
5. HYPOTHESIS / OBJECTIVE. 
 
This unicentric, double-blind, randomized study investigates the efficacy and tolerance 
of Hemopatch in the prevention of POPF type B and C after a PD. The goal for 
Hemopatch is to reduce the risk of POPF type B and C from 30% to 15%. 
 
 
6. STUDY DESIGN. 
 
6.1. Type of study. 
 
Unicentric, randomized, controlled, double-blind, prospective study with a parallel 
design of two groups. After giving informed consent, patients will not know to which 
group they have been assigned (reinforcement with Hemopatch or not). After the last 
follow-up visit on postoperative day 30, the patients can receive this information if they 
wish. 
This study is also blind on the part of the observer; the final result will be determined by 
an independent observer, making this a double-blind study. 
 
6.2. Primary objective and secondary objectives. 
 
Primary endpoint: POPF type B and C, according to the definition of the ISGPF 
(Bassi, Surgery 2005), that is, the secretion of pancreatic fluid externalized through a 
drain or removed during a reoperation, independently of the color and / or appearance 
on day 3 or later, whose amylase is 3 times the values of serum amylase or collections 
(infected or not) detected by fistulography or other imaging techniques (computed 
tomography, ultrasound, magnetic resonance imaging). See attached table. 
 

Study protocol - Use of Hemopatch as a sealant in pancreaticojejunostomy after PD. 
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Grade 
A 
B 
C 
Clinical conditions 
Well 
Often well 
Ill appearing / bad 
Specific treatment* 
No 
Yes / no 
Yes 
US / CT (if 
obtained) 
Negative 
Negative / positive 
Positive 
Persistent drainage 
(after 3 weeks)** 
No 
Usually yes 
Yes 
Reoperation 
No 
No 
Yes 
Death related to 
POPF 
No 
No 
Possibly yes 
Signs of infections 
No 
Yes 
Yes 
Sepsis 
No 
No 
Yes 
Readmission 
No 
Yes / no 
Yes / no 
US, Ultrasonography; CT, computed tomographic scan; POPF, postoperative pancreatic fistula. 
*Partial (peripheral) or total parenteral nutrition, antibiotics, enteral nutrition, somatostatin 
analogue and/or minimal invasive drainage. 
**With or without a drain in situ 
 
              
 
Secondary endpoints: 
 
1) Duration of postoperative hospital stay. 
2) Duration of stay in intensive care unit. 
3) Measurement of drainage debit. 
4) Reinterventions including interventional radiology 
5) Infection of the surgical site and / or dehiscence of the wound; complications in the 
deep organ space up to 30 days postoperatively. 
6) Delayed gastric emptying. 
7) Biliary fistula. 
8) Postoperative hemorrhage. 
9) Death, regardless of the cause. 
 
 
6.3. Duration of the study. 
 
The study will begin on February 1, 2018. Patients will be recruited at Miguel Servet 
University Hospital from January 1, 2018 to July 31, 2019. All patients randomly 
assigned will be followed for 30 days after surgery, or during the total stay in case it is 
longer than 30 days. They will also be evaluated in external consultations in the 
postoperative period for 3 months. A period of 4-6 months is considered to evaluate the 
data and the study will entail 2 years in total. 
 
 
7. PATIENTS. 
 
7.1. Criteria. 
 
Despite improvements in morbidity after pancreatic resection, POPF after PD remains 
problematic. The incidence varies markedly in the literature, ranging from 0% to 64%, 
and 35% are clinically relevant. This great variability is attributed in part to the 

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indication and extension of the resection, as well as to the comorbidities of the patient. 
Other factors, such as age, male sex, obesity, prolonged operation time and a soft 
pancreas, as well as multivisceral resections increase the risk of fistula. The sequelae of 
pancreatic fistula after PD cover a broad spectrum. These patients often require visits to 
the emergency department, hospital readmissions, percutaneous drainage guided by 
interventional radiology, prolonged parenteral antibiotic therapy, radiological 
surveillance and numerous postoperative visits. The complications derived from the 
fistula double the cost of hospital treatment and dramatically increase the use of health 
resources. 
 
7.2. Recruitment. 
 
All patients undergoing PD, either by laparotomy or laparoscopy, are potential 
participants. Their diagnoses include chronic pancreatitis, benign (for example, 
cystadenoma) or malignant tumors (adenocarcinoma, NET, metastasis, etc.). They will 
be invited to participate in the study and will be informed of the possible advantages 
and disadvantages. The randomization process will begin for any patient who agrees to 
participate after informed consent. 
 
7.3. Inclusion and exclusion criteria. 
 
Inclusion criteria: patients submitted to PD by laparoscopic or open approach for 
benign / malignant tumor or chronic pancreatitis; ASA < 4; men and women ≥ 18 and ≤ 
80 years of age. 
 
Exclusion criteria: patients under 18 and over 80 years old; ASA score ≥ 4; subjected 
to multivisceral resections different from PD; patients with acute necrotizing 
pancreatitis; immunosuppressed patients; patients who have not signed the informed 
consent; patient with a contraindication to PD. 
 
7.4. Intervention techniques and materials. 
 
The indications for performing a PD are multiple. The type of reconstruction to be 
performed will depend basically on the characteristics of the pancreatic remnant. 
However, in our center, the usual reconstruction technique is the duct-to-mucosa type 
pancreaticojejunostomy. 
 
Depending on the randomization, patients will be operated as follows: 
 
1) Basic treatment: standard duct-to-mucosa pancreaticojejunostomy. 
 
2) Basic treatment plus Hemopatch: standard pancreaticojejunostomy + reinforcement 
with 2 Hemopatch of 90 x 45 mm, one on each side (lower and upper) as a "scarf". 
 
In both groups, passive external drainage is mandatory for a period of 7 days with 
drainage placed next to the anastomosis but not in contact with it. The drain can be a 
Penrose drain, a Jackson-Pratt drain or Blake without active suction. Suction drains are 
not allowed. 
 
 

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Adjuvant procedures 
 
Wrapping, sealing with fibrin or serous patch with another adjacent organ are not 
acceptable. No resection of adjacent hollow organ is allowed (excepting those included 
in the standard DPC). 
 
Materials 
 
Hemopatch is a hemostatic-sealant made of collagen that resorbs in 6-8 weeks. The 
active side is covered with a polyethylene glycol film for better adhesion. 
 
Hemopatch is a medical product with CE certificate (Annex IV - excluding section 4 of 
Council Directive 93/42 / EEC on medical devices) used for hemostasis. It is not 
designed for use with heavy or pulsatile bleeding or with acute infections. It also has 
indication of sealant from March 2016. Hemopatch should not be used intravascularly. 
It also can not be used for patients who are allergic to any of the materials listed by the 
manufacturer. The only known side effect is the rare case when Hemopatch can not 
achieve the desired hemostasis. With documentation of the patient's clinical course, 
regular blood tests and imaging tests when necessary, any undesirable effects derived 
from the use of Hemopatch must be diagnosed in a timely manner and appropriate 
measures will be taken, the coordinator will be immediately informed, the person in 
charge of the control of the test and, likewise, an immediate communication of the 
adverse effect to the manufacturer will be sent. 
 
 
7.5. Postoperative period. 
 
In the postoperative period, the parameters of inflammation, body temperature, visual 
analog pain scale (VAS), drainage debit and its amylase / lipase content will be 
documented. To facilitate the healing process, drainage should be left in place for at 
least 7 days. In the absence of evidence of fistula, the drainage may be withdrawn. If the 
7th postoperative day there is evidence of pancreatic fistula according to the ISGPF 
criteria, the drainage will be maintained until the resolution of the same. 
All patients are advised to follow the instructions given at discharge. If there is any 
reason for the alarm (pain, fever, tachycardia) the patient should go to the hospital 
where he was treated at any time. A final visit will be scheduled on postoperative day 
30 to evaluate any collection of intra-abdominal fluids through the clinical examination 
and the performance of an ultrasound or CT scan (as is done routinely). 
 
 
 
7.6. Complications / failure of the intervention. 
 
POPF are defined according to the definition published in 2005 by the International 
Study Group on Pancreatic Fistula (ISGPF), which is based on the concentration of 
amylase in the drainage fluid. A POPF is defined when the concentration of amylase in 
the drainage fluid is three or more times greater than in serum from the third 
postoperative day. 
 

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Pancreatic fistulas are classified in 3 grades, from A to C: 
 
- 
Grade A: clinically asymptomatic patient, persistent fistula, absence of 
intra-abdominal 
fluid 
collection 
in 
imaging 
test. 
No 
therapeutic 
consequence; the hospitalization is not prolonged. 
 
- 
Grade B: symptomatic patient, requires diagnostic evaluation and 
therapeutic management. Clinically stable patient, may complain of 
abdominal pain, fever, nausea and intolerance to oral intake. Normally there 
is a collection of at least 3 x 3 cm in image tests. Therapeutic consequences: 
you must start antibiotic treatment and absolute diet. Invasive intervention 
(percutaneous drainage) may be necessary; hospitalization usually lasts. 
 
- 
Grade C: clinically unstable patient (sepsis). Therapeutic consequences: it 
requires intensive care, percutaneous drainage or reoperation if the drainage 
has been removed or is not properly positioned. Hemorrhage is frequent; 
high expected mortality. 
 
The objective of this study is to evaluate the rate of type B and C fistulas after 
pancreatic resection with and without Hemopatch. 
 
 
7.7. Termination conditions / Adverse events / Suspected unexpected serious 
adverse reaction. 
 
Criteria for withdrawing a patient from the study: 
 
- 
Patient's desire to be removed from the study. 
- 
Intervention not performed (due to unresectability). 
- 
The investigator suspects a serious threat to the patient's well-being. Adverse 
events (any sign or symptom that affects the patient's well-being) and serious 
adverse events (life-threatening, prolongs hospital stay, results in persistent 
disability or leads to death during the observation period), as 
cardiopulmonary problems, in the gastrointestinal tract, anaphylactic shock 
or embolism will be recorded through daily postoperative visits until 
discharge and during the final visit on the 30th postoperative day. All 
adverse effects of clinical relevance and all serious adverse effects will be 
recorded in the case report form along with the degree of the complication 
(according to the Clavien-Dindo classification). The principal investigator 
must be informed within 24 hours about the serious adverse effects that 
occur during the hospital stay. The presence of a causal relationship between 
adverse affect or serious adverse effect and the intervention of the trial will 
be judged by the investigator. Serious adverse effects will be reported 
immediately (ie, within 5 days after recognition) by all investigators to the 
coordinating investigator. The coordinating researcher must inform the 
responsible ethics committee and the research sponsor. A list of all serious 
adverse effects must be compiled. 
 
 
 

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8. DATA. 
 
8.1. Calculation of the sample size. 
 
The sample size was calculated by comparing two proportions, with a level of statistical 
significance of 5% (alpha) and a statistical power of 80% (1-beta), and taking into 
account the preliminary data obtained regarding the rate of POPF in the two groups: 
23% for the control group, and 7% for the Hemopatch group. 
  
With these assumptions, it will take 57 patients to detect, with an 80% probability and a 
level of significance of 5%, a decrease of the POPF rate of 23% in the control group to 
7% in the experimental group (Hemopatch). Considering an expected proportion of 
losses of 10%, the sample size will be 64 patients. 
 
8.2. Randomization and groups. 
 
All patient data are anonymous. Each patient who meets the selection criteria and has 
signed the informed consent will be entered into a database and identified by a number 
(from 1 to 64). The list of patient identification numbers will be in the hands of the 
principal investigator. After carrying out the surgery, the patient number is entered into 
an online computerized randomization tool ("Randomizer for clinical trials"), 
https://www.meduniwien.ac.at/randomizer. It is a tool of the University of Vienna in 
Austria, where the study it is registered, which allows, once the patient number is 
entered, the randomization of the same, obtaining one of the two methods to compare, 
as explained in Section 7.4. (32 patients in each study group): 
 
- 
Basic 
treatment: 
duct-to-mucosa 
pancreaticojejunostomy 
WITHOUT 
Hemopatch reinforcement. 
- 
The same, but reinforced WITH Hemopatch. 
 
Once the treatment to be performed is obtained, surgery will be carried out according to 
the treatment obtained in the randomization. 
 
8.3. Efficacy assessments (that is, data that must be collected). 
 
- 
Daily drainage debit. 
- 
Concentration of amylase and lipase from the drainage fluid (days 3, 5 and 7 
postoperatively) and every 2 days in case of permanent fistula. 
- 
Number of postoperative days with drainage (minimum 7 days). If the 
amylase / lipase content of the drainage on the 7th postoperative day is 
within normal limits, it may be withdrawn. 
- 
Body temperature, VAS pain score, leukocyte count and CRP. 
- 
Duration of the stay in the ICU. 
- 
Duration of the total hospital stay. 
- 
Reinterventions, including percutaneous drainage of collections. 
- 
Re-entry. 
- 
Degree of complications according to the Clavien-Dindo classification, 
including both complications derived from surgery (delay of gastric 
emptying, bleeding, biliary fistula, wound infection, intra-abdominal 

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abscess, etc.) and general (atelectasis, pneumonia, urine infection, 
thromboembolism, etc.) 
 
8.4. Patient data sheet. 
 
It contains patient information including personal history (ie, smoking, diabetes, BMI), 
preoperative and postoperative data, intraoperative incidents, special treatment details, 
complications and adverse events such as new onset diabetes, pneumonia or heart 
problems. 
 
All the data are collected in a central database. 
 
All study personnel must sign a confidentiality agreement that covers all aspects of the 
study and its data. The study directors will take particular responsibility for the security 
of the data, the documents of origin and the information about the patients. 
 
The coordinator of the main study is also responsible for continuing education in Good 
Clinical Practices (GCP) in accordance with the Declaration of Helsinki. 
 
8.5. Statistical methods and data analysis. 
 
For the evaluation of the primary objective, patients will be dichotomized by the 
presence or absence of the sealant reinforcement. In addition, patients will be classified 
by the type of pancreatic fistula defined according to the ISGPF. Next, a contingency 
table will be created to calculate the positive predictive value, specificity, sensitivity 
and the c-index. The association between sealant reinforcement and pancreatic fistula 
rate will be expressed as an odds ratio calculated by logistic regression models with the 
appropriate covariates. The strength of association between the categorical variables 
will be tested with a chi-square test with the Yate correction. 
Secondary objectives will be analyzed descriptively by tabulation. Chi-square tests will 
be used to test associations between categorical variables, while Student's t-test or 
Mann-Whitney U-test will be used to compare normal or non-normal data, respectively. 
Time-dependent variables will be tested by Kaplan-Meier analysis and Cox regression. 
The statistical analysis will be carried out with R. 
 
 
 
 

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9. PATIENT SAFETY. 
 
A monitoring team will receive all patient data electronically including expected and 
unexpected events and side effects for all patients in the study. All patient data are 
analyzed to detect any unusual pattern. There will be permanent contact with the main 
coordinator of the study and will meet face to face three times a year to evaluate the 
course of the study based on the data collected. 
 
 
10. IMPACT ON CLINICAL PRACTICE. 
 
Hemopatch is expected to reduce the risk of postoperative type B and C pancreatic 
fistula from 30% to 15%, so that the number of patients currently requiring readmission 
with possible surgeries and interventional radiological procedures is halved. This 
implies not only clinical but also economic advantages, since a pancreatic fistula can 
double the cost of hospital treatment. 
 
 
11. ETHICS AND LEGAL REQUIREMENTS. 
 
This study is carried out in full compliance with the principles of the "Declaration of 
Helsinki" (amended at the 56th General Assembly of the AMM, Tokyo, Japan, 2008). 
Following good clinical practices should guarantee the scientific conduct of the clinical 
trial and the credibility of the results. This study is approved by the Clinical Research 
Ethics Committee of Aragon (CEICA). 
 
 
12. REGISTRATION. 
 
Once approved, this study will be registered in the EU Clinical Trials Register or 
ClinicalTrials.gov. 
 
 
13. PUBLICATION. 
 
Once the study is completed and the statistical study has been carried out, a publication 
will be made and sent to a high-impact surgical journal in English. 
 
 

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