Randomized Control Trial Comparing Somatostatin Analogues With Perioperative Antibiotics Versus Prolonged Antibiotics
Phase: PHASE2
Conditions: Pancreatic Diseases
Sponsor: Mayo Clinic

 
 
 
 
 
18-010128 
 
 
Randomized Control Trial Comparing Somatostatin Analogues 
with Perioperative Antibiotics versus Prolonged Antibiotics 
 
 
NCT04329039 
 
 
Document Date: 11/14/2022 

Protocol Version Date: V5 11 14 2022 
 
 
 
 
B. BACKGROUND 
 
In 2017, Shubert et al3 published our institutional results on comparison of historic controls with results 
following implementation of a prospective, surgeon-driven, risk based pathway following 
pancreaticoduodenectomy.  The results of the study showed that after implementation of this pathway 
there were significant differences observed in ICU length of stay as well as hospital length of stay.  
Among patients who developed postoperative pancreatic fistula, the pathway implementation was 
associated with decreased odds of having a higher grade of POPF.  
 
This table highlights the bundled approach involved in the pathway: 
 
 
 
 
To date, there has been an abundance of literature on the impact of somatostatin analogues on the 
incidence, morbidity and mortality associated with pancreatic fistula, leak and abscesses.  Meta analyses 
and Cochrane reviews have suggested that these analogues although, reduce perioperative complications; 
they do not reduce perioperative mortality 4,7,8.   

Protocol Version Date: V5 11 14 2022 
 
There is no data in the literature highlighting which components within the bundle independently 
contribute to outcomes such as differences in ICU length of stay, hospital stay as well as decreased 
severity of pancreatic fistula when they do occur.   There is minimal data in the literature on the impact of 
perioperative antibiotics on incidence of pancreatic fistula and/or if the severity of pancreatic fistula is 
reduced with the use of antibiotics. 
 
 
Therefore, we propose the first randomized, controlled trial in which there is a comparison of octreotide 
with routine prophylactic antibiotics (intraoperative dose plus 24 hours of postoperative antibiotics) 
compared to  octreotide with prolonged antibiotics (5days) in patients who are intermediate to high risk 
for fistula based on our pancreatic fistula score calculator. 
 
C. PRELIMINARY OBSERVATIONS:   
 
Preliminary observations based on the implementation of the surgeon driven pathway as mentioned above 
demonstrated statistically and clinically relevant improvement in outcomes, decreased costs and decrease 
in overall resource utilization on multivariate analyses. 
 
Between 2014 and 2017 multiple institutional studies have been conducted attempting to show that 
somatostatin analogues lead to a reduction in pancreatic fistulae.  Some authors have shown that this 
reduction may not exist but that they may have a role in reduction of postoperative complications such as 
bleeding.   
 
Given the incidence of pancreatic fistulae and its associated morbidity when it does occur, it is crucial to 
have a prospective randomized, controlled trial comparing these analogues with the use of antibiotics to 
understand which agent, if any, contributes to the reduction of this grave complication. 
 
It is imperative to identify the impact of the individual components of this pathway to help delineate the 
agents that contribute to the differences in outcomes and measures. Therefore, we propose this  

Protocol Version Date: V5 11 14 2022 
 
randomized trial to assess the impact of standard dosing of perioperative antibiotics with extended 
duration of antibiotics as described in the bundled pathway approach. 
 
 
D. METHODS AND DESIGN 
 
 
We propose to begin this prospective, randomized study to assess the benefit of standard perioperative 
antibiotics (3 doses) versus our current protocol of prolonged antibiotics (minimum 5 days). Both groups 
will receive somatostatin analogues per the existing risk-based pathway.    
  
Patients with planned pancreatoduodenectomy will be eligible for inclusion. Per our current standard 
practice, a pancreatic risk score will be assessed using established factors of gland texture, pathology, 
pancreatic duct diameter (mm) and intraoperative blood loss (ml). This data will be entered into the 
patient’s record  
As part of our current practice, intermediate or high risk patients receive the following treatment 
intervention: 
IV Antibiotic 
# of Postop Doses for 24 hour duration 
(Group 1) 
# of Postop Doses for 5 day duration 
(Group 2) 
Ceftriaxone 
1 
5 
Metronidazole 
2 
15 
Piperacillin/Tazobactam (Zosyn) 
3 
20 
Levofloxacin 
1 
5 
  
  
 
 
 
 
PATIENTS AND METHODS 
 
 
Study treatment:  
 
 
After intraoperative fistula risk score determination, patients will be randomly assigned to one of two 
treatment groups:  
 
Group 1 (200 people): therapy with octreotide (150mcg subcutaneous q8h for 7day) and routine 
perioperative dosing of antibiotics (intraoperative dose plus 24 hours of antibiotics postoperatively) 
 

Protocol Version Date: V5 11 14 2022 
 
Group 2 (200 people): therapy with octreotide (150mcg subcutaneous q8h for 7day) with one 
intraoperative dose of antibiotics plus extended duration (5 days).  
If surgery is on Friday study coordinator will call OR to collect risk score and randomize patient.  
 
After randomization via Redcap, an email will be sent out to Pharmacist, surgical team, and staff. 
 
Inclusion: 
 
1. Patients undergoing a Whipple procedure for various diagnoses (neuroendocrine tumors, 
adenocarcinoma, benign cystic neoplasms, duodenal and ampullary malignancies, etc) who are deemed 
intermediate-high risk as per our institutional protocol as shown above. 
 
2. Patients > 18 years of age with the above mentioned diagnoses 
 
Exclusion: 
 
1. Negligible and low risk patients 
2. All patients undergoing arterial resection. 
3. Age <18 years 
4. Currently pregnant 
 
Outcomes:  
 
The primary outcome will be length of hospital stay 
 
The secondary outcome will be the incidence of pancreatic fistula after pancreatic surgery (defined as 
postoperative drain output of fluid with amylase content more than 3 times the maximum normal serum 
value and exceeding 10 mL/24 h for more than 3 d).  This will be diagnosed based on clinical and 
biochemical parameters.  When clinical suspicion exist, cross sectional imaging in the form of CT 
abdomen/pelvis with intravenous contrast (when applicable) will be utilized to demonstrate the presence 
or absence of a drainable collection. 
 
The incidence of pancreatic fistula will be compared amongst the two groups to identify the impact of 
antibiotics on incidence of pancreatic fistula.  By comparing these two groups, we will be able to identify 
whether an extended course of antibiotics contribute to reduction in pancreatic fistula in intermediate and 
high risk patients undergoing pancreatic surgery.  Further, this can serve as a basis for future studies with 
respect to testing other analogues and their contribution to reduction of pancreatic fistula. 
 
SAMPLE SIZE and POWER: 
 
This study has been powered for the primary outcome; comparison of the length of hospital stay between 
the study arms of octreotide plus standard of care antibiotics versus octreotide plus prolonged antibiotics.  
The sample size assumes a two sample test comparison of independent groups, a two-sided test at α=0.05.  
Using preliminary estimates reported in a paper by Shubert, mean=12.0 days with a standard deviation of 
10.0.  With 200 patients in each of the two study arms there will be 80% power to detect a difference in 
LOS of greater than or equal to 2.8 days, and effect size of 0.28.  We will increase the sample size by 
10% to allow for dropouts, bring the total enrollment to the study to 440 patients. 
 
 
 
#patients/arm 
Total 
#patients 
Rate in 
“other” arm 
Rate 
reduction 

Protocol Version Date: V5 11 14 2022 
 
50 
100 
9.5% 
22.5% 
100 
200 
15.3% 
16.7% 
150 
300 
18.0% 
14.0% 
200 
400 
19.8% 
12.2% 
 
 
We are accounting for patients who may refuse to participate after randomization, patients who undergo 
laparoscopy and are found to have metastatic disease or those who are found to be inoperable at the time 
of laparotomy.  Therefore, to be included in the study, patients must be randomized, deemed fit to tolerate 
a somatostatin analogue, as well as undergo pancreatic resection, thereby having the appropriate risk 
factors should they develop a pancreatic fistula. 
 
RANDOMIZATION: 
 
Patient randomization will be conveyed using REDCAP system.  The randomization will be stratified on 
age (dichotomized as <60 versus ≥60), risk category (High versus Intermediate), and surgeon The 
randomization will be done using permuted blocks of size two and four. 
 
 
E.  DATA ANALYSIS: 
 
The primary outcome of this study is length of stay (LOS).  This outcome will be compared between 
treatment arms using a two-sample Test.  Linear regression in multiple variable models to assess the 
association of treatment arm with length of stay including relevant covariates in the model such as gender, 
age, Open versus minimally invasive approach, etc.   The secondary outcome of interest is the fistula rate 
within 90 days.  Assuming all patients have complete follow-up, univariate and multiple variable logistic 
regression will be used to assess the association of duration of antibiotic therapy and the odds of fistula.  
We assume that the number of fistulas identified will be approximately 60 in the enrolled patients.  With 
this number of events a multiple variable model may include up to six variables.  If there is censoring of 
follow-up in patients, death or lost to follow-up the survival methods will be used in analysis, Kaplan 
Meier estimates at 30 days and Cox models.  An alpha-level of 0.05 will be considered for statistical 
significance. 
 
F. DSMB approval 
 
The trial will require DSMB approval due to the large study population as well as randomized nature of 
the study. 
 
Given the duration of antibiotic use will be less in Group A compared to Group B this may account for 
increased incidence of pancreatic fistula and infection due to the shorter course .  
 
The Mayo Clinic Department of Surgery Data Safety and Monitoring Board (DSMB) will evaluate and 
adjudicate Serious Adverse Events and Specified Adverse Events as reported by the Investigators for 
relatedness to device and procedure. The DSMB will also be given the listings of all other adverse events 
(not Serious and not Specified) for review and to determine if additional adjudication is required. The 
DSMB will be given any information requested to adjudicate adverse events. The DSMB will meet 
yearly, or more or less often as needed. 
 
All adverse events grade III or higher will be recorded and monitored.  Serious adverse events reported to 
DSMB will include: 90-day postoperative mortality, any grade III (requiring surgical, endoscopic, or 
radiological intervention) or grade IV morbidity (life-threatening complications requiring ICU 

Protocol Version Date: V5 11 14 2022 
 
management of organ dysfunction), antibiotic-related complications (severe allergy, C. Difficile), 
pancreatic fistula, sepsis. 
 
 
The stopping rules specified below are based on the knowledge available at the study 
development.  We note that the adverse event stopping rule may be adjusted at any time during the 
conduct of the trial and in consideration of newly acquired information regarding the adverse event 
profile of the treatments under investigation.  The study team may choose to suspend accrual because 
of unexpected adverse event profiles that have not crossed the pre-specified rules below 
 
Accrual will be temporarily suspended to this study if at any time we observe events considered at 
least possibly related to study treatment (i.e. an adverse event with attribution specified as 
“possible”, “probable” or “definite”) that satisfy one of the following: 
 
• 
If  >10% experience a 90 day mortality 
• 
If >45% of all patients experience a Clavien Dindo grade 3 or higher adverse event 
We note that we will re-review all grade 4 and 5 adverse events deemed “unrelated” or unlikely to be 
related” to verify their contribution and monitor for previously unrecognized treatment-related 
adverse events.  
 
 

Protocol Version Date: V5 11 14 2022 
 
G. LITERATURE CITED 
 
1)Butturini G1, Daskalaki D, Molinari E, Scopelliti F, Casarotto A, Bassi C. Pancreatic fistula: definition 
and current problems.  J Hepatobiliary Pancreat Surg. 2008;15(3):247-51. doi: 10.1007/s00534-007-1301-
y. Epub 2008 Jun 6 
 
2)Pratt WB, Maithel SK, Vanounou T, Huang ZS, Callery MP, Vollmer CM Jr. Clinical 
and economic validation of the International Study Group of Pancreatic Fistula 
(ISGPF) classification scheme. Ann Surg 2007; 245:443-51. 
 
3) Shubert C, Kendrick M, Habermann E, Glasgow A, Borah B, MOriary P et al.  Implementation of a 
prospective surgeon driven, risk based pathway for pancreaticoduodenectomy results in improved clinical 
outcomes and first year cost savings of $1million. Surgery 2017 
 
4) Miller BC1, Christein JD, Behrman SW, Drebin JA, Pratt WB, Callery MP, Vollmer CM Jr. 
A multi-institutional external validation of the fistula risk score for pancreatoduodenectomy. J 
Gastrointest Surg. 2014 Jan;18(1):172-79; discussion 179-80. doi: 10.1007/s11605-013-2337-8. Epub 
2013 Sep 4. 
 
5)Grendar J1, Jutric Z1, Leal JN2, Ball CG3, Bertens K4, Dixon E3, Hammill CW1, Kastenberg  Z2, 
Newell PH1, Rocha F4, Visser B2, Wolf RF1, Hansen PD5.  Validation of Fistula Risk Score      
calculator in diverse North American HPB practices HPB (Oxford). 2017 Jun;19(6):508-514. doi:  
10.1016/j.hpb.2017.01.021. Epub 2017 Feb 21. 
 
6)Allen PJ, Gönen M, Brennan MF, Bucknor AA, Robinson LM, Pappas MM, Carlucci KE, D'Angelica  
MI, DeMatteo RP, Kingham TP, Fong Y, Jarnagin WR.Pasireotide for postoperative pancreatic fistula. N 
Engl J Med. 2014 May 22;370(21):2014-22. doi: 10.1056/NEJMoa1313688. 
 
7)Ma LW1, Dominguez-Rosado I, Gennarelli RL, Bach PB, Gonen M, D'Angelica MI, DeMatteo RP, 
Kingham TP, Brennan MF, Jarnagin WR, Allen PJ. The Cost of Postoperative Pancreatic Fistula Versus 
the Cost of Pasireotide: Results from a Prospective Randomized Trial. Ann Surg. 2017 Jan; 265(1):11-16. 
doi: 10.1097/SLA. 
 
8) Goyert N1, Eeson G, Kagedan DJ, Behman R, Lemke M, Hallet J, Mittmann N, Law C, Karanicolas 
PJ, Coburn NG.  Pasireotide for the Prevention of Pancreatic Fistula Following 
Pancreaticoduodenectomy: A Cost-effectiveness Analysis.  Ann Surg. 2017 Jan;265(1):2-10. doi: 
10.1097/SLA 
 
9)Denbo JW1, Slack RS2, Bruno M1, Cloyd JM1, Prakash L1, Fleming JB1, Kim MP1, Aloia TA1,  Vauthey 
JN1, Lee JE1, Katz MH3.  Selective Perioperative Administration of Pasireotide is More   Cost-Effective 
Than Routine Administration for Pancreatic Fistula Prophylaxis.  J Gastrointest Surg. 2017 Apr; 
21(4):636-646. doi: 10.1007/s11605-016-3340-7. Epub 2017 Jan 3. 
 
 
10) Koti RS1, Gurusamy KS, Fusai G, Davidson BR.  Meta-analysis of randomized controlled trials  on 
the effectiveness of somatostatin analogues for pancreatic surgery: a Cochrane review. HPB  (Oxford). 
2010 Apr;12(3):155-65. 
 
11) Jin K, Zhou H, Zhang J, Wang W, Sun Y, Ruan C, Hu Z, Wang Y.  Systematic review and meta- 
analysis of somatostatin analogues in the prevention of postoperative complication after  
 pancreaticoduodenectomy.  Dig Surg. 2015;32(3):196-207. 

Protocol Version Date: V5 11 14 2022 
 
 
12) Ismael Dominguez-Rosado, MD, Ryan C Fields, MD, FACS, Cheryl A Woolsey, PA-C, 
       Gregory Williams, MA, Timothy A Horwedel, PharmD, J Bart Rose, MD, Chet W Hammill, MD 
      Maria B Doyle, MD, MBA, William C Chapman, MD, FACS, Steven M Strasberg, MD, FACS, 
William G Hawkins, MD, FACS, Dominic E Sanford, MD, MPHS.Prospective Evaluation of      
Pasireotide in patients undergoing pancreaticoduodenectomy: The Wash U Experience, J Am Coll  
Surg 2017(in press) 
 
 
H. BUDGET JUSTIFICATION 
 
This study will be supported by the Department of Surgery Executive committee.  $10350.00 will be 
provided for statistical support.  Study coordinator support will be provided by the DOS Clinical 
Research Office.