Standard Versus Prolonged Antibiotic Prophylaxis After Pancreatoduodenectomy (SPARROW)

Pancreatic Cancer Clinical Trial

— SPARROW  

Official title:

Standard Versus Pre-emptive Antibiotic Treatment to Reduce the Rate of Infectious Outcomes After Whipple's Procedure (SPARROW): a Multicenter, Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05784311
• Other study ID #: NL82304.058.22
• Status: Recruiting
• Phase: Phase 4
• Start date: March 6, 2023
• Est. completion date: January 2026

Study information

• Verified date: October 2023
• Source: Leiden University Medical Center
• Contact: Daphne HM Droogh, MD
• Phone: 071 5261334
• Email: d.h.m.droogh[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this multicenter randomized controlled trial is to evaluate the additional value of pre-emptive antibiotic treatment on clinically relevant organ/space surgical site infections (OSIs) in patients undergoing pancreatoduodenectomy with a high risk for contaminated bile. The main objectives it aims to answer are:

• To evaluate the effect of pre-emptive antibiotic prophylaxis on clinically relevant OSIs in patients undergoing pancreatoduodenectomy with a high risk for contaminated bile

• To evaluate the effect of pre-emptive antibiotic prophylaxis on other postoperative outcomes (e.g. OSIs, superficial SSIs, POPF, PPH, major morbidity, ICU admission, readmission, length of hospital stay, and mortality).

• To evaluate concordance between perioperatively obtained bile cultures and postoperative cultures from infectious sites, and to evaluate antibiotic sensitivity patterns of the cultured microorganisms.

Participants will be randomized with a 1:1 allocation before surgery into the intervention or control group:

• Patients in the intervention group will receive perioperative prophylaxis (similar to the control group) followed by five days of 1500mg IV cefuroxime and 500mg IV metronidazole thrice daily.

• Patients in the control group will only receive perioperative prophylaxis (a single dose of 5-7mg/kg gentamicin followed by 2gr IV cefazolin and 500mg IV metronidazole every 4h of surgery), which will be discontinued after surgery.

Description:

Rationale: The additional value of pre-emptive antibiotic treatment after pancreatoduodenectomy is undetermined as previous research reported conflicting results regarding infectious complications. Prolonged antibiotic prophylaxis (formally pre-emptive antibiotic treatment) after pancreatoduodenectomy might reduce the rate of surgical site infections in patients with a high risk for contaminated bile (predominantly patients with preoperative biliary drainage or an ampullary malignancy). Current national and international guidelines lack clear recommendations regarding pre-emptive antibiotic treatment leading to substantially varying antibiotic prophylactic regimes between institutes.

Objective: This trial evaluates the additional value of pre-emptive antibiotic treatment on clinically relevant organ/space surgical site infections (OSIs) in patients undergoing pancreatoduodenectomy with a high risk for contaminated bile.

Study design: This multicenter, randomized controlled, superiority trial compares perioperative versus pre-emptive antibiotic treatment during five postoperative days after pancreatoduodenectomy in patients with a high risk for contaminated bile.

Study population: Adult patients undergoing pancreatoduodenectomy with a high risk for contaminated bile (patients with preoperative biliary drainage or an ampullary malignancy). Patients with a contraindication for the study antibiotics or a preoperative indication for antibiotics (e.g. cholangitis of preoperative abscesses) are excluded.

Intervention: Participants will be randomized to either perioperative prophylaxis (cefazolin, metronidazole and a single dose of 5-7mg/kg gentamicin, control arm) or additional cefuroxime and metronidazole for five postoperative days (experimental arm).

Main study endpoints: The primary endpoint are organ/space infections (OSIs) within 90 days after surgery requiring a therapeutic intervention. Secondary endpoints are OSIs, isolated OSIs, wound infections, postoperative pancreatic fistula, bile or enteric anastomotic leakage, post pancreatectomy hemorrhage, delayed gastric emptying, bacteremia, Clostridium difficile infection, major morbidity (Clavien-Dindo ≥III), reintervention, ICU admission, length of hospital stay, readmission, and in-hospital and 90-day mortality. Besides, switch of postoperative antibiotics, antibiotic sensitivity patterns and concordance between perioperative bile and postoperative surgical site cultures are analyzed.

Sample size: The sample size is calculated for superiority to achieve an OSI difference of 15% (40% vs 25%). With a 80% power (1-β) and a two-sided significance level (α) of 5.0%, a sample of 304 evaluable patients is required for superiority. Assuming a 3% non-resection rate due to metastatic disease and a 3% loss-of-follow-up rate, an expected number of 322 included patients are needed to reach the sample size of 304 evaluable patients to demonstrate superiority for the intervention.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 322
• Est. completion date: January 2026
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• Patients undergoing elective pancreatoduodenectomy with a high risk for contaminated bile defined as patients with preoperative biliary drainage or an ampullary malignancy.

• Age >18 years

Exclusion Criteria:

• Pregnancy

• Contraindication for the study antibiotics (e.g. allergy or intolerance)

• Preoperative planned therapeutic antibiotic treatment (i.e. for cholangitis or liver abscesses)

Related Conditions & MeSH terms

• Pancreatic Cancer

Intervention

Drug:
• Cefuroxime
1500mg IV cefuroxime thrice daily during five days.
• Metronidazole
500mg IV metronidazole thrice daily during five days.

Locations

Country	Name	City	State
Netherlands	Amsterdam University Medical Center	Amsterdam
Netherlands	Amphia Ziekenhuis	Breda
Netherlands	Jeroen Bosch Ziekenhuis	Den Bosch
Netherlands	Catharina Ziekenhuis	Eindhoven
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	Groningen University Medical Center	Groningen
Netherlands	Leiden University Medical Center	Leiden	Zuid Holland
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	Radboud University Medical Center	Nijmegen
Netherlands	Erasmus MC Cancer Institute	Rotterdam
Netherlands	Regional Academic Cancer Center Utrecht	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
Leiden University Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The percentage of patients with a deviation from antibiotic study protocol	Study protocol: Control arm: Perioperative antibiotic prophylaxis (cefazolin, metronidazole and single-dose gentamicin).; Intervention arm: Perioperative plus prolonged antibiotics (cefuroxime and metronidazole for five postoperative days).	5 days
Other	Antibiotic sensitivity patterns of microorganisms cultured from bile cultures and postoperative cultures from infectious sites between patients with perioperative versus prolonged antibiotic prophylaxis	Rate of Antibiotic sensitivity patterns in bile cultures and cultures from surgical sites	90 days
Other	The percentage of concordance of microorganisms in bile and cultures from infectious sites postoperatively	Defined as the similarity of microorganisms between perioperative bile cultures and postoperative cultures from infectious sites.	90 days
Primary	Rate of clinically relevant organ/space surgical site infection (OSI) between patients with perioperative versus prolonged antibiotic prophylaxis	A clinically relevant OSI is defined by the following criteria: A deep surgical site infection involving any part of the abdomen (e.g. organs and/or spaces) other than the surgical incision within 90 days after surgery.; AND Requires radiological, endoscopic or surgical intervention OR therapeutic antibiotics required for an episode of sepsis, defined as two or more SIRS criteria.; AND Organisms isolated from an aseptically obtained culture.	90 days after surgery
Secondary	The rate of organ/Space Infection (OSI) between patients with perioperative versus prolonged antibiotic prophylaxis	An OSI is defined by the CDC definition: o The infection appears to be related to the operative procedure and infection involves any part of the anatomy (e.g., organs or spaces) other than the incision opened or manipulated during the operative procedure, and at least one of the following is present: Purulent drainage from a drain that is placed into the organ/space.; Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/space.; An abscess or other evidence of infection involving the organ/space on direct examination, during reoperation, or by histopathologic or radiologic examination.; Diagnosis of an organ/space SSI by a surgeon or attending physician."	90 days
Secondary	The rate of isolated OSI between patients with perioperative versus prolonged antibiotic prophylaxis	Isolated OSI is defined as an OSI without concurrent anastomotic leakage (pancreatojejunostomy, hepaticojejunostomy or gastrojejunostomy). The concept of an isolated OSI is used to separately classify abdominal infections without concurrent anastomotic leakage.	90 days
Secondary	The rate of superficial incisional SSI between patients with perioperative versus prolonged antibiotic prophylaxis	A superficial surgical site infection after surgery which involves superficial or deep soft tissue (skin, muscle or fascia, but no intra-abdominal tissue), and at least one of the following criteria is present: Purulent drainage from the incision or subcutaneous tissue.; Isolation of microorganisms from an aseptically obtained culture of fluid or tissue from the superficial incision of subcutaneous tissue.; Superficial infections of the skin or subcutaneous tissue which is deliberately opened by a surgeon or attending physician OR at least one of the following signs are present: localizes pain, tenderness, swelling, heat or fever >38 degrees).	90 days
Secondary	The rate of clinically relevant postoperative pancreatic fistula between patients with perioperative versus prolonged antibiotic prophylaxis	Grade B or C postoperative pancreatic fistula (POPF) defined by the International Study Group of Pancreatic Surgery definition: Grade A: Amylase >3 times upper limit of the institutional normal serum amylase value; Grade B: Grade A + persistant drainage >3 weeks, clinically relevant change in management of POPF, percutaneous or endoscopic drainage, angiographic procedures for bleeding, or signs of infection without organ failure.; Grade C: Grade A or B requiring reoperation, resulting in organ failure or death.	90 days
Secondary	The rate of bile leakage between patients with perioperative versus prolonged antibiotic prophylaxis	Grade A, B or C defined by the ISGLS definition: Grade A: Bile leakage requiring no or little change in patients' clinical management.; Grade B: Bile leakage requiring a change in patients clinical management (eg, additional diagnostic or interventional procedures) but manageable without relaparotomy, or a Grade A bile leakage lasting for >1 week.; Grade C: Bile leakage requiring relaparotomy	90 days
Secondary	The rate of post pancreatectomy hemorrhage between patients with perioperative versus prolonged antibiotic prophylaxis	Grade A, B or C defined by the ISGPS definition: Grade A: Early (<24h after surgery), intra- or extraluminal, clinically mild.; Grade B: Early (<24h after surgery), intra- or extraluminal and clinically severe OR later (>24h after surgery), intra- or extraluminal and clincally mild.; Grade C: Late (>24h after surgery), intra- or extraluminal and clinically severe.	90 days
Secondary	The rate of delayed gastric emptying between patients with perioperative versus prolonged antibiotic prophylaxis	Grade A, B or C defined by the ISGPS definition: Grade A: Until day 4-7 or replacement of feeding tube > 3 days after surgery; Grade B: Until day 8-14 or replacement of feeding tube > 7 days after surgery; Grade C: >day 14 or replacement of feeding tube > 14 after surgery	90 days
Secondary	The rate of postoperative bacteremia between patients with perioperative versus prolonged antibiotic prophylaxis	Defined as a positive blood culture obtained during a septic period (defined as two or more SIRS criteria)	90 days
Secondary	The rate of Clostridium difficile infection between patients with perioperative versus prolonged antibiotic prophylaxis	Defined by a positive fecal culture for Clostridium difficile	90 days
Secondary	Rate of major complications between patients with perioperative versus prolonged antibiotic prophylaxis	Major complications is defined by a Clavien-Dindo score of =III.; Clavien-Dindo classification of Surgical Complications: Grade I: Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions.; Grade II: Requiring pharmacological treatment with drugs other than such allowed for grade I complications.; Grade IIIa: Requiring surgical, endoscopic or radiological intervention not under general anesthesia Grade IIIb: Requiring surgical, endoscopic or radiological intervention under general anesthesia; Grade IVa: Life-threatening complication (including CNS complications)* requiring IC/ICU-management with single organ dysfunction (including dialysis).; Grade IVb: Life-threatening complication (including CNS complications)* requiring IC/ICU-management with multi organ dysfunction.; Grade V: Death of a patient	90 days
Secondary	The number of reinterventions in patients with perioperative versus prolonged antibiotic prophylaxis	Reinterventions could be either radiological, surgical or endoscopic reinterventions	90 days
Secondary	The number of ICU admission in patients with perioperative versus prolonged antibiotic prophylaxis	ICU admission	90 days
Secondary	Length of hospital stay in patients with perioperative versus prolonged antibiotic prophylaxis	In days	90 days
Secondary	The number of readmissions between patients with perioperative versus prolonged antibiotic prophylaxis	Readmission into the hospital	90 days
Secondary	Mortality	In-hospital and 90-days mortality	90 days