Clinical trial NCT05784311: Standard Versus Prolonged Antibiotic Prophylaxis After Pancreatoduodenectomy (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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Pancreatic Cancer
Keywords: Antibiotic prophylaxis
Preoperative biliary drainage
Surgical site infection
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2023-03-24
Enrollment: 344
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients 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.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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)
* A reduced renal function, defined as an eGFR of \<60 ml/min/1.73m2 measured on the closest timepoint prior to pancreatoduodenectomy

Primary outcomes:
measure: Rate of clinically relevant organ/space surgical site infection (OSI) between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days after surgery
Secondary outcomes:
measure: The rate of organ/Space Infection (OSI) between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The rate of isolated OSI between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The rate of superficial incisional SSI between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The rate of clinically relevant postoperative pancreatic fistula between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The rate of bile leakage between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The rate of post pancreatectomy hemorrhage between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The rate of delayed gastric emptying between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The rate of postoperative bacteremia between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The rate of Clostridium difficile infection between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: Rate of major complications between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The number of reinterventions in patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The number of ICU admission in patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: Length of hospital stay in patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The number of readmissions between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: Mortality
timeFrame: 90 days
Other outcomes:
measure: The percentage of patients with a deviation from antibiotic study protocol
timeFrame: 5 days
measure: Antibiotic sensitivity patterns of microorganisms cultured from bile cultures and postoperative cultures from infectious sites between patients with perioperative versus prolonged antibiotic prophylaxis
timeFrame: 90 days
measure: The percentage of concordance of microorganisms in bile and cultures from infectious sites postoperatively
timeFrame: 90 days
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: Zuid Holland
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: Groningen University Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus MC Cancer Institute
city: Utrecht
country: Netherlands
facility: Regional Academic Cancer Center Utrecht
Study officials:
affiliation: Leiden University Medical Center
name: J. Sven D. Mieog, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: