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Intravenous Versus Combined Oral and Intravenous Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection in Elective Colorectal Surgery (COMBINE)

Primary Purpose

Elective Colorectal Surgery

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
ornidazole
Placebo
Sponsored by
University Hospital, Clermont-Ferrand
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Elective Colorectal Surgery focused on measuring Antimicrobial prophylaxis, Colorectal surgery, Surgical Site Infection, Postoperative morbidity

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age > 18
  • Laparoscopic or non-laparoscopic elective colorectal surgery

Exclusion Criteria:

  • Non elective colorectal surgery (emergent surgery and/or reintervention or revision of a previous colorectal procedure)
  • Significant concomitant surgical procedure (e.g., liver resection for metastasis)
  • Bacterial infection at the time of surgery or antimicrobial therapy up to 2 weeks before surgery
  • Inflammatory bowel disease
  • Severe obesity (defined as a BMI >35 kg/m2)
  • Known history of hypersensitivity to β-lactams and imidazoles
  • Preoperative severe impairment in renal function (creatinine clearance (MDRD) < 30 ml/min)
  • Patients with known colonization with multidrug-resistant digestive bacteria, especially multidrug-resistant gram-negative bacteria (requiring specific infection control measures)
  • Allergy to lactose, galactose intolerance, Lapp lactase deficiency or glucose/galactose malabsorption (rare metabolic disease)
  • Pregnant women, breastfeeding women, women of childbearing age without effective contraceptive- Refusal to participate or inability to provide informed consent

Sites / Locations

  • CHU Clermont-Ferrand

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ornidazole

placebo

Arm Description

oral antibiotic prophylaxis using ornidazole, which has a spectrum of activity extended to most anaerobic bacteria and whose pharmacokinetic profile allows a single administration the day before surgery, in addition to intravenous antibiotic prophylaxis could be more effective than intravenous antibiotic prophylaxis alone using cephalosporin in reducing the incidence of SSI after elective colorectal surgery. Given the number of patients operated of colorectal surgery each year, the study is of significant clinical importance

oral antibiotic prophylaxis using ornidazole, which has a spectrum of activity extended to most anaerobic bacteria and whose pharmacokinetic profile allows a single administration the day before surgery, in addition to intravenous antibiotic prophylaxis could be more effective than intravenous antibiotic prophylaxis alone using cephalosporin in reducing the incidence of SSI after elective colorectal surgery. Given the number of patients operated of colorectal surgery each year, the study is of significant clinical importance

Outcomes

Primary Outcome Measures

occurrence of any SSI within 30 days after surgery.
The primary end point of the trial is the occurrence of any SSI within 30 days after surgery. SSI will be classified as superficial, deep and/or organ-space infection according to validated and well-defined criteria developed by the Centers for Disease Control and Prevention (CDC).

Secondary Outcome Measures

Incidence of individual types of SSI according to the group of treatment
Incidence of individual types of SSI (superficial incision infection, deep incision infection and organ-space infection) according to the group of treatment, 30 days after surgery
Number of postoperative complications
Using the Dindo and Clavien classification
Number of surgical complications: anastomotic leakage and the need for abdominal reoperation and/or radiological intervention
Duration of hospital stay
Including hospital stay of patients who are readmitted after surgery
All-cause mortality
All-cause mortality
Time to introduction of adjuvant chemotherapy related to SSI
Postoperative syndrome of systemic inflammatory response (Infectious complications)
Number of Postoperative syndrome of systemic inflammatory responses, in each group
Sepsis (Infectious complications)
Number of Sepsis, in each group
Septic shock (Infectious complications)
Number of Septic shocks, in each group
Arrhythmia (Cardiovascular complications)
Number of arrhythmias, in each group
Myocardial infarction (Cardiovascular complications)
Number of myocardial infarctions, in each group
Acute cardiac failure (Cardiovascular complications)
Number of acute cardiac failures, in each group
Pneumonia (Respiratory complications)
Number of pneumonias, in each group
Need for postoperative reventilation (Respiratory complications)
Number of postoperative reventilations (intubation and/or non-invasive mechanical ventilation), in each group
Renal dysfunction
Number of Renal dysfunctions in each group. Defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification
Time to initiation of adjuvant chemotherapy
Comparaison of time to initiation of adjuvant chemotherapy between the 2 groups
Need for hospital readmission
Number of hospital readmissions, in each group
Unexpected admission to intensive care unit
Number of Unexpected admissions to intensive care unit, in each group
Hospital free days

Full Information

First Posted
November 5, 2015
Last Updated
July 4, 2022
Sponsor
University Hospital, Clermont-Ferrand
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1. Study Identification

Unique Protocol Identification Number
NCT02618720
Brief Title
Intravenous Versus Combined Oral and Intravenous Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection in Elective Colorectal Surgery
Acronym
COMBINE
Official Title
Intravenous Versus Combined Oral and Intravenous Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection in Elective Colorectal Surgery: A Double-blinded Multicenter Prospective Randomized Controlled Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
May 25, 2016 (Actual)
Primary Completion Date
November 26, 2019 (Actual)
Study Completion Date
June 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Clermont-Ferrand

4. Oversight

5. Study Description

Brief Summary
To assess the effects of a combined antimicrobial prophylaxis using oral ornidazole (the day before surgery) and intravenous cephalosporin (before surgical incision) with that of intravenous cephalosporin alone (standard of care) in combination with oral placebo on the incidence of SSI within 30 days after elective colorectal surgery.
Detailed Description
Surgical site infection (SSI) is a major cause of nosocomial infection in surgical patients, with the highest rates being reported (ranging from 15% to 30%) in colorectal surgery. SSI is an independent predictor of postoperative mortality and is associated with longer hospital stay, a 5-fold likelihood of postoperative readmission and a 2- to 3-fold increase in costs of care. Given the high prevalence and financial burden associated with SSI, American and European guidelines have been issued providing evidenced-based recommendations for the prevention of postoperative SSI. However, the prevalence of SSI remains high despite adherence to these guidelines and the application of evidence-based preventive measures. Risk factors for SSI, whether modifiable or not, are mainly related to the patient condition (including age, severe comorbidity, diabetes, nutritional status, steroid use, smoking, and immunosuppression) and/or the surgical procedure (especially the surgical duration and skin disinfection). The prevention of SSI consists of several individual measures, and antibiotic prophylaxis covering aerobic and anaerobic bacteria is highly recommended in patients scheduled to elective colorectal resection, with French and European guidelines recommending the administration of intravenous cephalosporin within 30 minutes before surgical incision. Recent data from retrospective studies and two meta-analyses of clinical trials provided compelling arguments that oral antibiotic administration before surgery in addition to conventional intravenous prophylaxis may be useful in further reducing by almost 75% the incidence of SSI (relative risk 0.55 [CI95%: 0.41 to 0.74]) after elective colorectal cancer surgery. However, most of these studies have limitations precluding extrapolation of data into routine care, especially: prolonged duration of intravenous antibiotic administration, which is no longer recommended in elective surgery; the use of antibiotics for oral prophylaxis whose availability is limited; only a few studies focused specifically on colorectal resection; most studies did not include enhanced recovery after surgery (ERAS) programs, which was found to improve outcome following colorectal surgery, and most studies have used mechanical bowel preparation, which is no longer recommended in colonic surgery while the issue still remains open for rectal surgery. Investigators hypothesized that oral antibiotic prophylaxis using ornidazole, which has a spectrum of activity extended to most anaerobic bacteria and whose pharmacokinetic profile allows a single administration the day before surgery, in addition to intravenous antibiotic prophylaxis could be more effective than intravenous antibiotic prophylaxis alone using cephalosporin in reducing the incidence of SSI after elective colorectal surgery. Given the number of patients operated of colorectal surgery each year, the study is of significant clinical importance

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Elective Colorectal Surgery
Keywords
Antimicrobial prophylaxis, Colorectal surgery, Surgical Site Infection, Postoperative morbidity

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
920 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ornidazole
Arm Type
Experimental
Arm Description
oral antibiotic prophylaxis using ornidazole, which has a spectrum of activity extended to most anaerobic bacteria and whose pharmacokinetic profile allows a single administration the day before surgery, in addition to intravenous antibiotic prophylaxis could be more effective than intravenous antibiotic prophylaxis alone using cephalosporin in reducing the incidence of SSI after elective colorectal surgery. Given the number of patients operated of colorectal surgery each year, the study is of significant clinical importance
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
oral antibiotic prophylaxis using ornidazole, which has a spectrum of activity extended to most anaerobic bacteria and whose pharmacokinetic profile allows a single administration the day before surgery, in addition to intravenous antibiotic prophylaxis could be more effective than intravenous antibiotic prophylaxis alone using cephalosporin in reducing the incidence of SSI after elective colorectal surgery. Given the number of patients operated of colorectal surgery each year, the study is of significant clinical importance
Intervention Type
Drug
Intervention Name(s)
ornidazole
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
occurrence of any SSI within 30 days after surgery.
Description
The primary end point of the trial is the occurrence of any SSI within 30 days after surgery. SSI will be classified as superficial, deep and/or organ-space infection according to validated and well-defined criteria developed by the Centers for Disease Control and Prevention (CDC).
Time Frame
30 days after surgery
Secondary Outcome Measure Information:
Title
Incidence of individual types of SSI according to the group of treatment
Description
Incidence of individual types of SSI (superficial incision infection, deep incision infection and organ-space infection) according to the group of treatment, 30 days after surgery
Time Frame
30 days after surgery
Title
Number of postoperative complications
Description
Using the Dindo and Clavien classification
Time Frame
30 days after surgery
Title
Number of surgical complications: anastomotic leakage and the need for abdominal reoperation and/or radiological intervention
Time Frame
30 days after surgery
Title
Duration of hospital stay
Description
Including hospital stay of patients who are readmitted after surgery
Time Frame
30 days after surgery
Title
All-cause mortality
Time Frame
30 days after surgery
Title
All-cause mortality
Time Frame
90 days after surgery
Title
Time to introduction of adjuvant chemotherapy related to SSI
Time Frame
30 days after surgery
Title
Postoperative syndrome of systemic inflammatory response (Infectious complications)
Description
Number of Postoperative syndrome of systemic inflammatory responses, in each group
Time Frame
30 days after surgery
Title
Sepsis (Infectious complications)
Description
Number of Sepsis, in each group
Time Frame
30 days after surgery
Title
Septic shock (Infectious complications)
Description
Number of Septic shocks, in each group
Time Frame
30 days after surgery
Title
Arrhythmia (Cardiovascular complications)
Description
Number of arrhythmias, in each group
Time Frame
30 days after surgery
Title
Myocardial infarction (Cardiovascular complications)
Description
Number of myocardial infarctions, in each group
Time Frame
30 days after surgery
Title
Acute cardiac failure (Cardiovascular complications)
Description
Number of acute cardiac failures, in each group
Time Frame
30 days after surgery
Title
Pneumonia (Respiratory complications)
Description
Number of pneumonias, in each group
Time Frame
30 days after surgery
Title
Need for postoperative reventilation (Respiratory complications)
Description
Number of postoperative reventilations (intubation and/or non-invasive mechanical ventilation), in each group
Time Frame
30 days after surgery
Title
Renal dysfunction
Description
Number of Renal dysfunctions in each group. Defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification
Time Frame
30 days after surgery
Title
Time to initiation of adjuvant chemotherapy
Description
Comparaison of time to initiation of adjuvant chemotherapy between the 2 groups
Time Frame
30 days after surgery
Title
Need for hospital readmission
Description
Number of hospital readmissions, in each group
Time Frame
30 days after surgery
Title
Unexpected admission to intensive care unit
Description
Number of Unexpected admissions to intensive care unit, in each group
Time Frame
30 days after surgery
Title
Hospital free days
Time Frame
30 days after surgery

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age > 18 Laparoscopic or non-laparoscopic elective colorectal surgery Exclusion Criteria: Non elective colorectal surgery (emergent surgery and/or reintervention or revision of a previous colorectal procedure) Significant concomitant surgical procedure (e.g., liver resection for metastasis) Bacterial infection at the time of surgery or antimicrobial therapy up to 2 weeks before surgery Inflammatory bowel disease Severe obesity (defined as a BMI >35 kg/m2) Known history of hypersensitivity to β-lactams and imidazoles Preoperative severe impairment in renal function (creatinine clearance (MDRD) < 30 ml/min) Patients with known colonization with multidrug-resistant digestive bacteria, especially multidrug-resistant gram-negative bacteria (requiring specific infection control measures) Allergy to lactose, galactose intolerance, Lapp lactase deficiency or glucose/galactose malabsorption (rare metabolic disease) Pregnant women, breastfeeding women, women of childbearing age without effective contraceptive- Refusal to participate or inability to provide informed consent
Facility Information:
Facility Name
CHU Clermont-Ferrand
City
Clermont-Ferrand
ZIP/Postal Code
63003
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
36328372
Citation
Futier E, Jaber S, Garot M, Vignaud M, Panis Y, Slim K, Lucet JC, Lebuffe G, Ouattara A, El Amine Y, Couderc P, Dupre A, De Jong A, Lasocki S, Leone M, Pottecher J, Pereira B, Paugam-Burtz C; COMBINE study group. Effect of oral antimicrobial prophylaxis on surgical site infection after elective colorectal surgery: multicentre, randomised, double blind, placebo controlled trial. BMJ. 2022 Nov 3;379:e071476. doi: 10.1136/bmj-2022-071476.
Results Reference
derived
PubMed Identifier
29654027
Citation
Vignaud M, Paugam-Burtz C, Garot M, Jaber S, Slim K, Panis Y, Lucet JC, Bourdier J, Morand D, Pereira B, Futier E; COMBINE trial management committee. Comparison of intravenous versus combined oral and intravenous antimicrobial prophylaxis (COMBINE) for the prevention of surgical site infection in elective colorectal surgery: study protocol for a multicentre, double-blind, randomised controlled clinical trial. BMJ Open. 2018 Apr 12;8(4):e020254. doi: 10.1136/bmjopen-2017-020254.
Results Reference
derived

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Intravenous Versus Combined Oral and Intravenous Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection in Elective Colorectal Surgery

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