The MANTRA Trial (MANdibular TRauma and Antibiotic Use)

Study Overview
=================
Brief Summary
-----------------
FULL TITLE OF THE PROJECT Should we use post-operative antibiotics following surgery for patients with mandible fractures? The MANTRA trial (MANdibular TRauma and Antibiotic use) SUMMARY OF RESEARCH (ABSTRACT) Research Question: Are post-operative antibiotics required following surgery for patients with mandible fractures? Background: Mandible fractures are the commonest facial fractures needing surgery and account for a significant percentage of the acute workload in Oral & Maxillofacial Surgery (OMFS) units. The UK records over 6000 new cases per year. Patients having surgery for mandible fractures have a theoretical risk of developing surgical site infection, due to the proximity of the fracture lines to the oral cavity microbes and the presence of foreign body (titanium fixation miniplates). For this reason, clinicians often prescribe antibiotics after surgery, to reduce the risk of infection. Previous systematic reviews and a multicentre cohort study performed by this team, revealed significant clinical variation in post-operative antibiotic prescription amongst UK OMFS clinicians and the presence of clinical equipoise. Antibiotic overuse can lead to antibiotic resistance and other antibiotic-related side effects; judicious antibiotic use and stewardship is of paramount importance. Aim: To determine whether post-operative antibiotics are required at all, following surgery for mandible fractures, and, if so, what is the most clinically- and cost-effective regimen Objectives: Primary Objective To conduct a Randomized Controlled Trial (MANTRA) in order to establish the non-inferiority (or not) of not giving post-operative antibiotics versus 2 other post-operative antibiotic regimens. An internal pilot phase will optimise recruitment and retention. Secondary Objectives Measure the cost-effectiveness of the proposed antibiotic pathways Assess patient and clinician acceptability to change clinical practice Process evaluation to inform dissemination and implementation Methods: The investigators designed and propose the MANTRA RCT to compare 3 post-operative antibiotic approaches to prevent Surgical Site Infections (SSIs) following surgery for mandible fractures. The MANTRA trial is a large open label, multicentre study in NHS OMFS units. The 3 study arms represent the most common clinical pathways in the UK based on previous work; the control group is the approach prescribed by most UK OMFS clinicians. All patients will receive 1 dose of IV antibiotics (co-amoxiclav 1.2g, if no penicillin allergy, which is the most commonly used prophylactic antibiotic currently) on induction of anaesthesia, prior to their surgery. The participants will be randomised to the following (1:1:1): Group A: No further antibiotics Group B: 2 further postoperative IV doses of co-amoxiclav 1.2g Group C: 2 further postoperative IV doses (as above), followed by a 5-day course of oral co-amoxiclav 625mg every 8 hours if no penicillin allergy (Control). Trial processes will be optimised by an internal pilot phase ensuring we recruit, randomise, and retain participants with clear progression criteria. We will also conduct cost-effectiveness analyses and process evaluation for dissemination and implementation Timeline: Start of grant: 1st July 2023 Start of RCT / pilot: 1st January 2024 End of pilot: 30th June 2024 End of recruitment: 31st December 2026 End of follow-up: 30th June 2027 Completion: 31st December 2027 Impact and dissemination: Practice changing outputs that standardise the use of antibiotics in mandible fractures in the NHS and provide a framework for other surgical prophylaxis research A bespoke clinical dissemination plan via an engagement and training legacy Cost-effectiveness data to inform policy making A research legacy and change of culture in the specialty of OMFS

Official Title
-----------------
Should we Use Post-operative Antibiotics to Prevent Surgical Site Infections (SSIs) Following Surgery for Patients With Mandible Fractures? The MANTRA Trial - a Phase III, Non-inferiority, Non-blinded, Pragmatic Randomized Controlled Trial

Conditions
-----------------
Mandible Fracture, Post-operative Antibiotics

Intervention / Treatment
-----------------
* Drug: Different post-operative antibiotic regimens following surgical treatment of mandible fractures


Participation Criteria
=================
Eligibility Criteria
-----------------
All adult patients aged 18 years or over with mandible fractures requiring surgery. Most of these patients will be identified from the A&E department via the on-call OMFS team or seen in dedicated OMFS trauma clinics. A small proportion of our study population will be seen in an OMFS clinic following referral from GP/GDP. Inclusion Criteria: Ability to provide written informed consent Age≥18 years Hospital episode of mandible fracture(s) Planned treatment is surgery - (ORIF with titanium miniplates) Exclusion Criteria: Isolated mandibular condylar fractures Existing fracture site infection Immunocompromised (transplant patients, haematological malignancies, HIV/AIDS) - a clear definition will be provided in the protocol Pathological fracture (e.g., malignancy, osteoradionecrosis, cysts, Medication-Related Osteonecrosis of the Jaws [MRONJ]) Fractures open to skin Inability to provide written informed consent Other injuries or infections mandating ongoing post-operative antibiotics (e.g., panfacial fractures with mandible fracture component) Patients allergic to first and second-line antibiotic prophylaxis (as outlined above)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Non-inferiority RCT
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Group A: One induction IV dose | Drug: Different post-operative antibiotic regimens following surgical treatment of mandible fractures<br>* The 3 study arms represent the most common antibiotic regimens used in current clinical practice following surgery for mandible fractures. The control group is the most common approach. All patients will receive 1 dose of IV antibiotics (co-amoxiclav 1.2g), if no penicillin allergy, on induction of anaesthesia, prior to their surgery. The participants will be randomised to the following (1:1:1): Group A: No further antibiotics Group B: 2 further postoperative IV doses of co-amoxiclav 1.2g Group C: 2 further postoperative IV doses (as above), followed by a 5-day course of oral co-amoxiclav 625mg every 8 hours if no penicillin allergy (Control).<br>|
| Experimental: Group B<br>Group B: One induction IV dose and 2 further postoperative IV doses | Drug: Different post-operative antibiotic regimens following surgical treatment of mandible fractures<br>* The 3 study arms represent the most common antibiotic regimens used in current clinical practice following surgery for mandible fractures. The control group is the most common approach. All patients will receive 1 dose of IV antibiotics (co-amoxiclav 1.2g), if no penicillin allergy, on induction of anaesthesia, prior to their surgery. The participants will be randomised to the following (1:1:1): Group A: No further antibiotics Group B: 2 further postoperative IV doses of co-amoxiclav 1.2g Group C: 2 further postoperative IV doses (as above), followed by a 5-day course of oral co-amoxiclav 625mg every 8 hours if no penicillin allergy (Control).<br>|
| Active Comparator: Group C<br>Group C: One IV dose of antibiotics on induction and 2 further postoperative IV doses (as above), followed by a 5-day course of oral co-amoxiclav 625mg every 8 hours if no penicillin allergy | Drug: Different post-operative antibiotic regimens following surgical treatment of mandible fractures<br>* The 3 study arms represent the most common antibiotic regimens used in current clinical practice following surgery for mandible fractures. The control group is the most common approach. All patients will receive 1 dose of IV antibiotics (co-amoxiclav 1.2g), if no penicillin allergy, on induction of anaesthesia, prior to their surgery. The participants will be randomised to the following (1:1:1): Group A: No further antibiotics Group B: 2 further postoperative IV doses of co-amoxiclav 1.2g Group C: 2 further postoperative IV doses (as above), followed by a 5-day course of oral co-amoxiclav 625mg every 8 hours if no penicillin allergy (Control).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical Site Infection | Incidence of Surgical Site Infection (CDC definition) following surgery for mandible fractures | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Return to theatre within 30 days |  | 30 days | 
| Length of hospital stay |  | 14 days, 30 days, 180 days | 
| Death and cause of death |  | 14 days, 30 days, 180 days | 
| Hospital readmission |  | 30 days | 
| Malunion: fracture non-healing | Fibrous union, fracture mobility, absence of callus formation | 180 days | 
| Malocclusion: teeth not meeting as they should | When the fracture reduction failed to restore the dental occlusion | 180 days | 
| Metalwork removal | When the fixation titanium miniplates need to be removed at any point and for any reason | 14 days, 30 days, 180 days | 
| Overall antibiotic exposure |  | 14 days, 30 days, 180 days | 
| Antibiotic related adverse events/serious adverse events |  | 14 days, 30 days, 180 days | 
| Cost |  | 14 days, 30 days, 180 days | 
| HRQoL (EQ-5D-5L) | Health Related Quality of Life | 14 days, 30 days, 180 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Mandible fractures, Antibiotics, Open Reduction and Internal Fixation, Co-amoxiclav, Antibiotic Resistance, Surgical Site Infection