Artificial joint infections are treated with different types of antibiotics and surgery. The ROADMAP study aims to find out which treatments currently used work best in regards to surgery, antibiotic choice as well as the time taking antibiotics. The study will compare different treatments against each other to see which treatment or treatment combination works to provide the best outcome and cure at 12 months. The study will focus on adults with infected artificial hips and knees.
ROADMAP trial looks at normal good clinical care and does not ask any person taking part in the study to have any extra tests or treatments.
If a person takes part in the study they will:
* Sign a consent form * Give permission for infection and treatment information to be collected and entered into a central ROADMAP specific database and a separate registry of prosthetic joint infection patients. This medical information will include participants medical history, test results and treatment they received. The study will also collect information about medical care and how the participant is feeling at Day 100 and Day 365 (1 year) after starting the study.
There are several different study parts. Each part focuses on research focus areas called domains. ROADMAP has 3 different domains; 1. Surgical, 2. Antibiotic choice and 3. Antibiotic Duration domains. Not every hospital is taking part in all 3 domains and if someone chooses to participate they do not have to participate in all domains. Specific domain details are:
1. Surgical Treatment Domain This domain will find out if it is better to do an operation to clean out the infection but keep the artificial joint in place (this is called a Debridement, Antibiotics and Implant Retention operation (DAIR)) or to clean out the infection and swap the artificial joint out for a new one (this is called a "revision" operation).
DAIR usually involves a single operation but sometimes needs more. Revision surgery may be done in one operation (single stage revision) or two operations (two stage revision). Previous research has suggested that cure rates may be better with revision operations than with DAIR, but this is not clear.
If the participant consents to the surgical domain they will be randomly allocated to either a DAIR, to clean the artificial joint but keep it in place, or to have surgery that cleans and replaces the artificial joint with a new one (revision). A revision operation, may involve one (single stage) or two different surgeries which can be days, weeks or months apart (two stage).
The participants surgeon and treating team in consultation with the participant will decide what kind of treatment they are best to receive, DAIR, single stage or two stage revision. 2. Antibiotic Choice Domain Many different microorganisms (germs) can cause artificial joint infections and many different antibiotics are used to fight infections. ROADMAP will look at different antibiotics commonly used to treat artificial joint infection. This domain will focus on an antibiotic called rifampicin (also sometimes known as rifampin) as it is often added to other antibiotics to help treat artificial joint infections. Rifampicin is not a new antibiotic but it is not clear if treatment cure rates are better if it is added.
All people taking part in this domain will be given antibiotics that will treat their artificial joint infection, called the "backbone antibiotics", but some will be given "backbone antibiotics" plus rifampicin. "Backbone antibiotics" can be either one antibiotic or a number of different antibiotics. These will be given into a vein (IV) at first, and will be changed to tablets or capsules later.
All antibiotics in this domain are commonly used and the "backbone antibiotics" will be chosen by treating doctors after looking at the type of germ and what antibiotic may work for the germ, as well as medical history including past antibiotic reactions. Antibiotics are taken for approximately 12 weeks after DAIR surgery, however after revision surgery then the time taking antibiotics may be shorter or longer. 3. Antibiotic Duration Domain Antibiotic treatment times are the focus of this domain as it is not clear how long someone should take antibiotics when revision surgery is used to treat artificial joint infection. To show what antibiotic time period is best for treatment and cure people who have had revision surgery participating in this domain will receive either "standard" or "extended" duration of antibiotics.
In this domain, after a one-stage revision, the participant will be randomised to have either 6 weeks or 12 weeks of antibiotics after the operation. If a two-stage revision operation has been done the participant will receive around 6 weeks of antibiotics between the two operation stages. After the two stage revision has been completed the participant will be randomised to either stop antibiotics or have a further 12 weeks of antibiotic treatment.
"Confirmed" or "Likely" Prosthetic joint infection of a large joint according to European Bone and Joint Infection Society (EBJIS) criteria (2021)
Physically present at participating hospital at time of eligibility assessment
"Current" prosthetic joint infection, meaning symptoms and/or signs of the PJI are present at the time of eligibility assessment.
The index prosthetic joint is a shoulder, elbow, wrist or ankle.
Known previous participation in the randomised ROADMAP randomised platform for the index joint.
Known previous participation in the randomised ROADMAP platform for a joint other than the index joint within the 12 months prior to eligibility assessment
Treating clinician believes that death is imminent and inevitable.
Factorial
Debridement and Implant Retention (DAIR)
Procedure/SurgeryIntervention 1: DAIR- cleaning of infected joint including irrigation, debridement and exchange of modular components (those not fixed to bone) with implant retention. Intervention 2: Single stage revision - cleaning of infected joint including irrigation, removal and placement of "definitive" new components which could be primary or revision components.
Antibiotic Choice
DrugNo intervention: Backbone antibiotic therapy only depends on the organism and is detailed in the protocol. Intervention: Backbone antibiotic therapy plus rifampicin. Dosage 600-900mg per day orally for as long as oral antibiotic treatment continues, but not more than 12 weeks. Prescribed according to local recommended practices and dosed as per local therapeutic guidelines.
Antibiotic duration Part A - Single stage revision
DrugIntervention Arm: Short course 6-week (42 +/- 7 days) antibiotic course - combined intravenous and oral with antibiotic choice according to organism and patient tolerability factors. Intervention Arm: Long course 12- week (84 +/- 7 days) antibiotic course - combined intravenous and oral with antibiotic choice according to organism and patient tolerability factors.
Antibiotic Duration Part B - Two stage revision
DrugIntervention Arm: Extended prophylaxis for 12 weeks after the 2nd stage revision surgery. Intervention Arm: No extended antibiotic prophylaxis after the 2nd stage revision surgery. Antibiotic choice by treating team with reference to the original causative organism(s), susceptibility and patient tolerability.
Treatment success at 12 months
The primary endpoint for all cells and domains will be treatment success at 12 months, defined as ALL FOUR OF: 1. Patient is alive. 2. Clinical cure = no clinical or microbiological evidence of ongoing infection in the index joint 3. The patient is no longer taking antibiotics for the index joint. 4. The destination prosthesis is still in place. The primary endpoint is determined through a search of hospital databases for a record of participant's death, or follow-up contact with participant's community healthcare provider, or follow-up contact with patient or their nominated carer, or linkage with death registries. The preferred method is through direct face to face clinic visit. However, phone contact with the patient may occur. In addition, any or all of the four components of the primary endpoint can be derived from external data such as GP records or specialist letters.
A "desirability of outcome ranking" DOOR
DOOR - A "desirability of outcome ranking" Each element of this composite ordinal outcome (DOOR) is already included as an endpoint in its own right (clinical cure, mortality, Oxford joint score and EQ5D5L). The DOOR is simply a way of using a combination of these outcomes to rank participants and then compare the ranks between two treatments. DOOR - an ordinal outcome which ranks participants based on a combination of the endpoints A: Clinical Cure - Primary outcome measure 1. B: Mortality - Primary outcome measure 1. C: Oxford Joint Score - Secondary outcome 3. D: EQ5D5L - Secondary outcome 4.
Patient-reported joint function (Oxford hip or knee score) at 12 months after platform entry.
Log cumulative odds ratio of intervention compared to domain control for having Oxford hip or knee score j or higher compared to j-1 or lower (assumed constant for all j), within a domain (d) and estimated for each silo (s)
Patient-reported quality of life (EuroQol-5 Dimensions-5 Levels (EQ5D5L)) at 12 months after platform entry.
Difference in mean EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) utility score between intervention and control group within a domain (d) and estimated for each silo (s).ED-5D-5L consists of EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). There are 3,125 possible health states defined by combining one level from each dimension, ranging from 11111 (full health) to 55555 (worst health). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'.
Cost effectiveness over the first 12 months after platform entry.
Bayesian statistical techniques - Monte Carlo simulation-used to estimate incremental cost-effectiveness ratios and net monetary benefits for each treatment comparison. Incremental costs and outcomes are measured arithmetic mean differences with prior distributions informed by observed data. Resource use data over 12 month follow up period.; 1)treatment costs 2) surgical cost including implant costs 3) operating theatre costs 3) ICU lengths of stay, and 4) readmissions. Quality-adjusted life years calculated using EQ-5D-5L at baseline and 12 months. To incorporate data uncertainty, results will be reported using mean of 10,000 simulations, alongside 95% credible intervals. Overall results will be presented as a probability of an intervention being cost-effective, which has the advantage of being easily interpreted. Deterministic (one-way) and probabilistic sensitivity analyses to test assumptions in modelling and impact of changing key parameters, and joint parameter uncertainty.
Click on the lead sponsor to view all of their trials.
University of Newcastle, Australia
Lead sponsor
Hunter Medical Research Institute (HMRI)
Collaborator
The University of Western Australia
Collaborator
Michael Garron Hospital
Collaborator
Aotearoa Clinical Trials
Collaborator
University of Sydney
Collaborator
University of Melbourne
Collaborator
The Peter Doherty Institute for Infection and Immunity
Collaborator
