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About
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:
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:
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.
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.
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.
Full description
Over 120,000 hip or knee replacements are performed in Australia every year, and there are ~1 million Australians living with one or more joint replacements. Approximately 3,900 prosthetic joint infections (PJI) are diagnosed in Australia every year. The burden is similar in other resource-rich countries. For example, in Canada, over 130,000 hip and knee replacements are performed yearly and 2% of primary arthroplasties require a revision within 2 years. Infection has been identified as the most common cause for a revision surgery, which translates to $42.1 million CAD in inpatient costs to the Canadian health care system.
PJIs are difficult to treat, because of the presence of a foreign body, which encourages biofilm formation, and the need for combined surgical and prolonged antibiotic management. Outcomes are generally poor, with substantial variation in reported treatment success (ranging from 10 to 90%, median 50% after 2 years) and PJIs have striking health care costs. Existing treatment guidelines are informed by low quality evidence, with fewer than 1,700 participants ever enrolled into published randomised controlled trials comparing management approaches. Defining the optimal surgical and antibiotic approaches to PJI is a critical unmet need.
The Investigators are using an adaptive platform trial to allow the investigators to simultaneously address these questions in the management of PJI. The trial will include 3 silos (Early, Late Acute and Chronic PJI) and evaluate treatments and outcome of treatments over a 12 month period. Time points for data collection and analysis will be Day 100 and Day 365 post platform entry.
The Investigators plan to test interventions within 3 initial domains of:
Surgical Domain comparing outcomes of surgical strategies - Debridement and Implant Retention (DAIR) vs Revision arthroplasty.
Antibiotic Choice Domain comparing outcomes of antibiotic treatment - Backbone antibiotic regimen plus the addition of oral rifampicin (AKA rifampin) vs Backbone antibiotic regimen without rifampicin.
Antibiotic Duration Domains comparing the duration of antibiotics treatment in relation to one stage and also two stage surgical Revision arthroplasty strategies
The ROADMAP trial infrastructure will also have the potential to add further domains to the platform.
RANDOMISATION Participants will be randomly allocated to one arm within each domain for which they are eligible, which their site is participating in, and for which they have consented, using a web-based module available 24h a day 7 days a week. Randomisation within the patient's known silo, for all available domains will occur immediately following provision of consent (which is considered the time of platform entry), however, the reveal of each treatment allocation(s) will be delayed subject to confirmation of domain eligibility.
BLINDING This will be an open-label study unless otherwise specified in a domain-specific appendix. For the overall data and results, only specified members of the statistical analytical team and Data and Safety Monitoring Committee (DSMC) will have access to unblinded results, with other trial investigators and staff remaining blinded to the aggregate results until completion of final analysis for a domain or cell.
ANALYSIS The ROADMAP trial will repeatedly fit Bayesian hierarchical logistic models to the accumulating data (interim analyses), over the life of the trial, to estimate model parameters and evaluate pre-specified decision criteria either within a cell or a whole domain.
CORE PRIMARY OUTCOME MEASURE Treatment success assessed at 12 months post-platform entry, defined as all of: i) Alive; ii) Clinical cure (no clinical or microbiological evidence of infection); iii) No ongoing use of antibiotics for the index joint; and iv) "Destination prosthesis" (the prosthesis present after the initial management strategy is complete) still in place
CORE SECONDARY OUTCOME MEASURES
A core set of secondary endpoints will be evaluated across all domains:
ROADMAP Registry ROADMAP registry is a planned adjunct to the ROADMAP main platform study. The ROADMAP registry aims to describe the entire group of people who get large joint prosthetic joint infections, many of whom have never been a part of other previous research studies. The ROADMAP registry is interested in the different factors that can be examine to identify patterns in the medical history of people that get prosthetic joint infections, what sorts of testing and treatments they receive, and how these might affect their outcome. The registry information when analysed will be used to improve knowledge about prosthetic joint infections and also patient care.
The registry will include participants of the main platform study and also seek independent consent from patients with prosthetic joint infection that choose not to participate in the main platform study. Data for the registry will be collected from participants medical records with participant provided permissions. In addition, all ROADMAP registry participants will be asked to provide specific consent for data linkage that may occur with existing datasets, such as hospital records, national joint replacement registries, and registries of birth, deaths and marriages.
Apart from collecting available information from medical records, there are no additional tests or treatments involved.
Enrollment
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Inclusion criteria
Exclusion criteria
Potentially eligible participants meeting any of the following criteria at the time of eligibility assessment for platform entry will be excluded from the randomised platform (but may still participate in the registry):
To be included in any of the following Domains the participant must be eligible for the PLATFORM ( as listed above) and none of the platform-level exclusion criteria AND all of the domain-level inclusion and none of the domain-level exclusion criteria.
Domain-specific eligibility criteria Each domain may have additional criteria for eligibility. Participants who fulfil the above criteria will be assessed for enrolment into all domains active at a participating site. At least 2 interventions (which may include standard of care) within a domain must be available to an eligible participant in order for that participant to enter the domain. The minimum number of interventions within a domain is two. The availability of interventions within domains will be region- and site-specific, although the default position is that all interventions within a domain will be available at all sites.
Surgical Strategy Domain: Late Acute Silo inclusion criteria
Patient is in the Late Acute silo, meaning all of the following 3 criteria are met:
Antibiotic Choice Domain inclusion criteria
The time of eligibility assessment is between 48h and 7 days following initial surgical treatment.
One or more of the causative organisms is a Gram-positive of interest OR the infection is culture negative.
Antibiotic Choice Domain exclusion criteria
Antibiotic Duration Part A Domain inclusion criteria
A single stage revision procedure has been performed
For the purposes of this domain, the definition of a single stage revision procedure is as follows:
A one-stage revision means:
• Arthrotomy
• Removal of all prosthetic components
• Comprehensive synovectomy
• Placement of "definitive" new components
Additional recommended elements (not part of definition, but considered 'ideal' elements of this procedure):
Antibiotic Duration Part A Domain exclusion criteria
Patients will be excluded from this domain if, at the time of eligibility assessment, they have any of the following:
Antibiotic Duration Part B Domain Eligibility assessment and allocation reveal will be performed at day 7 (+/- 3 days) from the time of the reimplantation operation - i.e. between 4 and 10 days following the reimplantation operation. The purpose of this time frame is to confirmation of negative reimplantation cultures.
Antibiotic Duration Part B Domain inclusion criteria
A two-stage revision procedure has been performed
For the purposes of this domain, the definition of two-stage revision and reimplantation procedures are defined as follows:
A two-stage revision means:
• Removal of all existing prosthetic components (including metal, ceramic, polyethylene) and any loose cement
Additional recommended elements (not part of definition, but encouraged):
• Use of antibiotic-loaded cement as the spacer
A reimplantation procedure as the second stage of a two-stage revision means:
• Removal of the temporary prosthesis and all associated cement
The infected prosthesis was a primary (not revision) arthroplasty
At least 6 weeks of antibiotics have been received following the first stage revision, intended as treatment of the index infection
The reimplantation operation was done 4-10 days ago
Antibiotic Duration Part B Domain exclusion criteria
Primary purpose
Allocation
Interventional model
Masking
2,500 participants in 4 patient groups
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Central trial contact
Joshua S Davis, Chief Investigator; Marline L Squance, Global Clinical Trial Manager
Data sourced from clinicaltrials.gov
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