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Trial registered on ANZCTR


Registration number
ACTRN12617000127303
Ethics application status
Approved
Date submitted
13/12/2016
Date registered
24/01/2017
Date last updated
22/04/2022
Date data sharing statement initially provided
22/04/2022
Date results information initially provided
22/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Pilot trial evaluating the efficacy of different antibiotic treatments for the treatment of prosthetic joint infection in adults who have undergone joint replacement surgery.
Scientific title
Pilot trial evaluating the efficacy of different antibiotic treatments for the treatment of prosthetic joint infection in adults who have undergone joint replacement surgery.
Secondary ID [1] 290759 0
Nil
Universal Trial Number (UTN)
Trial acronym
PIANOFORTE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prosthetic joint infection 301335 0
Condition category
Condition code
Infection 301088 301088 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
At least 14 days of intravenous antibiotics (chosen by the clinician but must be active against the infecting organisms), times from the date of the first adequate debridement. In addition, patients will receive a backbone of oral antibiotics starting 7-14 days after the first adequate debridement and continuing until 12 weeks after the first adequate debridement. For those with one or more Gram positive causative organisms, this will be rifampicin 300-450mg twice daily orally plus either fusidic acid 500mg 3 times a day orally OR ciprofloxacin 750mg twice daily orally OR doxycycline 100mg twice daily orally. The doses given are recommended but not mandated. The dose and choice of companion agent will be determined by the treating clinician(s), based on the organism’s susceptibility profile, and patient tolerability. For those with one or more aerobic Gram negative rods as causative organisms, the oral agent(s) will be ciprofloxacin 750mg twice daily orally alone, or if there is a mixed infection (Gram positive and negative), ciprofloxacin 750mg twice daily orally plus rifampicin 300-450mg twice daily orally.
Intervention code [1] 296653 0
Treatment: Drugs
Comparator / control treatment
At least 42 days of intravenous antibiotics (chosen by the clinician but must be active against the infecting organisms), times from the date of the first adequate debridement. In addition, patients will receive a backbone of oral antibiotics starting 7-14 days after the first adequate debridement and continuing until 12 weeks after the first adequate debridement. For those with one or more Gram positive causative organisms, this will be rifampicin 300-450mg twice daily orally plus either fusidic acid 500mg 3 times a day orally OR ciprofloxacin 750mg twice daily orally OR doxycycline 100mg twice daily orally. The doses given are recommended but not mandated. The dose and choice of companion agent will be determined by the treating clinician(s), based on the organism’s susceptibility profile, and patient tolerability. For those with one or more aerobic Gram negative rods as causative organisms, the oral agent(s) will be ciprofloxacin 750mg twice daily orally alone, or if there is a mixed infection (Gram positive and negative), ciprofloxacin 750mg twice daily orally plus rifampicin 300-450mg twice daily orally.
Control group
Active

Outcomes
Primary outcome [1] 300506 0
Seven level ordinal outcome including clinical cure 12 months after randomisation and antibiotic-related adverse events (the categories are as follows:
1. Clinical cure with no antibiotic (AB)-related complications
2. Clinical cure with minor AB-related complications
3. Clinical cure with major AB-related complications
4. Lack of clinical cure, with no AB-related complications
5. Lack of clinical cure, with minor AB-related complications
6. Lack of clinical cure, with major AB-related complications.
7. Death from any cause.)
Clinical cure will be defined as no clinical or microbiological evidence of infection; original prosthesis still present; and no use of ongoing antibiotic therapy for the index joint.
Timepoint [1] 300506 0
At 12 months post randomisation
Secondary outcome [1] 330142 0
1. Clinical cure at 12 months defined as no clinical or microbiological evidence of infection; original prosthesis still present; and no use of ongoing antibiotic therapy for the index joint.
Timepoint [1] 330142 0
12 months post randomisation
Secondary outcome [2] 330398 0
Functional outcome at 12 months (Oxford hip or knee scores as a continuous variable)
Timepoint [2] 330398 0
12 months post randomisation
Secondary outcome [3] 330399 0
Major antibiotic-associated adverse effects
Major antibiotic-related complications are any of the following:
a) Death as a result of antibiotic induced adverse effect
b) New hospital admission or prolongation of existing admission as a result of antibiotic induced adverse effect
c) Catheter-related blood stream infection
d) PICC-line related DVT
e) Acute kidney injury defined as stage 1 modified RIFLE criteria or greater (1.5-fold increase in the serum creatinine, or glomerular filtration rate (GFR) decrease by 25 percent) clinically judged as at least possibly related to AB exposure).
f) Clostridium difficile-associated diarrhoea
g) Anaphylaxis or angioedema
a) Raised liver enzymes >10 times ULN
Timepoint [3] 330399 0
Within first 12 months post randomisation
Secondary outcome [4] 330400 0
4. Duration of intravenous antibiotics determined by review of prescribing records
Timepoint [4] 330400 0
Within first 12 months post randomisation
Secondary outcome [5] 330401 0
5. Estimated total direct treatment costs derived from length of hospital inpatient and hospital in the home stay and drug acquisition costs
Timepoint [5] 330401 0
Within first 12 months post randomisation

Eligibility
Key inclusion criteria
1) Aged >=18 years
2) Prosthetic joint infection of the hip or knee (according to IDSA diagnostic criteria)
3) Acute infection (either a. Diagnosis <4 weeks from date of implantation of prosthesis OR b. Suspected acute haematogenous infection with <3 weeks from symptom onset to diagnosis)
4) Meet IDSA criteria for DAIR (stable implant, no sinus, absence of septic shock).
5) One or more identified causative organisms (can be Gram positive, Gram negative or mixed)
6) Adequate debridement has been performed or is planned (this means an open as opposed to arthroscopic debridement and exchange of modular components)
7) Initial diagnosis is <21 days prior to randomisation.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Additional diagnosis requiring >2 weeks of IV antibiotics in the opinion of the site PI (e.g. Staphylococcus aureus bacteraemia).
2) Patient not treated with curative intent.
3) Patient unlikely to survive for > 12 months (in the opinion of the site PI).
4) Gram positive rifampicin resistant causative organism.
5) Gram negative ciprofloxacin resistant causative organism.
6) At least one causative organism is Proprionibacterium spp., Gram negative anaerobes, Fungi, Mycobacteria.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
We propose a pilot, 5-centre, investigator-initiated, open label, parallel group randomised controlled trial.
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
This is a pilot study and hence the sample size is largely determined by feasibility. Based on the PIANO study, we expect to randomise 46 patients per year, and approximately 60 in 18 months. This number will allow us to refine our study design and will provide 90% power to detect a 2 point difference in mean ordinal ranking (1 to 7) between the 2 groups.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
9/01/2018
Actual
8/05/2017
Date of last participant enrolment
Anticipated
31/10/2018
Actual
18/11/2019
Date of last data collection
Anticipated
31/10/2019
Actual
15/12/2020
Sample size
Target
60
Accrual to date
Final
60
Recruitment in Australia
Recruitment state(s)
NSW,WA
Recruitment hospital [1] 7127 0
John Hunter Hospital - New Lambton
Recruitment hospital [2] 7128 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [3] 7129 0
Royal Perth Hospital - Perth
Recruitment hospital [4] 9696 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 14888 0
2305 - New Lambton
Recruitment postcode(s) [2] 18465 0
5000 - Adelaide
Recruitment postcode(s) [3] 14890 0
6000 - Perth
Recruitment postcode(s) [4] 14889 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 8503 0
New Zealand
State/province [1] 8503 0
Hamilton and Christchurch

Funding & Sponsors
Funding source category [1] 295176 0
Hospital
Name [1] 295176 0
John Hunter Hospital
Country [1] 295176 0
Australia
Primary sponsor type
Hospital
Name
John Hunter Hospital
Address
John Hunter Hospital, Lookout Road New Lambton, NSW 2305
Country
Australia
Secondary sponsor category [1] 294003 0
None
Name [1] 294003 0
Address [1] 294003 0
Country [1] 294003 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296523 0
Hunter New England Research Ethics & Governance
Ethics committee address [1] 296523 0
Locked Bag 1, New Lambton, NSW, 2305
Ethics committee country [1] 296523 0
Australia
Date submitted for ethics approval [1] 296523 0
24/08/2016
Approval date [1] 296523 0
11/10/2016
Ethics approval number [1] 296523 0
HREC/16/HNE/393

Summary
Brief summary
Prosthetic joint infection is a common and expensive problem. Over 100,000 elective joint replacements are performed in Australia each year and this number is growing. Approximately 2% of these will become infected. Prosthetic Joint Infections are a devastating complication of joint replacement, as they are difficult to cure, and treatment generally involves multiple operations and prolonged courses of antibiotics. There is a lack of high quality evidence to inform us of the management of Prosthetic Joint Infections. Acute Prosthetic Joint Infection is most commonly managed with open debridement of the prosthesis, followed by a period of antibiotics, aiming for cure. Despite the overall burden to the health sector and variable outcomes for individuals there is a lack of high quality evidence to inform the management of these infections.The correct duration of intravenous antibiotics is unknown. Following surgical debridement, patients are treated for a variable period with intravenous antibiotics, followed in most cases by a course of oral antibiotics (ranging from none at all to over 12 months, depending on the institution and situation). However, there is a lack of evidence to guide decisions about choice and duration of antibiotic regimens. This uncertainty is reflected in international guidelines: the Infectious Diseases Society of America guidelines recommend “from 2 to 6 weeks” of IV antibiotics (with no guidance or evidence about how to choose this duration). The Musculoskeletal Infection Society guidelines also recommends between 2 and 6 weeks. Both guidelines also recommend 3 to 6 months of oral antibiotic therapy,
In adults with acute prosthetic hip or knee joint infection treated with debridement and implant retention is 2 weeks of intravenous antibiotics superior to 6 weeks (with both arms receiving 10 to 12 weeks of oral antibiotic therapy), in terms of an ordinal outcome including clinical cure 12 months after randomisation and antibiotic-related adverse events.
Trial website
None
Trial related presentations / publications
None
Public notes
None
Attachments [1] 1330 1330 0 0
/AnzctrAttachments/371568-PIANOFORTE_PIS_JHH Site_v1.0_01112016_clean copy.docx (Participant information/consent)
Attachments [2] 1331 1331 0 0
/AnzctrAttachments/371568-1609213.02 Ongoing Approval Clinical Trial Single-site LeadHREC.pdf (Ethics approval)

Contacts
Principal investigator
Name 69330 0
A/Prof Joshua Davis
Address 69330 0
John Hunter Hospital, Lookout Road New Lambton NSW 2305
Country 69330 0
Australia
Phone 69330 0
+612 49214853
Fax 69330 0
+612 49855978
Email 69330 0
Joshua.Davis@menzies.edu.au
Contact person for public queries
Name 69331 0
Ms Kellie Schneider
Address 69331 0
John Hunter Hospital, Lookout Road New Lambton NSW 2305
Country 69331 0
Australia
Phone 69331 0
+612 49 223444
Fax 69331 0
+612 49855978
Email 69331 0
kelliea.schneider@hnehealth.nsw.gov.au
Contact person for scientific queries
Name 69332 0
A/Prof Joshua Davis
Address 69332 0
John Hunter Hospital, Lookout Road New Lambton NSW 2305
Country 69332 0
Australia
Phone 69332 0
+612 49214853
Fax 69332 0
+612 49855978
Email 69332 0
Joshua.Davis@menzies.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All deidentified data
When will data be available (start and end dates)?
01/07/2023 to 30/06/2028
Available to whom?
Only if a researcher submits a research proposal and this is approved by the PIANOFORTE study management committee
Available for what types of analyses?
Any analysis approved by PIANOFORTE study management committee
How or where can data be obtained?
By getting in contact with Joshua.Davis@menzies.edu.au


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseShort- versus standard-course intravenous antibiotics for peri-prosthetic joint infections managed with debridement and implant retention: a randomised pilot trial using a desirability of outcome ranking (DOOR) endpoint.2022https://dx.doi.org/10.1016/j.ijantimicag.2022.106598
N.B. These documents automatically identified may not have been verified by the study sponsor.