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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

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]

Nil

Universal Trial Number (UTN)

Trial acronym

PIANOFORTE

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Prosthetic joint infection

Condition category

Condition code

Infection

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]

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]

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]

At 12 months post randomisation

Secondary outcome [1]

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]

12 months post randomisation

Secondary outcome [2]

Functional outcome at 12 months (Oxford hip or knee scores as a continuous variable)

Timepoint [2]

12 months post randomisation

Secondary outcome [3]

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]

Within first 12 months post randomisation

Secondary outcome [4]

4. Duration of intravenous antibiotics determined by review of prescribing records

Timepoint [4]

Within first 12 months post randomisation

Secondary outcome [5]

5. Estimated total direct treatment costs derived from length of hospital inpatient and hospital in the home stay and drug acquisition costs

Timepoint [5]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,WA

Recruitment hospital [1]

John Hunter Hospital - New Lambton

Recruitment hospital [2]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [3]

Royal Perth Hospital - Perth

Recruitment hospital [4]

The Royal Adelaide Hospital - Adelaide

Recruitment postcode(s) [1]

2305 - New Lambton

Recruitment postcode(s) [2]

6150 - Murdoch

Recruitment postcode(s) [3]

6000 - Perth

Recruitment postcode(s) [4]

5000 - Adelaide

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Hamilton and Christchurch

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

John Hunter Hospital

Address [1]

Lookout Road New Lambton, NSW 2305

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Hunter New England Research Ethics & Governance

Ethics committee address [1]

Locked Bag 1, New Lambton, NSW, 2305

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/08/2016

Approval date [1]

11/10/2016

Ethics approval number [1]

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]

/AnzctrAttachments/371568-PIANOFORTE_PIS_JHH Site_v1.0_01112016_clean copy.docx (Participant information/consent)

Attachments [2]

/AnzctrAttachments/371568-1609213.02 Ongoing Approval Clinical Trial Single-site LeadHREC.pdf (Ethics approval)

Contacts

Principal investigator

Name

A/Prof Joshua Davis

Address

John Hunter Hospital, Lookout Road New Lambton NSW 2305

Country

Australia

Phone

+612 49214853

Fax

+612 49855978

Joshua.Davis@menzies.edu.au

Contact person for public queries

Name

Kellie Schneider

Address

John Hunter Hospital, Lookout Road New Lambton NSW 2305

Country

Australia

Phone

+612 49 223444

Fax

+612 49855978

kelliea.schneider@hnehealth.nsw.gov.au

Contact person for scientific queries

Name

Joshua Davis

Address

John Hunter Hospital, Lookout Road New Lambton NSW 2305

Country

Australia

Phone

+612 49214853

Fax

+612 49855978

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

Source	Title	Year of Publication	DOI
Embase	Short- 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.	2022	https://dx.doi.org/10.1016/j.ijantimicag.2022.106598

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added automatically