Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000253606
Ethics application status
Approved
Date submitted
3/02/2023
Date registered
9/03/2023
Date last updated
4/08/2023
Date data sharing statement initially provided
9/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
The Australasian Malignant PLeural Effusion (AMPLE)-4 Trial: Topical Antibiotic Prophylaxis for Infections of Indwelling Pleural Catheters in Patients with Malignant Pleural Effusions
Scientific title
The Australasian Malignant PLeural Effusion (AMPLE)-4 Trial: Topical Antibiotic Prophylaxis on the Incidence of Infections of Indwelling Pleural Catheters in Patients with Malignant Pleural Effusions
Secondary ID [1] 308711 0
None
Universal Trial Number (UTN)
Trial acronym
AMPLE-4
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant pleural effusion 328643 0
Condition category
Condition code
Respiratory 325655 325655 0 0
Other respiratory disorders / diseases
Infection 326103 326103 0 0
Other infectious diseases
Cancer 326104 326104 0 0
Lung - Mesothelioma
Cancer 326105 326105 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomly assigned (1:1) to either:
a. Topical mupirocin
Topical mupirocin 2% cream will be applied around the exit-site of the indwelling pleural catheter (IPC) for an area approximating a 50 cents coin. An information sheet with a picture of how to apply the cream will be provided to patients/carers. The antibiotics should be applied after each drainage but at least twice weekly (with dressing change) even if draining less frequently for 6 months or until IPC is removed, whichever is earlier. Compliance is monitored via weekly phone calls to the patient or nurse. Mupirocin is a topical antibiotic used worldwide for decades with a strong safety record. It binds specifically to bacterial isoleucyl transfer-RNA synthetase and inhibits bacterial protein synthesis.

b. No topical mupirocin (standard care)

Standard Care
Participants in both arms will be managed by their own clinical teams and receive all other medical treatments (including chemotherapy and radiotherapy) as deemed clinically appropriate. Patients’ medical care, including IPC care, oncology management etc, will be directed by their attending physicians, as per standard practice in the treatment hospital, regardless of study group allocation. This includes the frequency of drainage, drainage device (suction bottle or drainage bag), administration of talc pleurodesis via IPC, etc. All patients will receive standard education on IPC aftercare, have access to support services (eg direct phone line) and standard care from their attending physicians, eg chemo-irradiation and immunotherapy. Decision of IPC removal is made by the physicians in-charge. Generally, IPC can be removed if drainage is <50mL on 3 consecutive drainages and there is no significant fluid accumulation on imaging. All participants and carers will have the support and care of the respiratory unit. They will have access to the respiratory research staff via a direct phone line should any concerns arise.
Intervention code [1] 325172 0
Treatment: Drugs
Comparator / control treatment
No topical mupirocin (standard care)

Patients will be managed in the conventional manner with the usual education and care of the IPC verbally, and without topical mupirocin prophylaxis. We have elected not to use placebo as a layer of ointment itself can potentially increase risks of infection and confound outcomes.
Control group
Active

Outcomes
Primary outcome [1] 333500 0
The primary outcome is the percentage of patients who developed an IPC-related infection from catheter insertion until death, or end of 6-month follow-up. IPC-related infection can be any one of the followings:
• Pleural infection: presence of pus and/or bacteria by Gram stain or culture in pleural fluid plus clinical picture compatible with infection (eg fever, leucocytosis, raised inflammatory markers).
• Catheter tract infection: signs of inflammation along the tract usually with swelling and significant tenderness plus clinical presentation compatible with infection.
• Cellulitis at exit site: signs of inflammation clinically warranting systemic antibiotic treatment as determined by the attending physician.
Timepoint [1] 333500 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [1] 417288 0
Infection will also be analysed as the total number of episodes for all patients in each group. Data will be collected from medical records,
Timepoint [1] 417288 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [2] 417289 0
Infection will also be analysed as percentage of patients and as total number of episodes - each adjusted for number of days IPC is in situ for each patient. Data will be collected from medical records,
Timepoint [2] 417289 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [3] 417290 0
Infection will also be analysed as each of the individual types of infection. Data will be collected from medical records,
Timepoint [3] 417290 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [4] 417291 0
Infection will also be analysed as time of first episode of infection. Data will be collected from medical records,
Timepoint [4] 417291 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [5] 417292 0
Infection will also be analysed for organisms causing infection (eg S aureus vs others). Data will be collected from medical records,
Timepoint [5] 417292 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [6] 419114 0
Hospital days will be analysed as total days in hospital for any reasons.

All records of hospitalisation will be reviewed by an independent investigator.
Timepoint [6] 419114 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [7] 419115 0
Hospital days will be analysed as days related to IPC-related infections.

All records of hospitalisation will be reviewed by an independent investigator.
Timepoint [7] 419115 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [8] 419116 0
All adverse and serious adverse events will be recorded, such as cellulitis, as assessed via clinical examination
Timepoint [8] 419116 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [9] 419117 0
Resource utilisation associated with antibiotics use, and that associated with IPC-related infections will be obtained from discharge letters and hospital inpatient enquiry coding. In-/out- patient management of any related complications will be captured from hospital records or self-reports from patients and will include treatments, imaging and other interventions related to the adverse events. An experienced health economist, will oversee this study aspect.
Timepoint [9] 419117 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)
Secondary outcome [10] 419118 0
Survival will be measured from randomisation to death or end of study follow-up. Data will be collected from medical records.
Timepoint [10] 419118 0
weekly from randomisation until death or 6 months post-randomisation follow-up (if IPC is removed, then follow-ups will be monthly)

Eligibility
Key inclusion criteria
Patients who require insertion of an IPC for control of malignant pleural effusion (MPE).
°MPE is defined as an effusion in which cancer cells are identified in the fluid or pleural biopsy; or is a large exudative effusion without other causes in a patient with advanced disseminated malignancy.
Minimum age
19 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age <18 yrs
2. Allergy to mupirocin
3. Ipsilateral pleural infection within past three months
4. Inability to consent
5. Inability to comply with the protocol.

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)
The NHMRC Clinical Trials Centre will manage randomization through an automated telephone based interactive voice response service (IVRS) that is available 24 hours a day.
Randomisation will be performed and participants will be assigned 1:1 to either the mupirocin or no mupirocin arms. The allocation will be concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Dynamic (adaptive) random minimisation allocation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
This study will enrol 419 patients to detect a difference in IPC-related infection rate between the treatment arms. The difference that we wish to detect is 7% in the Antibiotics Prophylaxis arm vs 20% in the no antibiotics arm. The sample size calculation was carried out using an anticipated chi square test to compare these proportions, assuming a 5% significance level and a power of 80%. To achieve this, we would need 105 patients (with an additional 5 to allow for dropouts) per group, giving a total of 220 patients. The calculations were based on:

• IPC infections (pleural + tract + skin):

The pleural infection rate varied with clear dichotomy of UK/Australasian vs North American data. This is directly related to duration of catheter in situ, and affected by two key factors: In UK/Australasia i) significantly higher proportion of IPC patients have mesothelioma (and longer survival than those with metastatic carcinoma; hence longer catheter duration); ii) it is common practice to insert IPC early (as soon as MPE diagnosed) instead of using it as a last resort in the terminal phase. The TIME-2 (UK) and AMPLE-2 (Australasia) RCTs both registered a pleural infection rate of ~10%.
The track infection and cellulitis rates are less well documented in the literature but (combined) are often similar to the pleural infection rates in published papers. Hence we estimated a 20% incidence for overall IPC-related infections.

• In the RCTs of topical antibiotics in PD patients, a two-third reduction in infection rates (vs control arms) were commonly reported. We therefore estimated an incidence of 7% in our treatment arm. Mahajan et al found that mupirocin not only reduced the incidence of exit-site infection (ESI) and peritonitis caused by S. aureus (65% and 100% reduction respectively), but also led to a relative reduction of 60.5% and 55.0% for ESI and peritonitis respectively. A systemic analysis of 14 studies found that mupirocin prophylaxis decreased the risk of S. aureus ESI by 72% [95%CI 60-81%] and peritonitis by 70% (52-81%) among PD patients. Mupirocin reduced the risks of ESI and peritonitis due to all organisms by 57% and 41% respectively.

• Drop-out: We have allowed a 5% drop-out rate, based on our AMPLE-1 trial (4.8%; 7/146).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2023
Actual
21/07/2023
Date of last participant enrolment
Anticipated
1/03/2026
Actual
Date of last data collection
Anticipated
1/09/2026
Actual
Sample size
Target
418
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 23783 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 39230 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 312934 0
Charities/Societies/Foundations
Name [1] 312934 0
WA Cancer Council
Country [1] 312934 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Institute for Respiratory Health
Address
Harry Perkins Institute of Medical Research
Level 2, QQ Block, QE11 Medical Centre
6 Verdun Street, Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 314620 0
None
Name [1] 314620 0
Address [1] 314620 0
Country [1] 314620 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312207 0
Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee
Ethics committee address [1] 312207 0
Human Research Ethics Office
Sir Charles Gairdner Hospital
A Block
Hospital Avenue
Nedlands
WA
6009
Ethics committee country [1] 312207 0
Australia
Date submitted for ethics approval [1] 312207 0
03/02/2023
Approval date [1] 312207 0
06/04/2023
Ethics approval number [1] 312207 0

Summary
Brief summary
Malignant Pleural Effusion (MPE) can complicate most cancers and commonly causes disabling breathlessness and impairs quality of life. Patients who develop MPE often have an indwelling pleural catheter (IPC) inserted to drain excess fluid from their lungs, however these catheters can increase patients' risk of infection. This study aims to assess the use of regular preventative antibiotic cream on the incidence of infections for patients with MPE who have been fitted with an IPC.

Who is it for?
You may be eligible for this study if you are aged 19 years or older, you require insertion of an IPC for the control of malignant pleural effusion and you are willing to comply with the research procedures.

Study details
Participants who choose to enrol in this study will be randomly allocated by chance (similar to flipping a coin) to one of two groups. The first group will be given antibiotic cream to apply around the insertion site for their catheter, together with instructions on how to care for their catheter, how to change the catheter and dressings and how to apply the antibiotic cream. The first group will be asked to apply the antibiotic cream after each catheter drain for up to 6 months. The second group will not be given antibiotic cream but will be given instructions on how to care for their catheter and how to change the catheter and dressings. Both groups will receive standard care from their treating physician throughout the study, including access to support services (e.g. direct phone line). All participants and carers will have the support and care of the respiratory unit. They will have access to the respiratory research staff via a direct phone line should any concerns arise.

It is hoped this research will demonstrate whether using preventative antibiotics prior to an infection occurring reduces the number, type and severity of infections that patients with an indwelling pleural catheter may experience. If this study does show a positive impact on the infection rate, it may be expanded to a larger number of patients with indwelling pleural catheters to improve their quality of life.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123846 0
Prof YC Gary Lee
Address 123846 0
Pleural Medicine Unit
B-Block
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands
WA 6009
Country 123846 0
Australia
Phone 123846 0
+61 861510913
Fax 123846 0
Email 123846 0
gary.lee@uwa.edu.au
Contact person for public queries
Name 123847 0
Ms Estee Lau
Address 123847 0
Pleural Medicine Unit
B-Block
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands
WA 6009
Country 123847 0
Australia
Phone 123847 0
+61 421253918
Fax 123847 0
Email 123847 0
estee.lau@resphealth.uwa.edu.au
Contact person for scientific queries
Name 123848 0
Prof YC Gary Lee
Address 123848 0
Pleural Medicine Unit
B-Block
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands
WA 6009
Country 123848 0
Australia
Phone 123848 0
+61 861510913
Fax 123848 0
Email 123848 0
gary.lee@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17982Study protocol  estee.lau@resphealth.uwa.edu.au 385197-(Uploaded-03-02-2023-04-11-24)-Study-related document.pdf
17983Informed consent form  estee.lau@resphealth.uwa.edu.au
17986Ethical approval  estee.lau@resphealth.uwa.edu.au



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.