Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001013257
Ethics application status
Approved
Date submitted
5/06/2018
Date registered
18/06/2018
Date last updated
18/08/2024
Date data sharing statement initially provided
22/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Australasian Malignant PLeural Effusion (AMPLE) Trial - 3: A Randomised Study Comparing Combined Indwelling Pleural Catheter (IPC) and Talc Pleurodesis with Video-Assisted Thoracoscopic Surgery (VATS) for the Management of Patients with Malignant Pleural Effusion
Scientific title
The Australasian Malignant PLeural Effusion (AMPLE) Trial - 3: A Randomised Study Comparing Combined Indwelling Pleural Catheter (IPC) and Talc Pleurodesis with Video-Assisted Thoracoscopic Surgery (VATS) for the Management of Patients with Malignant Pleural Effusion
Secondary ID [1] 292197 0
NCT04322136
Universal Trial Number (UTN)
Trial acronym
AMPLE-3
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Malignant pleural effusion 303677 0
Condition category
Condition code
Respiratory 303056 303056 0 0
Other respiratory disorders / diseases
Cancer 303057 303057 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomly assigned (1:1) to one of two arms:
Arm 1: Indwelling pleural catheter (with talc pleurodesis if suitable)
Arm 2: Pleurodesis via Video-assisted thoracoscopic surgery

Arm 1: Indwelling pleural catheter is a long-term catheter that is tunnelled under the skin and allows ongoing drainage of pleural fluid by the patient or carer at home. It is inserted using local anaesthetic with or without sedation depending on local practice. An experienced respiratory physician inserts the catheter. Once the catheter is inserted, the pleural fluid will be evacuated as completely as possible. If the lung fully re-expands and there is no contraindication to talc pleurodesis, 4-5g of sterile graded talc will be instilled via the IPC. The participant will then be discharged on a daily drainage regimen for 14 days. The drainage will either be performed by the participant's carer or nurses in the community. A bottle or bag will be attached to the drain to allow for removal of accumulated pleural fluid. Once completed the drain will be reattached to the pleural catheter. At review in clinic on day 14 (+/- 2 days), the participant will be assessed for spontaneous pleurodesis (<50ml drainage on 3 consecutive drainage attempts). If pleurodesis has occurred and there is no residual symptomatic effusion, arrangements will be made for IPC removal. Otherwise the participant will switch to a symptom-guided drainage regimen. If the lung does not fully re-expand following complete fluid evacuation, they will be discharged on a symptom-guided regimen without instillation of talc. The drainage regimen will continue for the duration of the study and beyond if pleurodesis has not occurred and pleural fluid continues to accumulate. All participants will remain under the care of their study doctors who are also their usual physicians, after the end of the study.

Arm 2: Video-assisted thoracoscopic surgery is a type of key-hole surgery performed under general anaesthetic and usually single lung ventilation by a cardio-thoracic surgeon. This is expected to take about 1 hour. Between one and three ports are used to insert a camera and instruments into the chest cavity. Adhesions can be broken down if present and the lining of the lung (visceral pleura) can sometimes be removed (decortication) to facilitate lung re-expansion. The surgeon can then perform either mechanical abrasion or talc poudrage to induce inflammation and subsequent pleurodesis. A chest drain is left in situ post-operatively and is removed when the fluid draining is below a certain volume depending on local practice.

Participants in both arms will be reviewed at the same time points - at discharge, 14 days post-procedure, monthly to 6 months, then 3-monthly to 1 year. The reviews will include quality of life and breathlessness questionnaires.

All data will be obtained by the designated study research team who will carry out the IPC insertions and where VATs pleurodesis is undertaken, the research team will liaise directly wit the study surgeon.
Intervention code [1] 298353 0
Treatment: Surgery
Intervention code [2] 298354 0
Treatment: Devices
Comparator / control treatment
Trial treatments- control

The IPC arm: The patients will undertake daily drainage to day 14 post insertion. The drainage will either be performed by the participant's carer or nurses in the community. A bottle or bag will be attached to the drain to allow for removal of accumulated pleural fluid. Once completed the drain will be reattached to the pleural catheter.
Participants will be taught how to perform pleural drainage by the main study doctor at the hospital or a specialist nurse. They will drain their own IPCs at home with the either the help of a family member or friend or have access to community nursing support systems.
Control group
Active

Outcomes
Primary outcome [1] 302436 0
Proportion of participants requiring an ipsilateral (on the same side) pleural procedure for management of symptomatic re-accumulation of pleural fluid including surgical procedure, chest drain insertion, attempted therapeutic thoracentesis. This is a composite outcome.
Data will be obtained from the participants and the hospital record.
Timepoint [1] 302436 0
Participants will be followed for a maximum of 12 months or until death if sooner.
Secondary outcome [1] 335993 0
Proportion of participants requiring an ipsilateral pleural procedure including diagnostic aspirate.
Data will be obtained from the participants and the hospital record.
Timepoint [1] 335993 0
The study is for 12 months or until death if prior.
Secondary outcome [2] 335994 0
Time to effusion recurrence - will be assessed using chest x-ray and ultrasound at each visit. Recurrent effusion is defined as greater than 25% opacity on chest x-ray on the side of the intervention as judged by two independent clinicians and evidence of pleural fluid on ultrasound.
Timepoint [2] 335994 0
The study is for 12 months or until death if prior.
Secondary outcome [3] 335995 0
All-cause hospital days. Length of stay post-procedure and hospitalization for any cause (except for elective admissions for chemotherapy) will be recorded for all patients post randomisation. Admissions will be analysed as total admission days and also pleural-related admission days.
The data will be collected from participants and the hospital records.
Timepoint [3] 335995 0
The study is for 12 months or until death if prior.
Secondary outcome [4] 335996 0
Degree of breathlessness will be measured by a 100mm Visual Analogue Scale (VAS). The VAS is a 100mm line anchored with “no breathlessness” at 0mm and “worst breathlessness imaginable” at 100mm.
Timepoint [4] 335996 0
Scores will be recorded daily for 28 days, then monthly to 6 months and 3-monthly until 12 months.
Secondary outcome [5] 335998 0
Pain will be assessed using a 100mm visual analogue scale. The 100mm horizontal line will be anchored with "no pain" at 0mm and "worst pain imaginable" at 100mm.
Timepoint [5] 335998 0
Scores will be recorded daily for 28 days, monthly to 6 months and then 3-monthly to 12 months.
Secondary outcome [6] 336000 0
Quality of Life (QoL) will be measured using two instruments: EQ-5D-5L is a standardised measure of HRQoL that comprises five dimensions including mobility, self-care, usual activities, pain//discomfort and anxiety/depression. VAS QoL records self-rated health on a 100mm line anchored with “best imaginable health state” at 0mm and “worst imaginable health state” at 100mm.
Timepoint [6] 336000 0
post discharge follow up appointments:
7-10 days
28 days
Then monthly to 6 months
9 months
12 months
Secondary outcome [7] 336001 0
Actigraphy is one part of the study and is an outcome comprising a few different factors. Physical activity patterns, vigorous activity and periods of sedentary behaviour, will be evaluated by a well validated triaxial accelerometer (ActiGraph GT3X+, Pensacola, FL, USA). Objective physical activity patterns will be assessed by 7-day triaxial accelerometer assessment providing an indication of functional status. The Actigraph device is reliable, with excellent test-retest reproducibility in cancer research and rated as ‘user friendly’ by both healthy and patient populations.
Timepoint [7] 336001 0
Monthly to 12 months at lead site only.
Secondary outcome [8] 336002 0
Adverse events from randomization until end of follow-up or death. An adverse event is defined as any participant-reported or medical records complications associated with the IPC or VATS pleurodesis, such as pleural infection, cellulitis, pain, symptomatic loculation, tube blockage, catheter tract metastases, parenchymal air leak etc., and any peri/post-procedural complications such as prolonged air-leak, atelectasis, pneumonia, cardiovascular complications, acute kidney injury or drop in haemoglobin requiring transfusion.
Timepoint [8] 336002 0
Assessed continuously up to 12 months.
Secondary outcome [9] 336003 0
Overall survival from randomisation.
Timepoint [9] 336003 0
From randomisation up to 12 months.
Secondary outcome [10] 347881 0
Pleural-related hospital days. Length of stay post-procedure and hospitalization for any cause (except for elective admissions for chemotherapy) will be recorded for all patients post randomisation. Admissions will be analysed as total admission days and also pleural-related admission days.
The data will be collected from participants and the hospital records.
Timepoint [10] 347881 0
The study is for 12 months or until death if prior.

Eligibility
Key inclusion criteria
1. Patients with a symptomatic MPE*
2. Predicted survival of more than 6 months
3. Eastern Cooperative Oncology Group (ECOG) score = Peformance status defined as a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working, etc. ECOG 0-1 (or ECOG greater than or equal to 2 if it is felt that removal of pleural fluid would improve their status to 0 or 1).
*MPE is defined as histologically/cytologically proven pleural malignancy or an otherwise unexplained pleural effusion in the context of clinically proven cancer elsewhere.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age <18 yrs
2. Unfit to undergo surgical procedure (American Society of Anaesthesiology Score = 4)
3. Significant loculations likely to preclude effective drainage via IPC
4. Pleural infection
5. Chylothorax
6. Pregnancy or lactation
7. Un-correctable bleeding diathesis
8. Previous ipsilateral lobectomy/pneumonectomy
9. Inability to consent
10. 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 IPC (+/-talc pleurodesis) or VATS 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
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
This study will enrol 158 patients to detect a difference in re-intervention rate between the two treatment arms (5% significance, 80% power) assuming a 5% lost-to-follow up rate. The calculations were based on:
• IPC re-intervention rate: Data from seminal RCTs in IPC therapy (TIME-2, AMPLE-1) showed a 12-month re-intervention rate of 4-6% in the IPC arm.
• VATS re-intervention rate: The largest observational study of VATS pleurodesis vs talc slurry pleurodesis (Fysh et al) in which re-intervention for fluid recurrence was documented, found a rate of 32% irrespective of the mode of administration.
• Loss to follow-up: Only 4.8% (7/146) patients in AMPLE-1 withdrew or were lost to follow-up.

Data will be analysed on an intention-to-treat basis and per protocol basis. The primary outcome will be analysed using a Fisher’s exact test for comparing two proportions and subsequent logistic regression analyses allowing adjustments for minimisation variables. A secondary analysis of the primary outcome will use a competing risks time to event analysis with the competing risk of death.
For the secondary outcomes, e.g. hospital days and VAS measurements, the difference between the groups will initially be examined using two sample t-tests and further adjustments will be made for minimisation variables. Subsequent analyses will use linear mixed-effects model taking into account the repeated VAS scores measured on the same patient, and missing VAS scores (assuming that missing scores are missing at random) and will include a time by treatment interaction term along with random intercepts and time effects as appropriate.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/07/2018
Actual
23/04/2019
Date of last participant enrolment
Anticipated
31/12/2024
Actual
5/08/2024
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
158
Accrual to date
Final
158
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 8351 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 8353 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [3] 8354 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 8356 0
The Sutherland Hospital - Caringbah
Recruitment hospital [5] 8358 0
St George Hospital - Kogarah
Recruitment hospital [6] 8359 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 8377 0
St John of God Hospital, Murdoch - Murdoch
Recruitment hospital [8] 18871 0
The Northern Hospital - Epping
Recruitment hospital [9] 18872 0
Hollywood Private Hospital - Nedlands
Recruitment hospital [10] 18873 0
Wellington Health Service - Wellington
Recruitment hospital [11] 18874 0
St John of God Hospital, Midland - Midland
Recruitment hospital [12] 18875 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [13] 18876 0
Concord Repatriation Hospital - Concord
Recruitment hospital [14] 18877 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [15] 21828 0
Westmead Hospital - Westmead
Recruitment hospital [16] 21829 0
John Hunter Hospital - New Lambton
Recruitment hospital [17] 25501 0
The Wesley Hospital - Auchenflower
Recruitment postcode(s) [1] 16423 0
6009 - Nedlands
Recruitment postcode(s) [2] 16425 0
6150 - Murdoch
Recruitment postcode(s) [3] 16426 0
4032 - Chermside
Recruitment postcode(s) [4] 16428 0
2229 - Caringbah
Recruitment postcode(s) [5] 16430 0
2217 - Kogarah
Recruitment postcode(s) [6] 16431 0
5000 - Adelaide
Recruitment postcode(s) [7] 16444 0
6150 - Bateman
Recruitment postcode(s) [8] 33376 0
3076 - Epping
Recruitment postcode(s) [9] 33377 0
2820 - Wellington
Recruitment postcode(s) [10] 33378 0
6056 - Midland
Recruitment postcode(s) [11] 33379 0
4575 - Birtinya
Recruitment postcode(s) [12] 33380 0
2139 - Concord
Recruitment postcode(s) [13] 33381 0
3065 - Fitzroy
Recruitment postcode(s) [14] 36886 0
2145 - Westmead
Recruitment postcode(s) [15] 36887 0
2305 - New Lambton
Recruitment postcode(s) [16] 41312 0
4066 - Auchenflower
Recruitment outside Australia
Country [1] 8983 0
New Zealand
State/province [1] 8983 0
Wellington
Country [2] 8985 0
United Kingdom
State/province [2] 8985 0
London
Country [3] 23517 0
Canada
State/province [3] 23517 0
Toronto
Country [4] 25758 0
Malaysia
State/province [4] 25758 0
Kuala Lumpur

Funding & Sponsors
Funding source category [1] 296733 0
Charities/Societies/Foundations
Name [1] 296733 0
Western Australian Cancer and Palliative Care Network
Country [1] 296733 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] 295708 0
None
Name [1] 295708 0
Address [1] 295708 0
Country [1] 295708 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297961 0
Sir Charles Gairdner and Osborne Park Healthcare Group Human Research Ethics Committee
Ethics committee address [1] 297961 0
Ethics committee country [1] 297961 0
Australia
Date submitted for ethics approval [1] 297961 0
27/06/2017
Approval date [1] 297961 0
16/03/2018
Ethics approval number [1] 297961 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75590 0
Prof Y C Gary Lee
Address 75590 0
Pleural Medicine Unit
B-Block
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands
WA 6009
Country 75590 0
Australia
Phone 75590 0
+61 861510913
Fax 75590 0
Email 75590 0
[email protected]
Contact person for public queries
Name 75591 0
Deirdre Fitzgerald
Address 75591 0
Pleural Medicine Unit
B-Block
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands
WA 6009
Country 75591 0
Australia
Phone 75591 0
+61 424334525
Fax 75591 0
Email 75591 0
[email protected]
Contact person for scientific queries
Name 75592 0
Deirdre Fitzgerald
Address 75592 0
Pleural Medicine Unit
B-Block
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands
WA 6009
Country 75592 0
Australia
Phone 75592 0
+61424334525
Fax 75592 0
Email 75592 0
[email protected]

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
10924Study protocol  [email protected]
10925Statistical analysis plan  [email protected]
10926Informed consent form  [email protected]
10927Clinical study report  [email protected]
10928Ethical approval  [email protected]
10929Analytic code  [email protected]



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseMalignant pleural effusion management: keeping the flood gates shut.2020https://dx.doi.org/10.1016/S2213-2600%2819%2930373-X
EmbaseAustralasian Malignant PLeural Effusion (AMPLE)-3 trial: study protocol for a multi-centre randomised study comparing indwelling pleural catheter (+/-talc pleurodesis) versus video-assisted thoracoscopic surgery for management of malignant pleural effusion.2022https://dx.doi.org/10.1186/s13063-022-06405-7
N.B. These documents automatically identified may not have been verified by the study sponsor.