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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
18/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The Australasian Malignant PLeural Effusion (AMPLE) Trial - 3: A randomised study of the relative benefits of combined Indwelling Pleural Catheter (IPC) and talc pleurodesis therapy or Video-Assisted Thoracoscopic Surgery (VATS) in the management of patients with Malignant Pleural Effusion.
Scientific title
The Australasian Malignant PLeural Effusion (AMPLE) Trial - 3: A randomised study of the relative benefits of combined Indwelling Pleural Catheter (IPC) and talc pleurodesis therapy or Video-Assisted Thoracoscopic Surgery (VATS) in the management of patients with Malignant Pleural Effusion.
Secondary ID [1] 292197 0
Nil known
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
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age <18yrs;
2. Unfit to undergo a surgical procedure (American Society of Anaesthesiologists Score >/=4); 3. Pleural infection;
4. Chylothorax;
5. Pregnancy or lactation;
6. Uncorrectable bleeding diathesis;
7. Previous ipsilateral lobectomy/pneumonectomy;
8. Inability to consent or comply with 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 160 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
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA
Recruitment hospital [1] 8351 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 8352 0
Royal Perth Hospital - Perth
Recruitment hospital [3] 8353 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 8354 0
The Prince Charles Hospital - Chermside
Recruitment hospital [5] 8356 0
The Sutherland Hospital - Caringbah
Recruitment hospital [6] 8358 0
St George Hospital - Kogarah
Recruitment hospital [7] 8359 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [8] 8377 0
St John of God Hospital, Murdoch - Murdoch
Recruitment postcode(s) [1] 16423 0
6009 - Nedlands
Recruitment postcode(s) [2] 16424 0
6000 - Perth
Recruitment postcode(s) [3] 16425 0
6150 - Murdoch
Recruitment postcode(s) [4] 16426 0
4032 - Chermside
Recruitment postcode(s) [5] 16428 0
2229 - Caringbah
Recruitment postcode(s) [6] 16430 0
2217 - Kogarah
Recruitment postcode(s) [7] 16431 0
5000 - Adelaide
Recruitment postcode(s) [8] 16444 0
6150 - Bateman
Recruitment outside Australia
Country [1] 8983 0
New Zealand
State/province [1] 8983 0
Wellington
Country [2] 8984 0
Hong Kong
State/province [2] 8984 0
West cluster
Country [3] 8985 0
United Kingdom
State/province [3] 8985 0
London

Funding & Sponsors
Funding source category [1] 296733 0
Charities/Societies/Foundations
Name [1] 296733 0
Western Australian Cancer and Palliative Care Network
Address [1] 296733 0
Department of Health
Ground Floor, C-block,
189 Royal Street,
East Perth
WA
6004
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
Human Research Ethics Office
Sir Charles Gairdner Hospital
A Block
Hospital Avenue
Nedlands
WA
6009
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
The purpose of this study is to determine if an indwelling catheter is more effective than surgical pleurodosis in treating malignant pleural effusion.

Who is it for?

You may be eligible for this study if you are an adult who is suffering from symptomatic proven pleural malignancy or an otherwise unexplained pleural effusion.

Study details

Consenting participants will be randomised to one of two treatment arms:
- Arm 1: Indwelling pleural catheter. A long term catheter is inserted under the skin in order to allow ongoing drainage of the pleural fluid. Participants will then be instructed to undergo a daily drainage regimen for 14 days at home.
- Arm 2: Surgical pleurodesis. Participants under a key-hole surgery to remove fluid and facilitate lung re-expansion.
Participants will then be followed up at discharge, 14 days, monthly for 6 months and then every 3 months up to one year post-procedure. These visits will include completion of Quality of Life questionnaires, a chest xray, an ultrasound (if thought necessary) and if you are at the lead site (Sir Charles Gairdner Hospital) a review of your Actigraphy logs up to 6 months after discharge.

It is hoped this research will help to provide effective symptom control with minimal intervention for those with malignant pleural effusion.
Trial website
N/A
Trial related presentations / publications
N/A
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
gary.lee@uwa.edu.au
Contact person for public queries
Name 75591 0
Dr 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
deirdre.fitzgerald@health.wa.gov.au
Contact person for scientific queries
Name 75592 0
Dr 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
deirdre.fitzgerald@health.wa.gov.au

No data has been provided for results reporting
Summary results
Not applicable