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Trial registered on ANZCTR


Registration number
ACTRN12615000963527
Ethics application status
Approved
Date submitted
23/07/2015
Date registered
14/09/2015
Date last updated
27/04/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
The Australasian Malignant Pleural Effusion (AMPLE) trial - 2: A study to evaluate the effect of aggressive daily versus symptomatic IPC drainage on breathlessness and quality of life in patients with a malignant pleural effusion
Scientific title
The Australasian Malignant Pleural Effusion (AMPLE) trial - 2: A study to evaluate the effect of aggressive daily versus symptomatic IPC drainage on breathlessness and quality of life in patients with a malignant pleural effusion

Secondary ID [1] 287143 0
None
Universal Trial Number (UTN)
Trial acronym
AMPLE-2

(Australasian Malignant PLeural Effusion trial-2)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Pleural Effusion 295691 0
Condition category
Condition code
Respiratory 295971 295971 0 0
Other respiratory disorders / diseases
Cancer 295972 295972 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All patients who require IPC placement for management of a MPE will be identified by the PI of each study site or his/her team. Screening criteria are based on standard clinical practice and consecutive eligible patients will be offered trial entry. The principal investigator or a nominated member of staff will approach participants who fulfil the criteria to enter the trial. Screening logs will be kept.
The inclusion and exclusion criteria are in keeping with those employed in large RCTs of MPE.
Trial treatments- interventional and control
Participants will be randomly assigned (1:1) to either one of two IPC drainage strategies:
i) The Aggressive Drainage arm: Patients will drain their effusions every day for the first 60 days unless
- clinically contraindicated
- if spontaneous pleurodesis occurred. This is defined as less than 50mL of fluid removed on three consecutive drainages, in the absence of any significant residual pleural fluid collections on imaging.
Participants will be taught how to 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. Drainage will take up to 30 minutes. The IPC will remain in situ until either spontaneous pleurodesis or death.
Intervention code [1] 292407 0
Treatment: Other
Comparator / control treatment
Trial treatments- control

The Symptomatic Drainage arm: In these patients, drainage will only be performed if the patients felt that the effusion-related symptoms (usually breathlessness, cough and/or tightness) have recurred.

Participants will be taught how to 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] 295649 0
The degree of breathlessness will be assessed using a 100mm VAS score, recorded daily in the first 60 days, then weekly until the end of the study or death. VAS score is the most validated measure of dyspnoea in MPE and was successfully used in MPE trials, e.g. TIME-212 (n=106) and AMPLE-130 (n=146). Relief from breathlessness is the key goal of MPE care and will be the appropriate primary endpoint.

The VAS is a 100mm line anchored with “no breathlessness” at 0mm and “worst breathlessness imaginable” at 100mm. Patients are asked to make a mark along the line at a point representing their level of breathlessness over the preceding 24hours and at the same time each day. All VAS scores will be measured by two independent researchers and the mean score calculated. If the two measurements differ by more than 3mm, both measurements will be repeated by the same observers.
The mean difference between the two groups will be calculated using a mixed-effects linear regression model that will take into account the correlation between VAS scores measured on the same patient, and will also account for missing VAS scores (assuming that missing scores are missing at random). The model will be adjusted for the minimization variables. Time from randomisation will be modelled using fractional polynomials, and will be included in the model as a random effect. A secondary analysis will include a time-treatment interaction term.
Timepoint [1] 295649 0
The degree of breathlessness will be assessed using a 100mm VAS score, recorded daily in the first 60 days, then weekly until the end of the study or death.
Secondary outcome [1] 316101 0
Activity Levels
The goals of MPE treatment are to improve patient related outcomes such as palliation of breathlessness, pain and ultimately to improve functional levels. Objective physical activity patterns will be assessed by 7-day triaxial accelerometer assessment (ActiGraph GT3X+, Pensacola, FL, USA). Triaxial accelerometry is a validated and one of the most accurate assessments for physical activity in chronic disease populations. The Actigraph device is reliable, with excellent test-retest reproducibility (kappa=0.97 for exercise intensity, and 0.75 for posture classification).
In COPD, the ActiGraph device has been shown to be a valid technique for assessing physical activity in both controlled and free-living environments, with the ability to discriminate different walking speeds during standardized physical activity. Actigraph has also been used extensively in cancer research and rated as ‘user friendly’ by both healthy and patient populations. Standard data processing will be applied and the weekly duration of low, moderate and vigorous-intensity physical activity determined in accordance with established ranges. CPI has recently confirmed the feasibility, acceptability and compliance of the use of Actigraph in 25 MPE patients (each for a 7 day period). Prof Newton (AI) has used this technology to assess physical activity behaviour in patients with advanced cancer.
Timepoint [1] 316101 0
Patients' activity levels will be reviewed at 2 and 4 weeks, and thereafter monthly for a minimum of 6 months and a maximum of 12 months.
Secondary outcome [2] 316102 0
Hospital Admission (days and number of episodes - from hospital electronic data)
These will be recorded as previously used in AMPLE [ACTRN12611000567921] (not yet published). Hospitalization for any causes (except for elective admissions for chemotherapy) will be recorded for all patients post randomization until time of death or end of follow-up period, whichever comes first. Admission will be analysed as total admission days (and number of episodes) and also as effusion-related admissions. The latter will include all hospitalizations for drainage purposes, for pleural or IPC-related complications such as infection, symptomatic loculation and for removal of the IPC if indicated. These endpoints are important as patients with MPE have a limited lifespan and providing ambulatory care without hospitalization is one of the key goals of care.
Timepoint [2] 316102 0
Hospital Admission (composite outcome of days and number of episodes) will be reviewed at all study visits for a minimum of 6 months and a maximum of 12 months.
Secondary outcome [3] 316103 0
The percentage of patients who achieve spontaneous pleurodesis allowing removal of IPCs
Spontaneous pleurodesis is defined as no fluid accumulation which would allow removal of the IPC. This definition has been used in previous trials. This is important and relevant for patients as freedom from the IPC means no further risks of complications, e.g. infection, and its routine care of the catheter. Prevention of accumulation of pleural effusion allows maximal symptom control.
In the aggressive drainage group, spontaneous pleurodesis is defined as <50mL drained in each of three consecutive daily drainages without significant residual fluid on imaging. In the symptom guided drainage arm, it is defined as <50mL drainage in two attempts two weeks apart.
Drainage is carried out by the participant or their carer or a home nurse and the volumes are base on self-reports.
Timepoint [3] 316103 0
Spontaneous pleurodesis will be reviewed at 2 and 4 weeks, and thereafter monthly for a minimum of 6 months and a maximum of 12 months.
Secondary outcome [4] 316104 0
Adverse events from randomization until end of follow-up or death
Adverse events is defined as any complications that associated with the IPC such as pleural infection, cellulitis, pain, symptomatic loculation, tube blockage, catheter tract metastases, parenchymal air leak etc.
Timepoint [4] 316104 0
Adverse events will be reviewed at 2 and 4 weeks, and thereafter monthly for a minimum of 6 months and a maximum of 12 months.
Secondary outcome [5] 316105 0
Quality of life (QoL)
QoL will be measured in all patients at the start of randomization, after 2 weeks and at intervals of every 4 weeks until the end of follow-up or death. QOL will be assessed using the EQ-5D-5L questionnaire and a 100 mm visual analogue scale (VAS). The EQ-5D-5L is a standardised measure of health-related quality of life providing a single value for health status. Its descriptive system comprises five dimensions including mobility, self-care, usual activities, pain/discomfort and anxiety/depression, with each dimension having 5 levels: no problems, slight problems, moderate problems, severe problems or extreme problems. The EQ-VAS records self-rated health on a straight line, where the endpoints are labelled ‘the best imaginable health state’ and ‘the worst imaginable health state’.
The EQ-5D-5L has been used extensively in cancer related patients to assess QOL38. QOL has been assessed before in MPE treated with IPC as a primary endpoint (using VAS).
Timepoint [5] 316105 0
QoL will be measured in all patients at the start of randomization, after 2 weeks and every 4 weeks until the end of follow-up or death for a minimum of 6 months and a maximum of 12 months.
Secondary outcome [6] 316106 0
Health economics
Data will be captured from local department coding data and community based costs from patient data. No studies have compared the costs of different IPC drainage regimes.
The cost category will be divided into costs of ongoing drainage and adverse events.
Resource use associated with the different IPC drainage regimes, including drainage kits and the drainage time by community nurse (if needed), will be obtained from hospital records and patient self-report, the latter at patient review sessions. Inpatient/outpatient management of complications will also be either captured in hospital records or obtained from patient self-report and will include treatments (e.g. antibiotics), diagnostic imaging and other interventions related to the adverse events.
Timepoint [6] 316106 0
Health economics
Inpatient/outpatient management of complications will also be either captured in hospital records or obtained from patient self-report and will include treatments (e.g. antibiotics), diagnostic imaging and other interventions related to the adverse events. To be assessed at study completion.
Secondary outcome [7] 316107 0
Survival
Survival of all patients will be recorded from date of randomization to death or end of study follow-up. Survival difference between different IPC drainage regimes in MPE has not been studied before.
Timepoint [7] 316107 0
Patient survival will be noted up until 1 year study completion.

Eligibility
Key inclusion criteria
Patients with a symptomatic MPE in whom fluid drainage is considered appropriate by the managing clinician. A MPE is defined as one in which malignant cells are identified in the pleural fluid or pleural biopsy; or a large exudative pleural effusion without other causes in a patient with known disseminated extra-thoracic malignancy.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Age <18 yrs; expected survival <3 months; pleural infection; chylothorax; pregnancy or lactation; un-correctable bleeding diathesis; previous ipsilateral lobectomy/pneumonectomy; significant loculations likely to preclude effective fluid drainage; significant visual impairment and inability to consent or 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)
All patients with Malignant Pleural Effusions (MPE) and require IPC insertion presenting to participating centres, who meet the inclusion criteria and not exclusion
criteria, will be offered entry to the study.

Central randomisation by phone. Allocation concealed.

When informed consent to participate is obtained the participants will initially be drained to dryness over 72 hrs. Baseline radiography and symptoms will then be evaluated. Education regarding IPC drainage and care will be provided during this period.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation will be used using a randomisation table created by computer software.

Randomisation will be performed and participants will be assigned 1:1 to either the 'aggressive' drainage or 'symptomatic' drainage arms. The allocation will be concealed.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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] 4083 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 4084 0
Royal Perth Hospital - Perth
Recruitment hospital [3] 4085 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 4086 0
St John of God Hospital, Bunbury - Bunbury
Recruitment hospital [5] 4087 0
St George Hospital - Kogarah
Recruitment hospital [6] 4088 0
The Sutherland Hospital - Caringbah
Recruitment hospital [7] 4089 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [8] 4091 0
The Royal Adelaide Hospital - Adelaide
Recruitment outside Australia
Country [1] 7047 0
New Zealand
State/province [1] 7047 0
Papatoetoe
Country [2] 7048 0
Hong Kong
State/province [2] 7048 0
Country [3] 8101 0
Malaysia
State/province [3] 8101 0
Kota Kinabalu

Funding & Sponsors
Funding source category [1] 291707 0
Charities/Societies/Foundations
Name [1] 291707 0
Cancer Council of Western Australia
Address [1] 291707 0
46 Ventnor Ave, West Perth, WA 6005
Country [1] 291707 0
Australia
Primary sponsor type
Individual
Name
Prof YC Gary Lee
Address
UWA School of Medicine & Pharmacology
533, Harry Perkins Research Building
QE II Medical Centre
Hospital Avenue
Nedlands
Perth, WA 6009


Country
Australia
Secondary sponsor category [1] 290382 0
Individual
Name [1] 290382 0
Dr Rajesh Thomas
Address [1] 290382 0
Dept of Respiratory Medicine
B Block
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
Perth
WA 6009
Country [1] 290382 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293229 0
Sir Charles Gairdner Group Human Research and Ethics Committee
Ethics committee address [1] 293229 0
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
WA 6009
Ethics committee country [1] 293229 0
Australia
Date submitted for ethics approval [1] 293229 0
23/03/2015
Approval date [1] 293229 0
21/05/2015
Ethics approval number [1] 293229 0
2015-043

Summary
Brief summary
This study will compare the effect of two different indwelling pleural catheter (IPC) drainage strategies on breathlessness and quality of life in patients with a malignant pleural effusion (MPE). Who is it for? You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with a symptomatic malignant pleural effusion (MPE) for which drainage is considered appropriate by the managing clinician. Study details All participants in this study will be eligible if they need to have an indwelling Pleural Catheter (IPC) inserted for the management of their malignant pleural effusion. IPC allow fewer invasive procedures and reduced hospitalizations than conventional talc pleurodesis. Participants will then be randomly allocated (by chance) to one of two groups. Participants in one group will be asked to drain their effusions every day for the first 60 days (unless certain criteria are met). For participants in the other group, drainage will only be performed if the patient feels that the effusion-related symptoms (usually breathlessness, cough and/or tightness) have recurred. All participants will be asked to complete regular questionnaires for up to 1 year in order to rate their level of breathlessness and quality of life. Other clinical outcomes, any adverse events, and health care utilisation will also be monitored throughout the study. We hope to determine which regime is superior in improving clinical outcomes so that management of cancer patients with an MPE can be optimised.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58990 0
Prof YC Gary Lee
Address 58990 0
UWA School of Medicine & Pharmacology
533, Harry Perkins Research Building
QE II Medical Centre
Hospital Avenue, Nedlands
Perth, WA 6009


Country 58990 0
Australia
Phone 58990 0
61 8 61510913
Fax 58990 0
Email 58990 0
gary.lee@uwa.edu.au
Contact person for public queries
Name 58991 0
Dr Rajesh Thomas
Address 58991 0
Dept of Respiratory Medicine
Sir Charles Gairdner Hospital
First Floor, B Block
Hospital Avenue
NEDLANDS WA 6009

Country 58991 0
Australia
Phone 58991 0
+61 8 93461754
Fax 58991 0
Email 58991 0
rajesh.thomas@health.wa.gov.au
Contact person for scientific queries
Name 58992 0
Dr Rajesh Thomas
Address 58992 0
Dept of Respiratory Medicine
Sir Charles Gairdner Hospital
First Floor, B Block
Hospital Avenue
NEDLANDS WA 6009
Country 58992 0
Australia
Phone 58992 0
+61 8 9346 1754
Fax 58992 0
Email 58992 0
rajesh.thomas@health.wa.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary