Setting

Three hundred and thirty patients requiring a pleurodesis intervention for a confirmed MPE will be recruited from UK hospitals (see online supplementary appendix 1 for details of recruiting centres). Patients will be randomised to undergo either chest drain insertion followed by 4 g talc slurry instillation, or to undergo medical thoracoscopy with 4 g talc poudrage. The study flow diagram is shown in figure 1.

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Figure 1

Trial flow chart (BTS, British Thoracic Society; CI, chief investigator; CXR, chest X-ray; QoL, quality of life; VAS, visual assessment scale; PA, pleural apposition; SOB, shortness of breath).

Subject screening and selection

Patients with MPE will be identified following early discussion at each centre's cancer multidisciplinary team meetings (MDT), at routine outpatient appointments and during inpatient reviews. Eligible patients will be invited to participate on a consecutive basis, and will be provided with a patient information leaflet at the earliest opportunity (see online supplementary appendix 2). Patients can be enrolled only once into the TAPPS trial.

Inclusion criteria

1. Clinically confident diagnosis of MPE requiring pleurodesis, defined as:

   1. Pleural effusion with histocytologically proven pleural malignancy; or

   2. Pleural effusion in the context of histocytologically proven malignancy elsewhere, without a clear alternative cause for fluid; or

   3. Pleural effusion with typical features of malignancy with pleural involvement on cross-sectional imaging without a clear alternative cause for fluid.

2. Fit enough to undergo local anaesthetic thoracoscopy.

3. Expected survival >3 months.

4. Written informed consent to trial participation.

Exclusion criteria

1. Patients in whom thoracoscopy is the only reasonable approach to making a diagnosis, and in whom such a diagnosis would significantly influence further management;

2. Age <18 years;

3. Females who are pregnant or lactating;

4. Evidence of extensive lung entrapment on CXR or a CT scan, or significant fluid loculation on an ultrasound scan, to a level which would normally be a contraindication to attempted talc pleurodesis;

5. Insufficient volume or position of pleural fluid on lateral decubitus thoracic ultrasound to safely perform local anaesthetic thoracoscopy without further intervention being necessary;

6. Previously documented adverse reaction to talc;

7. Clear contraindication to thoracoscopy or chest tube insertion.

Informed consent

A doctor will confirm patient eligibility prior to consent being taken. Participation in the trial will be discussed with the patient by a medical or nursing member of the local trial team. Patients will be given sufficient time (in their own opinion) to fully consider trial entry, as well as to ask questions of investigators. The consent form (see online supplementary appendix 3) will be countersigned by either a medical or nursing member of the trial team.

Randomisation

Following informed consent, patients will be randomly assigned in a 1:1 ratio using minimisation with a random element to undergo either chest drain insertion with talc slurry pleurodesis or thoracoscopy with talc poudrage. The day of randomisation is defined as day 0. Although the allocated trial procedure may be performed within 3 days of randomisation, every effort should be made to perform the procedure immediately afterwards.

Treatment allocation will be performed over the telephone by the ORTU. The randomisation sequence will be generated using a validated, online randomisation service (Sealed Envelope, London, UK; http://www.sealedenvelope.com).

The minimisation factors are:

• Type of underlying malignant disease (mesothelioma, lung cancer, breast cancer, other);

• WHO/Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1; 2 or 3).

Patients and clinicians will not be blinded to treatment allocation.

Standard care

All patients should have been discussed in their local or regional tumour-specific MDT. For all issues other than those pertaining to the drainage and management of the MPE, treatment discretion lies with the primary clinician.

Normal clinical review during the trial period will take place in the usual outpatient or inpatient setting, and will typically be carried out by oncologists or respiratory physicians. The frequency of clinical review will depend on patient choice, severity of symptoms and clinical discretion. In general, patients who are managed with chemotherapy for underlying malignancy are typically reviewed every 2–3 months.

Patients can withdraw from the trial at any time without their clinical care being affected.

Co-enrolment in other clinical trials will be discussed on an individual patient basis, but patients should not be co-enrolled into any trial which specifically aims to directly influence pleural fluid production or drainage.

Interventions

The full trial specific procedures (TSP) for the two treatment arms can be found in online supplementary appendices 4 and 6.

Data collection and management

Primary outcome

The primary outcome is the number of patients who experience pleurodesis failure up to 3 months (90 days) postrandomisation.

A patient is defined as experiencing pleurodesis failure if they undergo any of the following procedures on the side ipsilateral to their trial intervention:

• Therapeutic pleural aspiration of ≥100 mL; or

• Insertion of an intercostal drain for fluid drainage; or

• Insertion of an indwelling pleural catheter; or

• Medical or surgical thoracoscopy.

A patient is also deemed to have failed pleurodesis if their primary physician decides that they require one of the above pleural interventions, but the intervention is not performed. The primary physician is not blind to the treatment arm; however, all decisions to intervene or not in effusions which occupy less than or equal to one-third of the hemithorax will be discussed with a second clinician who is blind to treatment allocation.

Secondary outcomes

The trial's secondary outcomes are:

1. The number of patients with pleurodesis failure up to 30 days postrandomisation.

2. The number of patients with pleurodesis failure up to 180 days postrandomisation.

3. Requirement for further pleural procedures up to 180 days postrandomisation, based on an independent assessment performed by two adjudicators who are blind to the treatment outcome and clinical course.

4. Percentage pleural opacification (on CXR) at 1-month, 3-month and 6-month postrandomisation follow-up visits, and after initial drain removal.

5. Self-reported health-related quality of life at 1-month, 3-month and 6-month follow-up postrandomisation visits, measured using SF-36 and EQ-5D questionnaires.

6. Self-reported thoracic pain and breathlessness (postrandomisation) at 7, 30, 90 and 180 days, measured using VAS scores.

7. All-cause mortality up to 180 days postrandomisation.

8. Time to pleurodesis failure, censored at 180 days postrandomisation.

9. Number of nights spent in the hospital up to 90 days postrandomisation, including length of initial hospital stay.

Sample size calculation

Previous literature and our own audit data suggest that patients with a WHO performance status score of 2 or better have approximate pleurodesis failure rates of ≤10% with thoracoscopy, and ≥30% with a ‘best standard of care’ standard chest tube and talc slurry pleurodesis.5

In order to detect a ≥15% difference in pleurodesis failure at 3 months (10% thoracoscopy and poudrage vs 25% chest drain and talc slurry) with 90% power, a 5% significance level and 10% loss to follow-up, the study requires 325 patients. For the present analysis, numbers have been rounded up to include 330 patients (165 patients in each treatment arm).

Statistical analysis plan

The full statistical analysis plan is published elsewhere.

The primary analysis for each outcome will be by intention to treat. All tests will be two-sided, and will be considered statistically significant at the 5% level. For each analysis, the following summaries will be provided:

• The number of patients in each treatment group who are included in the analysis.

• The mean (SD) or median (IQR) in each treatment group for continuous outcomes, or the number (%) of patients experiencing an event for binary or time-to-event outcomes (time-to-event outcomes will also present the median time to event in each treatment arm if applicable).

• The treatment effect (difference in means for continuous outcomes, OR for binary outcomes, HR for time-to-event outcomes, rate ratio for count outcomes) with its 95% CI and a p value.

All analyses will adjust for minimisation variables (type of underlying malignant disease (mesothelioma, lung cancer, breast cancer, other) and WHO performance status (0–1 or 2–3)).6–9 The minimisation variables will be included as covariates in the regression model for each outcome.

CONSORT data will be presented, including: the number of patients screened for the study; the numbers randomised; the numbers receiving the interventions; the numbers lost to follow-up and excluded (with reasons) and the number of patients included in the primary analysis.

Subgroup analyses will be performed for the primary outcome, and the following secondary outcomes: pleurodesis failure at 30 and 180 days; requirement for further pleural procedures; and percentage CXR opacification. Results from subgroup analyses will be viewed as hypothesis generating, and will not be used to make definitive statements about treatment efficacy in a specific subgroup of patients. The following subgroup analyses will be performed:

• Patients receiving anticancer therapy at baseline versus those not receiving;

• Previous radiotherapy to chest versus no previous radiotherapy to chest;

• WHO performance status 0–1 versus 2–3;

• Patients on non-steroidal anti-inflammatory drugs (NSAIDS) at baseline versus those not on NSAIDS at baseline;

• Patients on steroids at baseline versus those not on steroids at baseline;

• Previous attempt at pleurodesis within the past month versus no attempt in the past month;

• Patients with primary malignancy of breast cancer versus mesothelioma versus lung cancer versus other.

Changes to the protocol after trial commencement

The trial details documented here are consistent with the TAPPS Trial protocol V.6 (date: 06/10/2014). A summary of the trial amendments can be found in online supplementary appendix 8.

In September 2013, the ‘window’ in which individuals could undergo their allocated trial procedure was extended from 24 to 72 h postrandomisation.

End of trial

The trial will end once 330 patients have been recruited and all patients have died or completed 6 months of trial follow-up (whichever is sooner).

Monitoring

An independent data monitoring committee (IDMC) will be convened at regular intervals, consisting of members who are independent of the trial investigators. The role of the IDMC is to review study safety data and provide advice to the trial steering committee (TSC), specifically as to whether recruitment can continue. No interim analysis is planned.

Safety reporting

Data will be collected at each patient's trial visit regarding any serious adverse events (SAE; as defined by GCP). All SAEs causally related to trial interventions will be reported to the sponsor and to the relevant oversight bodies, and will be followed until they resolve or stabilise.

Trial monitoring and oversight

The TSC will be responsible for overseeing the progress of the trial and will meet at approximate six monthly intervals. The TSC will comprise of independent chairperson, independent members, statistician, patient and public representative and members of the trial team.

Dissemination

The trial will be publicised at regional and national conferences. The final results will be presented at scientific meetings and published in a peer-reviewed journal (authorship will be according to the journal's guidelines). In addition, a lay summary of the study results will be circulated to potentially interested parties.