The efficacy of Sonographic and biological pleurodesis Indicators of Malignant Pleural Effusion (SIMPLE) - a randomised trial

Pleural effusion is a build-up of fluid in the pleural space. The main causes
of pleural effusion are: infection, cancer and heart failure. When patients
with cancer develop fluid around the lungs, it is called a malignant pleural
effusion (MPE). More than half of patients with cancer will develop an MPE.
The way of treating the pleural effusion is drainage with a tube and then
sealing the two pleural layers together (pleurodesis) to reduce the chances of
fluid recurrence. Pleurodesis is performed by putting sterile talc into the
pleural space, *sticking* the lung to the chest wall. Before this can be given,
the fluid needs to be drained away using a small chest tube (placed under local
anaesthetic), which is then also used to administer the powder. Talc
pleurodesis has a success rate of 70-80% in randomised studies, and is
associated with modest equipment cost. However, talc pleurodesis requires
insertion of a chest drain and thus in-hospital stay while the drain is in
situ, which is associated with substantial overall hospital costs.
MPE is usually the manifestation of metastatic malignancy, and thus patients
undergoing this procedure are of limited life expectancy. Therefore, minimising
hospital stay and enabling the patients to spend more time at home with family
and friends is a priority.
Currently, there is no reliable data to inform the clinician of the optimal
timing of drain withdrawal post talc pleurodesis. The majority of hospital stay
associated with talc pleurodesis is related to the post administration drain in
situ phase, and this is the outcome most amenable to change.

Inflammation appears to play a critical role in MPE by contributing to both
morbidity and mortality. Markers of both systemic inflammation (for example
blood neutrophil-lymphocyte ratio (NLR)) and localised pleural inflammation
(such as pleural fluid lactate dehydrogenase (LDH)) have been shown to be
associated with a worse prognosis. This has led to a need for more accurate
prognostication tools to assist clinicians and patients in selecting the most
appropriate treatment for an individual. There is lack of data in assessing
pleural fluid protein expression profile to predict pleurodesis success.
Identifying the pleural fluid biomarkers of pleurodesis success will enable the
clinicians to stratify patients' management to either pleurodesis or
alternative treatments. This will improve the efficacy and quality of care of
patients with MPE.

Use of TUS for detection of pleural fluid and to guide pleural interventions is
becoming widely available. Pleural adherence may be detectable via TUS. An
observational study has shown that fibrin strands on ultrasound may be
associated with higher pleurodesis success, suggesting sonographic markers may
offer prognostic information.The technique of ultrasound diagnosis of pleural
adherence at the bedside within 24-48 hours of talc administration is the key,
novel application of TUS proposed in this trial, with the primary outcome being
reduction of hospital stay. Pilot data suggests pleurodesis may occur within 24
hours of talc administration and be detectable via TUS.

Identification of factors that predict pleurodesis success is of paramount
importance in the clinical care of patients with malignant pleural effusion.
The value of thoracic ultrasound (TUS) imaging, before and post talc
administration, in improving the quality and efficacy of care for patients
still remains unknown. Additionally, there is no evidence for the use of
pleural fluid proteins profile as markers for identification of patients who
will have a successful pleurodesis. This trial will prospectively test the use
of ultrasound imaging and pleural fluid analysis in improving the management of
patients with malignant pleural effusion.

This trial will prospectively test the use of ultrasound imaging and pleural
fluid analysis in improving the management of patients with malignant pleural
effusion.

Primary objective:
Establish if the use of TUS before and during the first 24-72 hours post talc
administration can improve quality and efficacy of care for MPE patients
undergoing talc pleurodesis.

Secondary objectives:
1. Determine whether the pleural fluid protein profile can predict pleurodesis
success.
2. Time to chest drain removal,
3. Quality of life,
4. Patient reported dyspnoea /chest pain (VAS methodology),
5. Use of healthcare resources and costs.
6. Identify pleural fluid and radiological biomarkers to predict mortality at
12 months.
7. Time to pleurodesis failure.

SIMPLE is a multi-centre randomised controlled trial to evaluate whether the
use of TUS, before and during the first 24-72 hours post talc administration,
in patients with MPE accurately identifies pleural adherence early in
treatment, permitting shorter hospital stay without reducing pleurodesis
success. The trial will also assess the pleural fluid protein profile,
unblinded post randomisation, to determine factors that predict pleurodesis
success.

Patients will be randomised to standard care or TUS guided care. These are
specified in detail in the appropriate trial specific instructions (TSI).
* * Standard care: Patients will have either thoracoscopy with talc poudrage or
a chest drain with talc slurry. Talc slurry pleurodesis will occur as indicated
by radiological results (chest x-ray (CXR) after drainage). The drain will be
removed post pleurodesis, at 24 hours or later, provided that fluid drainage is
less than 250mls in 24 hrs, the lung remains fully re-expanded and there is
satisfactory evacuation of pleural fluid on the chest x-ray as per usual
practice and guideline based management.
* * TUS guided care: Patients will have either thoracoscopy with talc poudrage
or a chest drain with talc slurry. The pleurodesis will be performed once there
is ultrasound scan evidence of effusion resolution. The drain will be removed
post pleurodesis on the basis of bedside ultrasound appearances: either the
sonographic pleural adherence score of >20 or complete pleural adherence in the
mid-axillary line region.

All other interventions will be identical in the treatment arms, including
access to further pleural procedures in the case of pleurodesis failure, cancer
specific treatments and supportive care including palliative measures.

No significant safety concerns are anticipated in relation to any additional
measurements or procedures carried out specifically as part of this study. The
proposed study intervention (i.e. thoracic ultrasonography) is non-invasive and
not expected to present any additional risk to participants or result in any
complications.

There are no specific benefits for taking part in SIMPLE however the
information we get from this trial may help us to develop new markers of
pleurodesis success that will lead to early discharge from hospital and thus
benefit patients in the future.