STOPPE is a pilot, multicentre, double-blinded, placebo-controlled randomised controlled trial to be conducted by the Western Australia pleural teams at Sir Charles Gairdner (lead site), Fiona Stanley, Royal Perth and SJoG Midland Hospitals. Eighty patients admitted with CAP who have an effusion will be randomized 2:1 to receive intravenous dexamethasone (4mg bd for 48 hours) or placebo. Exclusion criteria will include immunosuppression, long-term steroid use and poorly-controlled diabetes. Randomisation will be minimized for likelihood of a complicated effusion (Chalmers score), size of the effusion on chest x-ray and diabetes. Outcomes will include time to clinical stability, change in markers of inflammation, proportion requiring a pleural procedure, change in pleural effusion volume and adverse events.
The study will establish the feasibility and safety of adjunct corticosteroid therapy in patients with pneumonia and associated pleural effusions. Participants will be randomized at trial entry, on a 2:1 basis, to either IV dexamethasone 4mg bd for 48 hours or placebo. They will be further managed according to best clinical practice with decisions about care made by the treating physician.
Publication: Am J Respir Crit Care Med
Our dose de-escalation series aim to establish the lowest effective dosing regimen for tPA/DNase. ADAPT-2 aims to provide pilot data to evaluate the efficacy and safety of a regimen of twice-daily intrapleural instillation of 2.5mg of tPA (as a starting dose) with 5mg of DNase in 69 patients.
88.4% of patients were successfully treated with 2.5mg tPA/5mg DNase. This provides the platform for further dose de-escalation studies (ADAPT-3 using 1mg tPA is underway) and eventual comparison trials against standard doses.
Long term safety and efficacy of tPA and DNAse
Pleural infection affects ~65000 in patients in the UK and USA each year. Patients who fail treatment with systemic antibiotics and pleural fluid drainage often require surgical drainage to clear infected fluid and loculations. A recent randomised controlled study has shown that intrapleural tPA/DNase can improve clinical outcome, by improving pleural fluid drainage, reducing the need for surgical referral and reducing the length of hospital stay. Western Australian hospitals have been active in helping to setup this therapy within the state and Australasia. This treatment is now being utilised in many centres worldwide in order to prevent the need for surgery in this patient group. The long-term effects on respiratory functionality and safety however have not been investigated in patients receiving this novel treatment. A study investigating the effects of this new treatment on patient safety is therefore essential as this treatment becomes more common. This protocol describes a prospective follow-up study of the safety and efficacy of intrapleural tPA and DNase for pleural infection in patients who have already received this treatment ≥12 months earlier. Patients who have previously received tPA and DNase will be invited to participate in the study. This will involve one visit to the patient’s base hospital where patients will have a chest X-Ray and full lung function testing. Self reported quality of life and breathlessness scores and adverse events will also be recorded. A comparison of the patient’s chest Xray will be made to the patient’s chest X-ray at time of discharge. Lung function results and quality of life questionnaires will be compared to normative data for the population. Information on patient safety and efficacy from this trial is crucial in establishing tPA and DNase as a viable alternative to surgical intervention for patients with pleural infection who fail to respond to first line therapy. Furthermore this proposed study will help determine the safety and efficacy in patients who have already received this novel treatment.
The Australian Malignant PLeural Effusion (AMPLE) trial-2 is a multi-centre, open-labelled, randomized, controlled trial that aims to evaluate the best drainage frequency for IPC in patients with a MPE. Specifically, patients will be randomized to either the aggressive (daily) drainage regime or symptom-guided drainage arm. The trial will include 86 patients with MPEs randomized 1:1 to either the aggressive (daily) or symptom-guided drainage regimes after IPC insertion. This study will define if any of the two common drainage regimes is superior to the other in improving patient-relevant clinical outcomes, especially breathlessness, and their safety.
The primary endpoint will be the level of breathlessness, as measured by a 100 mm visual-analogue scale, over the 60 days post-IPC insertion. This is the most validated measure of dyspnoea in MPE and was successfully used in MPE trials, e.g. TIME-212 (n=106) and AMPLE-1 (n=146)30.
Secondary endpoints include
- physical activity level, as measured by Actigraphy (SCGH only)
- days spent in hospital from insertion of IPC to death (a minimum of 60 days)
- rate of spontaneous pleurodesis that allows removal of IPC
- complications: especially pleural infection, cellulitis, catheter blockage and symptomatic loculation, etc.
- quality of life measures (using EQ5D)
- healthcare economics
Publication: The Lancet
We have recently identified that FGF-9 is significantly over-expressed in mesothelioma. This observation has been confirmed in five separate clinical cohorts (by microarray gene profiling, RT-PCR and immunohistochemistry on pleural biopsies; by ELISA in pleural fluids of two separate populations, totalling >1000 patient samples). In vitro studies using over 10 human or murine mesothelioma cell lines have demonstrated that FGF-9 promotes mesothelioma proliferation, cell matrix invasion and release of cytokines known to be important in mesothelioma growth. Using gene-silencing strategies (i.e. shRNA) we have shown that reducing FGF-9 expression significantly reduces the growth rate of mesothelioma tumours in vivo. Importantly, we have demonstrated that therapeutic targeting FGF receptors (FGFR) using oral delivery of BJG398 from Novartis strikingly reduces tumour burden in three separate mesothelioma mouse models. The same effects were observed with other FGF receptor inhibitors (Dovitinib and PD173074), further supporting a key role of FGF-9 in mesothelioma pathogenesis. AZD4547 has a very similar activity profile to BJG398. It is a potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases (enzyme and cellular phosphorylation endpoints), and has a significantly lower potency for inhibition of FGFR4, insulin-like growth factor 1 receptor and kinase insert domain receptor (ie, vascular endothelial growth factor receptor 2).
This study is a two-stage, open-label, phase II trial of single oral agent AZD4547. A phase II study is appropriate to identify a signal for activity of this agent in mesothelioma. The two stage design allows for earlier rejection of an inactive agent at stage 1, with proceeding to stage 2 allowing us to reduce the confidence intervals around efficacy for an agent with potential activity.
Publication: Lung Cancer
Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10mg and DNase 5mg administered twice daily has been shown to successfully manage over 90% patients with pleural infection without surgery. Our dose de-escalation series aim to establish the lowest effective dosing regimen for tPA/DNase. ADAPT-1 aims to evaluate the efficacy and safety of a reduced starting dose regimen of 5mg of tPA with 5mg of DNase administered intrapleurally twice daily in 61 patients.
93.4% of patients were successfully treated with 5mg tPA/5mg DNase without needing surgery. This provides the platform for further dose de-escalation studies.
Publication: J Thorac Dis.
PLEASE -1 (ACTRN12616000820404)
Pleural effusion is an abnormal collection of fluid between the chest wall and lungs. These effusions affect an estimated 60,000 Australians a year, especially those with cancer, such as mesothelioma and lung cancer, which amounts to 8000 patients every year. Patients with significant effusions often suffer from disabling breathlessness that could be relieved by pleural fluid drainage. However, not all patients have symptomatic benefits from drainage. Pleural drainage can be performed in different ways with varying degrees of invasiveness; all methods of drainage carry potential risks (e.g. pain, bleeding, infection, etc.), discomfort to patients and significant healthcare costs.
How pleural effusions cause breathlessness in patients is not well understood. Why some, but not all, patients experience significant relief of breathlessness and improved exercise tolerance following drainage of effusions has seldom been studied. Currently there is no accurate way to predict in advance which patient will benefit symptomatically from pleural drainage. As a result, many patients have to undergo pleural drainage, sometimes multiple times, with its associated discomfort (e.g. pain), risks and cost only to find minimal or no symptomatic benefits.
This study is the first to prospectively measure the effects of pleural effusion drainage. Detailed assessments of patient symptoms, physiologic measures, radiographic assessments and exercise performance will be performed before and after pleural fluid drainage. Results of these assessments together with patient clinical factors will be analyzed. These data will provide novel insight into the key factors governing the degree of breathlessness from pleural effusions and will potentially help identify patients who will benefit most from pleural drainage, thus avoiding unnecessary procedures in many patients.
Publication: Eur Respir J.
A cancer induced collection of fluid between the lung and the chest wall (a malignant pleural effusion) affects ~15,000 new patients each year (Australia), including 25% of patients with lung cancer, 95% with mesothelioma and 40% with breast cancer1. In WA alone the annual cost of inpatient care of this condition is currently $12 million, representing a major health burden for the state.
The accumulated fluid compresses the lung and weighs on the diaphragm, causing disabling breathlessness that requires painful pleural procedures to drain the fluid2. The average life expectancy for patients with this condition is just 3 to 9 months, and therefore it is crucial to minimise hospital admissions and maximise time spent with loved ones.
A variety of management strategies exist for the management of malignant effusions, though there is no general consensus governing the best choice. Conventional care involves in-patient drainage of the effusion and performing talc pleurodesis – it can be painful and has a success rate of about 70% even in selected patients3. Each procedure requires an average of 6 bed days and carries significant costs. Failure necessitates multiple further procedures and admissions to hospital. Ambulatory indwelling small-bore chest catheters, drained as required by patients and/or carers, present a new FDA-approved strategy that requires predominantly outpatient management and is free from the side effects and costs of pleurodesis4. Experience in North America and Europe suggests that uptake of this treatment and the magnitude of its cost savings depend on cultural factors and local health system costs.
This study is a randomised trial which will compare the total number of days in hospital for patients treated with indwelling catheter compared to talc pleurodesis in 146 patients with cancer-induced pleural effusion. It will measure the frequency of problems with the two treatment strategies. If this trial is positive, it will directly improve care for one of the commonest respiratory problems, to the benefit of ~15,000 patients each year.