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| [ Print-friendly version ] |
| A randomised controlled trial to evaluate whether use of intrapleural urokinase aids the drainage of multi-septated pleural effusion compared to placebo |
| ISRCTN | ISRCTN12852177 |
| ClinicalTrials.gov identifier | |
| Public title | A randomised controlled trial to evaluate whether use of intrapleural urokinase aids the drainage of multi-septated pleural effusion compared to placebo |
| Scientific title | Adjuvant urokinase in the treatment of malignant pleural effusion: The third Therapeutic Intervention in Malignant Effusion trial |
| Acronym | TIME3-UK |
| Serial number at source | N/A |
| Study hypothesis | A randomised controlled trial to evaluate whether use of intrapleural urokinase improves breathlessness and decreases the proportion of patients requiring further pleural fluid drainage to control breathlessness in subjects with septated/loculated malignant pleural effusions who are undergoing talc pleurodesis, compared to placebo. |
| Ethics approval | To be submitted as of 24/04/2008. |
| Study design | Multi-centre, randomised controlled trial |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Malignant pleural effusions |
| Participants - inclusion criteria |
1. Both males and females
2. A clinically confident diagnosis of pleural malignancy defined as: 2.1 Histocytologically proven pleural malignancy, or 2.2. Otherwise unexplained exudative pleural effusion in the context of histocytologically proven cancer elsewhere 2. A significant (>25% hemithorax area) multi-loculated or multi-septated pleural effusion (residual effusion on chest radiograph despite the presence of a patent in-situ chest tube) 3. Malignant pleural effusion requiring drainage and pleurodesis for symptom control 4. Written informed consent |
| Participants - exclusion criteria |
1. Age <18 years
2. Expected survival <28 days 3. Previous pneumonectomy on the side of the effusion 4. Positive ipsilateral pleural fluid gram stain or bacterial culture in the previous month 5. Previously received intra-pleural fibrinolytic agents into this effusion 6. Known sensitivity to urokinase 7. Coincidental stroke, major haemorrhage or major trauma 8. Major surgery in the previous 5 days 9. Chylothorax 10. Total blood white cell count <1.0 x 10^9 11. Patients who are pregnant or lactating 12. Irreversible bleeding diathesis or platelet count <100 x 10^9 13. Irreversible visual impairment 14. Inability to give informed consent or comply with the protocol |
| Anticipated start date | 01/10/2008 |
| Anticipated end date | 01/10/2010 |
| Status of trial | Ongoing |
| Patient information material | Not available in web format, please contact the Oxford Centre for Respiratory Medicine, Respiratory Trials Unit at +44 (0)1865 225205 to request a patient information sheet. |
| Target number of participants | 126 |
| Interventions |
Treatment (urokinase) arm: Intra-pleural urokinase (100,000 IU in 30 ml normal saline) administered 12 hourly for a total of 3 doses.
Placebo arm: Intra-pleural urokinase placebo (in 30 ml normal saline) administered 12 hourly for a total of 3 doses. All patients suitable for talc pleurodesis will receive this treatment after pleural drainage facilitated by the trial medication. For any patient where there is a contraindication to the administration of intrapleural talc, an alternative pleurodesis agent may be used. Total duration of follow-up: 12 months post-randomisation |
| Primary outcome measure(s) |
1. Breathlessness quantified from visual analogue scales. The primary outcome will be the change in mean daily visual analogue scale (VAS) score defining breathlessness over 28 days following randomisation. A daily VAS score will be obtained at a similar time each day to assess how breathless each patient has felt over the preceding 24 hours.
The minimum clinically significant changes in the VAS scores have been established based on pilot data from previous studies determining the improvement in breathlessness associated with complete pleural fluid drainage with a permanent indwelling catheter. These are used in the power calculations. VAS methodology has been shown to be robust and reproducible. Patients who are known to be unable to record VAS scales (particularly the visually impaired) will be excluded (see Participants - exclusion criteria). |
| Secondary outcome measure(s) |
After adjuvant urokinase/placebo treatment, all patients will have a sterile 4 g talc slurry pleurodesis. Pleurodesis will be performed with talc graded to exclude majority of <10 µm particles to minimise toxicity. The hypothesis is that the urokinase treatment will improve pleural drainage such that subsequent pleurodesis is more effective.
To assess whether adjuvant urokinase has improved the efficacy rate of pleurodesis, the failure rate of pleurodesis will be defined by the need for further pleural intervention within 28 days of randomisation. Recurrence of pleural fluid on imaging (e.g., chest radiograph or ultrasound) which is not causing sufficient breathlessness/pain to require further drainage will not be deemed pleurodesis failure. Secondary endpoints: 1. Radiographic improvement in the area of the pleural effusion (measured as the difference in the proportion of the ipsilateral hemithorax occupied by the pleural effusion opacity on chest radiograph) on day three (the day of pleurodesis) 2. Total volume of pleural fluid drained 3. The proportion of patients requiring a further pleural fluid drainage to control breathlessness at 3 months 4. Self reported health status ('quality of life'), quantified from standard questionnaires at each trial assessment: Chronic Respiratory Disease Questionnaire (CRDQ) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C-30) 5. Health care costs (from health care utilisation and cost utility analysis from EQ-5D) |
| Sources of funding | Grant application submitted to the National Cancer Research Institute (NCRI) (UK). Decision pending as of 01/05/2008. |
| Trial website | |
| Publications | |
| Contact name | Dr Robert Davies |
| Address |
Respiratory Trials Unit
Oxford Centre for Respiratory Medicine University of Oxford Nuffield Department of Clinical Medicine Churchill Hospital Old Road Headington |
| City/town | Oxford |
| Zip/Postcode | OX3 7LJ |
| Country | United Kingdom |
| Sponsor | University of Oxford (UK) |
| Address |
Clinical Trials and Research Governance (CTRG)
Manor House John Radcliffe Hospital Headington |
| City/town | Oxford |
| Zip/Postcode | OX3 9DU |
| Country | United Kingdom |
| Sponsor website: | http://www.ox.ac.uk |
| Date applied | 24/04/2008 |
| Last edited | 05/06/2008 |
| Date ISRCTN assigned | 05/06/2008 |
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| © 2010 ISRCTN unless otherwise stated. | |
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