Condition category
Cancer
Date applied
24/04/2008
Date assigned
05/06/2008
Last edited
09/08/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Contact information

Type

Scientific

Primary contact

Dr Najib Rahman

ORCID ID

Contact details

UKCRC Oxford Respiratory Trials Unit
University of Oxford
Respiratory Medicine
Churchill Hospital
Oxford
OX3 7LE
Oxford
OX3 7LJ
United Kingdom

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

Adjuvant urokinase in the treatment of malignant pleural effusion: The third Therapeutic Intervention in Malignant Effusion trial

Acronym

TIME3-UK

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.

On 22/02/2011 the overall trial end date was changed from 01/10/2010 to 31/12/2012.

Ethics approval

Oxfordshire Research Ethics Committee A, 20/03/2009, ref: 09/H0604/5

Study design

Multi-centre randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

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.

Condition

Malignant pleural effusions

Intervention

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

Intervention type

Drug

Phase

Phase III

Drug names

Urokinase

Primary outcome measures

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).

Added 09/08/2016:
2. 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 outcome measures

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)

Overall trial start date

01/10/2008

Overall trial end date

30/06/2014

Reason abandoned

Eligibility

Participant 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

71

Participant 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

Recruitment start date

01/09/2009

Recruitment end date

30/06/2014

Locations

Countries of recruitment

United Kingdom

Trial participating centre

UKCRC Oxford Respiratory Trials Unit
Oxford
OX3 7LJ
United Kingdom

Sponsor information

Organisation

University of Oxford (UK)

Sponsor details

Clinical Trials and Research Governance (CTRG)
Manor House
John Radcliffe Hospital
Headington
Oxford
OX3 9DU
United Kingdom

Sponsor type

University/education

Website

http://www.ox.ac.uk

Funders

Funder type

Government

Funder name

Grant application submitted to the National Cancer Research Institute (NCRI) (UK). Decision pending as of 01/05/2008.

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

09/08/2016: Changed number of participants from 126 to 71. Have amended outcome measures (see relevant section for details)