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Trial registered on ANZCTR


Registration number
ACTRN12618000947202
Ethics application status
Approved
Date submitted
22/05/2018
Date registered
5/06/2018
Date last updated
22/05/2019
Date data sharing statement initially provided
22/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Steroid Therapy and Outcome in Parapneumonic Pleural Effusion (STOPPE): A randomised double-blind placebo-controlled trial of intravenous steroid in the management of parapneumonic pleural effusion.
Scientific title
Steroid Therapy and Outcome in Parapneumonic Pleural Effusion (STOPPE): A randomised double-blind placebo controlled trial of intravenous dexamethasone in the management of parapneumonic pleural effusion (A safety and Efficacy Study).
Secondary ID [1] 292196 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Steroid Therapy and Outcome in Parapneumonic Pleural Effusion (STOPPE)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Parapneumonic effusion. 307727 0
Condition category
Condition code
Respiratory 306793 306793 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention in this study is the administration of intravenous dexamethasone (a type of steroid) 4mg twice daily for two days (4 doses total). The drug will be administered by registered nurses.

Arm 1: 2/3 (53 people) will receive the study drug.
Arm 2: 1/3 (27 people) will receive a placebo. A placebo is a medication that looks like the study medication (dexamethasone) but doesn't contain any active drug.

The study drug will be mixed with sterile normal saline and administered as an infusion over 15 minutes.
Intervention code [1] 301117 0
Treatment: Drugs
Comparator / control treatment
The control treatment (placebo) will be intravenous sterile normal saline administered twice daily for two days (4 doses total). Normal saline is a type of fluid that is often administered to patients who are unwell or fasting for any reason. The solution will be made up to look like the active medication. There are no known harmful effects from receiving small volumes of normal saline intravenously.
Control group
Placebo

Outcomes
Primary outcome [1] 305777 0
Time in hours taken to reach "clinical stability". This is defined as the time it takes for a participant to have all of their vital signs maintained within a certain range for at least 12 hours, or be well enough to be discharged home at the discretion of the treating doctor. Vital signs will be recorded every four hours in an observation chart by nursing staff. The observation chart will be reviewed every second day by the research team.
Timepoint [1] 305777 0
The time to clinical stability will be assessed while the participant remains in hospital to a maximum of 30 days.
Secondary outcome [1] 346504 0
Change in white cell count. White cell count will be measured on whole blood samples taken in edta-containing tubes.
Timepoint [1] 346504 0
Day 0, 1, 2, 3 and every second day (e.g. day 5, 7, 9 etc) thereafter until discharge or 48 hours post-resolution of infection, Day 14 post-randomisation and Day 30 post-randomisation. Resolution of infection will be defined as time at which the participant is determined to have reached clinical stability as per the primary outcome.
Secondary outcome [2] 346505 0
Proportion of participants who have a normal white cell count (White cell count <11 x 10 9/litre will be considered normal for this study).
Timepoint [2] 346505 0
Day 14 post-randomisation and Day 30 post-randomisation.
Secondary outcome [3] 346506 0
Change in percentage of the hemithorax that is obscured by effusion on chest x-ray.
Timepoint [3] 346506 0
Day 14 post-randomisation and Day 30 post-randomisation.
Secondary outcome [4] 346507 0
Proportion of participants with resolution of the pleural effusion on chest x-ray.
Timepoint [4] 346507 0
Day 14 post-randomisation and Day 30 post-randomisation.
Secondary outcome [5] 346508 0
Proportion of participants who require a pleural procedure (therapeutic thoracentesis, intercostal catheter insertion, pleuroscopy, video-assisted thoracic surgery, intrapleural fibrinolytic/deoxyribonuclease therapy) as assessed by clinical examination by the research team every second day and from medical records.
Timepoint [5] 346508 0
Day 0, 1, 2, 3 and every second day (e.g. day 5, 7, 9 etc) thereafter until discharge or 48 hours post-resolution of infection, day 14 post-randomisation and day 30 post-randomisation. Resolution of infection will be defined as time at which the participant is determined to have reached clinical stability as per the primary outcome.
Secondary outcome [6] 346510 0
Duration of antibiotic therapy as assessed from the medication record and discharge prescription.
Timepoint [6] 346510 0
Day 30 post-randomisation.
Secondary outcome [7] 346511 0
Length of hospital stay from commencement of treatment to discharge or death obtained from the hospital records and participant interview in the outpatient clinic. .
Timepoint [7] 346511 0
Day 30 post-randomisation.
Secondary outcome [8] 346512 0
Quality of Life (QoL) will be measured using a validated instrument: EQ-5D-5L is a standardised measure of HRQoL that comprises five dimensions including mobility, self-care, usual activities, pain//discomfort and anxiety/depression.
Timepoint [8] 346512 0
Day 0, day of discharge from hospital, day 30 post-randomisation.
Secondary outcome [9] 346513 0
Adverse events e.g. development of hyperglycaemia assessed by testing capillary blood glucose 6 hourly until 24 hours post-administration of the first dose of dexamethasone/placebo; evdence of inflammation or bleeding in the stomach, worsening infection, thrush and any other adverse events will be assessed by clinical assessment and review of hospital record.
Timepoint [9] 346513 0
Day 30 post-randomisation.
Secondary outcome [10] 346514 0
Overall survival will be assessed as the proportion of patients who are still alive at the Day 30 follow-up appointment as assessed at review in outpatient clinic and/or from hospital records.

Timepoint [10] 346514 0
Day 30 post-randomisation, 6-months post-randomisation, 12 months post-randomisation.
Secondary outcome [11] 347286 0
Change in C-reactive protein based on serum assay.
Timepoint [11] 347286 0
Day 0, 1, 2, 3 and every second day (e.g. day 5, 7, 9 etc) thereafter until discharge or 48 hours post-resolution of infection, day 14 post-randomisation and day 30 post-randomisation. Resolution of infection will be defined as time at which the participant is determined to have reached clinical stability as per the primary outcome.
Secondary outcome [12] 347287 0
Proportion of patients with a normal C-reactive protein (less than 5mg/dL) / blood test.
Timepoint [12] 347287 0
Day 14 post-randomisation and Day 30 post-randomisation.
Secondary outcome [13] 347288 0
Physical activity patterns will be measured using a tri-axial accelerometer (ActiGraph GT3X+). Accelerometers are objective measures of physical activity levels and sedentary time. Accelerometers are programmed to record raw data at a frequency of 30 Hz, which are reduced to vertical axis movement counts per 60-second epoch. Cut off points used are: sedentary time = <100 counts/minute (cpm), light activity = 100-1952 cpm and moderate and vigorous physical activity (MVPA) = >1952 cpm.
Timepoint [13] 347288 0
Day 30 post-randomisation.
Secondary outcome [14] 347354 0
Lung function measured using spirometry, specifically the forced expiratory volume and forced vital capacity in litres and as a percentage of the predicted volume.
Timepoint [14] 347354 0
6 months post-randomisation, 12 months post-randomisation

Eligibility
Key inclusion criteria
New pleural effusion on chest xray (confirmed using ultrasound at the bedside) with clinical evidence of pneumonia, as per the treating doctor's assessment, and no alternative cause identified.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age <18 yrs;
2. Haemodynamic/respiratory instability requiring intensive care;
3. Acute burn injury;
4. Gastrointestinal bleeding in the last 3 months;
5. Known adrenal insufficiency;
6. Other indication for steroids (e.g. asthma/COPD exacerbation);
7. Long-term steroid use (>0.5mg/kg/day prednisolone equivalent);
8. Acute delirium;
9. Previous steroid-induced psychosis;
10. Severe immunodeficiency (e.g. HIV infection and CD4 count <350 cells/?L, immunosuppressive therapy after organ transplant, leukocytopaenia (<1x109/L);
11. Cystic fibrosis;
12. Active tuberculosis;
13. Pregnancy/lactation;
14. Un-correctable bleeding diathesis;
15. Poorly-controlled diabetes mellitus (DM);
16. Blood Sugar Level over 20mmols/L at the time of screening;
17. Inability to consent.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The NHMRC Clinical Trials Centre will manage randomization through an automated telephone based interactive voice response service (IVRS) that is available 24 hours a day. Automatic randomisation following the entry of baseline and minimisation data will be confirmed by emails sent to the enrolling site and the lead site. The system will also generate the individual participant unique identity number (UIN). The lead site will regularly check randomisation arm parity.
The randomisation will be performed by the research team over the phone. A randomisation number will be allocated and added to the prescription form that is sent to pharmacy.
Only the site pharmacy will be contacted by email by the randomisation service to inform them as to whether the participant has been randomised to the treatment or the placebo arm (unblinded email).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Dynamic (adaptive) random allocation methods using minimisation for three variables:
1. A history of diabetes, aiming to have the risk of hyperglycaemia the same in each arm.
2. Chalmers' score, which is a prediction score for development of complicated parapneumonic effusion and will ensure the severity of the illness is even in each arm.
3. Size of pleural effusion on the chest x-ray.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
As this is a pilot study, no data exists to determine the sample size. We aim to recruit a total of 80 participants from the participating sites. This will allow inclusion of the full range of parapneumonic effusions at various stages. The 2:1 randomization strategy will include 50+ patients into the dexamethasone arm to increase the power of detecting treatment related adverse events. The results of this pilot study will inform the power calculation of future studies.
Data will be analysed on an intention-to-treat basis. As a general principle, intergroup comparison will be conducted using Student’s t test or Mann-Whitney rank sum test (for parametric and non-parametric distributions respectively). Changes in parameters before and after treatment within the same subject will be analysed using a paired t test or Wilcoxon signed rank test. Correlations will be analysed using Pearson’s or Spearman’s tests. Multivariate analyses may be performed if indicated.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 10850 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 10851 0
Royal Perth Hospital - Perth
Recruitment hospital [3] 10852 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [4] 11010 0
St John of God Hospital, Midland - Midland
Recruitment postcode(s) [1] 22594 0
6009 - Nedlands
Recruitment postcode(s) [2] 22595 0
6000 - Perth
Recruitment postcode(s) [3] 22596 0
6150 - Murdoch
Recruitment postcode(s) [4] 22801 0
6056 - Midland

Funding & Sponsors
Funding source category [1] 296732 0
Charities/Societies/Foundations
Name [1] 296732 0
Sir Charles Gairdner and Osborne Park Health Care Group Research Advisory Committee
Address [1] 296732 0
Sir Charles Gairdner and Osborne Park Health Care Group Research Advisory Committee
QEII site
Hospital Avenue
Nedlands
WA 6009
Country [1] 296732 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Institute for Respiratory Health
Address
Block E, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, WA 6009.
Country
Australia
Secondary sponsor category [1] 295703 0
None
Name [1] 295703 0
N/A
Address [1] 295703 0
N/A
Country [1] 295703 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297960 0
Sir Charles Gairdner and Osborne Park HealthCare Group HREC
Ethics committee address [1] 297960 0
Sir Charles Gairdner Hospital
Level 2, “A” Block, Hospital Avenue, NEDLANDS WA 6009
Ethics committee country [1] 297960 0
Australia
Date submitted for ethics approval [1] 297960 0
30/01/2018
Approval date [1] 297960 0
16/03/2018
Ethics approval number [1] 297960 0

Summary
Brief summary
The lung and the inside of the chest wall are both covered by a thin lining called the pleura, which produces a very small amount of fluid to lubricate the lung during normal breathing. Pneumonia can cause a build-up of fluid in between the pleural linings called a parapneumonic pleural effusion. In many cases, the effusion clears up with antibiotics; less commonly, a chest tube is required to drain the fluid.
Steroids are anti-inflammatory medications that have been used for many years in the management of many medical conditions such as rheumatoid arthritis and asthma. In certain serious infections, inflammation is thought to be the cause of some of the symptoms, and steroids have been used to reduce these effects. Steroids have been used in people with pneumonia in the past with some success, and importantly, few side effects.

There is some evidence to suggest that parapneumonic pleural effusions occur because of excessive inflammation, which may delay recovery. A recent study in children showed that patients with a parapneumonic effusion recovered faster if they were treated with steroids in addition to antibiotics. In this study, we aim to assess whether administering steroids to adults with a parapneumonic effusion will speed up their recovery from the illness.

Study participants will receive 4 doses of steroid or a placebo over 48 hours. A placebo is a medication that looks the same as the steroid but doesn't contain any active drug. This study will be "double-blind" which means that neither the participant, nor the doctor, will know which treatment is administered until the end of the study. It is a randomised clinical trial which means that each participant will be put in one of the study groups (to receive the active drug or placebo) by chance and will not be able to choose their treatment. Two-thirds of participants will receive the study drug and one third will receive placebo.

The 48 hour treatment course is considered to be short, which means that there is much less likelihood of any side effects. The main side effect of steroids is high glucose levels in the blood, which typically go back to normal once the treatment is stopped. Other possible side effects include inflammation/bleeding in the stomach, suppression of the immune system and worsening infection, oral thrush and mood disturbance. In studies that have been done so far, none of these were more common in the group treated with steroids compared to those who weren’t.

The outcomes that we will assess to compare the two groups will include the time to recovery from the illness, changes in blood tests and chest x-rays over time, duration of antibiotic therapy and length of stay in hospital, need for a procedure to drain the fluid, quality of life over the 30 days post-treatment, adverse events (side effects of treatments) and overall survival. The data collected will be analysed by a statistician.
Trial website
Not applicable
Trial related presentations / publications
Not applicable
Public notes

Contacts
Principal investigator
Name 75586 0
Prof YC Gary Lee
Address 75586 0
UWA School of Medicine & Pharmacology
533, Harry Perkins Research Building
QE II Medical Centre
Hospital Avenue, Nedlands
Perth, WA 6009
Country 75586 0
Australia
Phone 75586 0
+61 8 61510913
Fax 75586 0
Email 75586 0
gary.lee@uwa.edu.au
Contact person for public queries
Name 75587 0
Prof YC Gary Lee
Address 75587 0
UWA School of Medicine & Pharmacology
533, Harry Perkins Research Building
QE II Medical Centre
Hospital Avenue, Nedlands
Perth, WA 6009
Country 75587 0
Australia
Phone 75587 0
+61 8 61510913
Fax 75587 0
Email 75587 0
gary.lee@uwa.edu.au
Contact person for scientific queries
Name 75588 0
Prof YC Gary Lee
Address 75588 0
UWA School of Medicine & Pharmacology
533, Harry Perkins Research Building
QE II Medical Centre
Hospital Avenue, Nedlands
Perth, WA 6009
Country 75588 0
Australia
Phone 75588 0
+61 8 61510913
Fax 75588 0
Email 75588 0
gary.lee@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Summary results
No Results