Intrapleural DNase and Tissue Plasminogen Activator in Pediatric Empyema (DTPA Trial)

• Sponsor: The Hospital for Sick Children (Other)
• Overall Status: Completed
• CT.gov ID: NCT01717742
• Collaborator: Canadian Institutes of Health Research (CIHR) (Other), Children's Hospital of Eastern Ontario (Other), St. Justine's Hospital (Other), Unity Health Toronto (Other), The Physicians' Services Incorporated Foundation (Other), McMaster Children's Hospital (Other), British Columbia Children's Hospital (Other)
• Enrollment: 97
• Locations: 6
• Arms: 2
• Duration (Months): 60
• Patients Per Site: 16.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Bacterial pneumonia can be complicated by the development of excess fluid and pus (pleural empyema) around the lungs in children. The incidence of pleural empyema in children has increased significantly in the last 10 years.

Short term morbidity for this condition is substantial, but unlike in adults, the long term outcome of this condition for children in developed countries is favourable. Inserting a chest drain and then adding a medicine (tissue plasminogen activator - tPA) to break down organized pus has been shown to be an effective therapy for reducing the duration of illness. However, this treatment is still suboptimal and prolonged hospitalization is common. Recent data from adults suggests that adding an additional medicine (DNase) to decrease the viscosity (thickness) of the fluid improves drainage and leads to better patient outcomes; however, there are no published studies on children.

This is a multi-centre randomized controlled trial comparing the time to discharge from hospital after chest drain insertion in previously well children who present with pleural empyema, treated with intrapleural DNase and tissue plasminogen activator (tPA) by chest drain for three doses over 48 hours compared with three doses over 48 hours of tPA alone. Other outcomes related to effectiveness, safety and cost will be assessed as well.

Condition or Disease	Intervention/Treatment	Phase
Pleural Empyema	Drug: TPA (Tissue Plasminogen Activator); Drug: DNase; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Intrapleural DNase and Tissue Plasminogen Activator in Pediatric Empyema (DTPA Trial)
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Dec 1, 2017
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: tPA and placebo	Drug: TPA (Tissue Plasminogen Activator); Intrapleural administration of tPA 4 mg in 10 ml (≤10 kg) or 20 ml (>10 kg) normal saline once daily for 3 days; Other Names: Cathflo (alteplase, recombinant) ; Other: Placebo; Intrapleural administration of normal saline 10 ml (≤10 kg) or 20 ml (>10 kg); Other Names: Normal saline
Experimental: tPA and DNase	Drug: TPA (Tissue Plasminogen Activator); Intrapleural administration of tPA 4 mg in 10 ml (≤10 kg) or 20 ml (>10 kg) normal saline once daily for 3 days; Other Names: Cathflo (alteplase, recombinant) ; Drug: DNase; Intrapleural administration of DNase 5 mg diluted to 10 ml (≤10 kg) or 20 ml (>10 kg) normal saline once daily for 3 days; Other Names: Pulmozyme (Dornase alfa)

Outcome Measures

Primary Outcome Measures

1. Time to Hospital Discharge [up to 4 months]

   Time from insertion of the chest drain to discharge from hospital.

Secondary Outcome Measures

1. Time to Meeting Discharge Criteria [up to 4 months]

   Time from insertion of the chest drain to meeting discharge criteria. Discharge criteria: Chest tube removed No fever [temperature less than 38°C] Normal respiratory rate forage No hypoxia Drinking fluids wel

2. Time to Drain Removal [up to 4 months]

   Time from drain insertion to drain removal.

3. Duration of Fever After Intervention [up to 4 months]

   Duration of fever (defined as temperature >38 degrees celsius taken by any method) from insertion of the chest drain until resolution.

4. Number of Participants With Need for Ventilatory Support or Non-invasive Ventilation Following the Intervention [up to 4 months]

   Number of Participants with need for any kind of ventilatory support or any kind of non-invasive ventilation right after the intervention.

5. Number of Participants With Serious Bleeding [up to 4 months]

   Number of Participants who had intrapleural bleeding resulting in a drop in hemoglobin of greater than 20 g/L or needing a transfusion.

6. Number of Participants With Further Interventions [up to 4 months]

   Number of participants who needed further intervention such as placement of another chest drain (by any technique) or surgical intervention such as thoracotomy and decortication, video-assisted thorascopic surgery, or pneumonectomy.

7. Number of Participants With Hospital Readmission [3 months post-discharge]

   Number of Participants who had any hospital readmission after discharge from hospital for initial treatment for pleural empyema within three months related to pleural empyema or its treatment.

8. Cost of the Hospitalization [up to 4 months]

   An economic evaluation will compare the relative costs of DNase-tPA with tPA alone in previously well children who present with pleural empyema, using patient-level data from the trial.

9. Mortality [up to 4 months]

   Mortality from any cause during the hospitalization for empyema.

Other Outcome Measures

1. Chest Radiography [7 days after drain removal]

   The radiograph closest to the time of drain removal will be reviewed by a blinded study radiologist to determine the percentage of hemithorax occupied using a 5 point ordinal scale utilized in previous studies ranging from no fluid present to fluid occupying >75% of the most affected hemithorax.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. age 6 months to 18 years

2. hospitalized with diagnosis of pleural empyema requiring chest tube drainage with fibrinolytics as judged by the attending physician with the following criteria:

3. pneumonia with pleural effusion as documented on ultrasound of the chest; AND

4. need for further intervention in addition to antibiotics based on clinical criteria [persistent fever despite on antibiotics for at least 48 hours OR significant respiratory distress tachypnea, hypoxia) as a result of the pleural fluid collection]

Exclusion Criteria:

1. empyema as a result of tuberculosis, fungus or non-infectious causes (e.g. malignancy)

2. known coagulation impairment

3. suspected or proven allergy to tPA or DNase

4. chronic lung disease or other chronic illnesses (e.g. immunodeficiency or neurologic impairment)

5. child has already undergone a drainage procedure (e.g. chest drain or VATS).

6. recent administration of an investigational drug (within previous 30 days)

7. pregnancy

8. breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alberta Children's Hospital	Calgary	Alberta	Canada
2	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	BC V6H 3N1
3	McMaster Children's Hospital	Hamilton	Ontario	Canada	L8N 3Z5
4	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
5	The Hospital for Sick Children(SickKids)	Toronto	Ontario	Canada	M5G 1X8
6	CHU Sainte Justine	Montreal	Quebec	Canada	H3T 1C5

Sponsors and Collaborators

• The Hospital for Sick Children
• Canadian Institutes of Health Research (CIHR)
• Children's Hospital of Eastern Ontario
• St. Justine's Hospital
• Unity Health Toronto
• The Physicians' Services Incorporated Foundation
• McMaster Children's Hospital
• British Columbia Children's Hospital

Investigators

• Principal Investigator: Eyal Cohen, MD, MSc, The Hospital for Sick Children

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 29, 2017
• Informed Consent Form - Oct 12, 2017

More Information

Publications

None provided.

• Responsible Party: Eyal Cohen, Staff Physician, The Hospital for Sick Children
• ClinicalTrials.gov Identifier: NCT01717742
• Other Study ID Numbers: 1000033767
• First Posted: Oct 30, 2012
• Last Update Posted: Apr 14, 2020
• Last Verified: Apr 1, 2020

• Keywords provided by Eyal Cohen, Staff Physician, The Hospital for Sick Children: Randomized controlled trial; Pleural Empyema; tPA; DNase
• Additional relevant MeSH terms: Empyema; Empyema, Pleural; Tissue Plasminogen Activator; Plasminogen

Study Results

Participant Flow

Arm/Group Title	tPA (Tissue Plasminogen Activator) and Placebo	tPA (Tissue Plasminogen Activator) and DNase
Arm/Group Description	tPA: Intrapleural administration of tPA 4 mg in 10 ml (≤10 kg) or 20 ml (>10 kg) normal saline once daily for 3 days Placebo: Intrapleural administration of normal saline 10 ml (≤10 kg) or 20 ml (>10 kg)	tPA: Intrapleural administration of tPA 4 mg in 10 ml (≤10 kg) or 20 ml (>10 kg) normal saline once daily for 3 days DNase: Intrapleural administration of DNase 5 mg diluted to 10 ml (≤10 kg) or 20 ml (>10 kg) normal saline once daily for 3 days
Period Title: Overall Study
STARTED	48	49
COMPLETED	43	47
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	Intervention (tPA & DNase)	Placebo (tPA & Placebo)	Total
Arm/Group Description	Intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline	Total of all reporting groups
Overall Participants	49	48	97
Age (Count of Participants)
<=18 years	49 100%	48 100%	97 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (Months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Months]	58.4 (43.3)	64.1 (44.2)	61.3 (45.6)
Sex: Female, Male (Count of Participants)
Female	24 49%	21 43.8%	45 46.4%
Male	25 51%	27 56.3%	52 53.6%
Race/Ethnicity, Customized (Count of Participants)
First nations	0 0%	2 4.2%	2 2.1%
African	2 4.1%	0 0%	2 2.1%
Asian/Pacific Islander	14 28.6%	13 27.1%	27 27.8%
White	26 53.1%	26 54.2%	52 53.6%
Hispanic	1 2%	0 0%	1 1%
Middle Eastern	0 0%	1 2.1%	1 1%
South Asian	0 0%	1 2.1%	1 1%
Prefer not to answer	5 10.2%	4 8.3%	9 9.3%
Missing	1 2%	1 2.1%	2 2.1%
Region of Enrollment (Count of Participants)
Canada	49 100%	48 100%	97 100%

Outcome Measures

1. Primary Outcome

Title	Time to Hospital Discharge
Description	Time from insertion of the chest drain to discharge from hospital.
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Mean (Standard Deviation) [days]	9.0 (4.9)	9.1 (5.3)

2. Secondary Outcome

Title	Time to Meeting Discharge Criteria
Description	Time from insertion of the chest drain to meeting discharge criteria. Discharge criteria: Chest tube removed No fever [temperature less than 38°C] Normal respiratory rate forage No hypoxia Drinking fluids wel
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Mean (Standard Deviation) [days]	8.2 (4.5)	8.5 (5.4)

3. Secondary Outcome

Title	Time to Drain Removal
Description	Time from drain insertion to drain removal.
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Mean (Standard Deviation) [days]	6.9 (4.3)	6.9 (5.3)

4. Secondary Outcome

Title	Duration of Fever After Intervention
Description	Duration of fever (defined as temperature >38 degrees celsius taken by any method) from insertion of the chest drain until resolution.
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Mean (Standard Deviation) [days]	2.8 (3.4)	3.3 (3.4)

5. Secondary Outcome

Title	Number of Participants With Need for Ventilatory Support or Non-invasive Ventilation Following the Intervention
Description	Number of Participants with need for any kind of ventilatory support or any kind of non-invasive ventilation right after the intervention.
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Count of Participants [Participants]	9 18.4%	8 16.7%

6. Secondary Outcome

Title	Number of Participants With Serious Bleeding
Description	Number of Participants who had intrapleural bleeding resulting in a drop in hemoglobin of greater than 20 g/L or needing a transfusion.
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Count of Participants [Participants]	2 4.1%	4 8.3%

7. Secondary Outcome

Title	Number of Participants With Further Interventions
Description	Number of participants who needed further intervention such as placement of another chest drain (by any technique) or surgical intervention such as thoracotomy and decortication, video-assisted thorascopic surgery, or pneumonectomy.
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Count of Participants [Participants]	4 8.2%	2 4.2%

8. Secondary Outcome

Title	Number of Participants With Hospital Readmission
Description	Number of Participants who had any hospital readmission after discharge from hospital for initial treatment for pleural empyema within three months related to pleural empyema or its treatment.
Time Frame	3 months post-discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Count of Participants [Participants]	2 4.1%	0 0%

9. Secondary Outcome

Title	Cost of the Hospitalization
Description	An economic evaluation will compare the relative costs of DNase-tPA with tPA alone in previously well children who present with pleural empyema, using patient-level data from the trial.
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Mean (Standard Deviation) [2018 US $]	11329 (7139)	10760 (5071)

10. Secondary Outcome

Title	Mortality
Description	Mortality from any cause during the hospitalization for empyema.
Time Frame	up to 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
Count of Participants [Participants]	0 0%	0 0%

11. Other Pre-specified Outcome

Title	Chest Radiography
Description	The radiograph closest to the time of drain removal will be reviewed by a blinded study radiologist to determine the percentage of hemithorax occupied using a 5 point ordinal scale utilized in previous studies ranging from no fluid present to fluid occupying >75% of the most affected hemithorax.
Time Frame	7 days after drain removal

Outcome Measure Data

Analysis Population Description

Degree of opacification on chest radiography prior to chest tube removal

Arm/Group Title	Intervention	Control
Arm/Group Description	Intervention group received intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg	Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
Measure Participants	49	48
<=25%	33 67.3%	25 52.1%
26-50%	10 20.4%	11 22.9%
51-75%	1 2%	4 8.3%
>75%	2 4.1%	1 2.1%
Missing	3 6.1%	7 14.6%

Adverse Events

Time Frame	Over the course of the patient's hospitalization
Adverse Event Reporting Description	All serious unexpected adverse events were reported to the REB. All serious adverse drug reactions to the study medication were reported to Health Canada within 15 calendar days or for death or life-threatening events, within 7 calendar days. In the latter case, a follow-up report was filed within 8 calendar days. Adverse reactions will be managed according to the standard clinical management practices. All adverse events and adverse reactions were reported to the PI within 24 hours.
Arm/Group Title	Intervention		Control
Arm/Group Description	Intervention group received ) intrapleural tPA, 4 mg, followed by DNase (Roche), 5 mg		Control group received intrapleural tPA (Roche), 4 mg, followed by 5 mL of normal saline
All Cause Mortality
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/48 (0%)
Serious Adverse Events
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/49 (12.2%)		8/48 (16.7%)
Blood and lymphatic system disorders
Serious bleeding	2/49 (4.1%)	2	4/48 (8.3%)	4
Low hemoglobin levels	0/49 (0%)	0	2/48 (4.2%)	2
Septic shock	0/49 (0%)	0	1/48 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
TENSION PYOTHORAX	1/49 (2%)	1	0/48 (0%)	0
Bronchopleural fistula	2/49 (4.1%)	2	0/48 (0%)	0
Hemothorax	1/49 (2%)	1	1/48 (2.1%)	1
Other (Not Including Serious) Adverse Events
	Intervention		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/49 (16.3%)		13/48 (27.1%)
Blood and lymphatic system disorders
Mild bleeding	1/49 (2%)	1	0/48 (0%)	0
Cardiac disorders
Transient chest pain	1/49 (2%)	1	0/48 (0%)	0
Endocrine disorders
Low albumin	1/49 (2%)	1	1/48 (2.1%)	1
Elevated potassium	0/49 (0%)	0	1/48 (2.1%)	1
Gastrointestinal disorders
Nausea	0/49 (0%)	0	2/48 (4.2%)	2
Constipation	1/49 (2%)	1	2/48 (4.2%)	2
General disorders
Edema	0/49 (0%)	0	2/48 (4.2%)	2
Chest tube removed accidentally	0/49 (0%)	0	1/48 (2.1%)	1
Immune system disorders
Herpes simplex virus infection	1/49 (2%)	1	0/48 (0%)	0
Other bacterial infection	1/49 (2%)	1	0/48 (0%)	0
Renal and urinary disorders
Urinary infection	0/49 (0%)	0	1/48 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Kinked chest tube	1/49 (2%)	1	0/48 (0%)	0
Upper respiratory infection	0/49 (0%)	0	1/48 (2.1%)	1
Skin and subcutaneous tissue disorders
Rash	0/49 (0%)	0	2/48 (4.2%)	2
Pruritus	1/49 (2%)	1	0/48 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.