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

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.

Study Overview

• Status: Completed
• Conditions: Pleural Empyema
• Intervention / Treatment: Drug: TPA (Tissue Plasminogen Activator); Other: Placebo; Drug: DNase

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Alberta Children's Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, BC V6H 3N1
      • British Columbia Children's Hospital
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children(SickKids)
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • CHU Sainte Justine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

   1. pneumonia with pleural effusion as documented on ultrasound of the chest; AND
   2. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Meeting Discharge Criteria	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	up to 4 months
Time to Drain Removal	Time from drain insertion to drain removal.	up to 4 months
Duration of Fever After Intervention	Duration of fever (defined as temperature >38 degrees celsius taken by any method) from insertion of the chest drain until resolution.	up to 4 months
Number of Participants With Need for Ventilatory Support or Non-invasive Ventilation Following the Intervention	Number of Participants with need for any kind of ventilatory support or any kind of non-invasive ventilation right after the intervention.	up to 4 months
Number of Participants With Serious Bleeding	Number of Participants who had intrapleural bleeding resulting in a drop in hemoglobin of greater than 20 g/L or needing a transfusion.	up to 4 months
Number of Participants With Further Interventions	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.	up to 4 months
Number of Participants With Hospital Readmission	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.	3 months post-discharge
Cost of the Hospitalization	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.	up to 4 months
Mortality	Mortality from any cause during the hospitalization for empyema.	up to 4 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chest Radiography	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.	7 days after drain removal

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: Canadian Institutes of Health Research (CIHR); Unity Health Toronto; Children's Hospital of Eastern Ontario; British Columbia Children's Hospital; McMaster Children's Hospital; St. Justine's Hospital; The Physicians' Services Incorporated Foundation
• Investigators: Principal Investigator: Eyal Cohen, MD, MSc, The Hospital for Sick Children

Publications and helpful links

General Publications

• Livingston MH, Mahant S, Connolly B, MacLusky I, Laberge S, Giglia L, Yang C, Roberts A, Shawyer A, Brindle M, Parsons S, Stoian C, Walton JM, Thorpe KE, Chen Y, Zuo F, Mamdani M, Chan C, Loong D, Isaranuwatchai W, Ratjen F, Cohen E. Effectiveness of Intrapleural Tissue Plasminogen Activator and Dornase Alfa vs Tissue Plasminogen Activator Alone in Children with Pleural Empyema: A Randomized Clinical Trial. JAMA Pediatr. 2020 Apr 1;174(4):332-340. doi: 10.1001/jamapediatrics.2019.5863.
• Livingston MH, Mahant S, Ratjen F, Connolly BL, Thorpe K, Mamdani M, Maclusky I, Laberge S, Giglia L, Walton JM, Yang CL, Roberts A, Shawyer AC, Brindle M, Parsons SJ, Stoian CA, Cohen E. Intrapleural Dornase and Tissue Plasminogen Activator in pediatric empyema (DTPA): a study protocol for a randomized controlled trial. Trials. 2017 Jun 24;18(1):293. doi: 10.1186/s13063-017-2026-0.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: October 25, 2012
• First Submitted That Met QC Criteria: October 26, 2012
• First Posted (Estimate): October 30, 2012

Study Record Updates

• Last Update Posted (Actual): April 14, 2020
• Last Update Submitted That Met QC Criteria: April 6, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Randomized controlled trial; tPA; Pleural Empyema; DNase
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Inflammation; Pleural Diseases; Suppuration; Empyema; Empyema, Pleural; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Plasminogen
• Other Study ID Numbers: 1000033767