Efficacy and Safety of Activase (Ateplase) vs Placebo in Complicated Pleural Effusions (CPE)/Empyemas

• Sponsor: Midwest Pulmonary and Critical Care (Other)
• Overall Status: Completed
• CT.gov ID: NCT00468104
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 100
• Location: 1
• Arms: 2
• Duration (Months): 64
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The purpose of this study is to document the efficacy and safety of intrapleural instillation of Activase vs Placebo in the management of complicated pleural effusions and empyemas

Condition or Disease	Intervention/Treatment	Phase
Pleural Effusion Associated With Pulmonary Infection; Bacterial Pleural Effusion Other Than Tuberculosis	Drug: Alteplase; Drug: Placebo	N/A

Detailed Description

The current treatments available for complicated pleural effusions (CPE) include chest tube placement for drainage and IV antibiotics. If this fails and CPE occurs then in most patients thoracotomy is performed. Patients that are not surgical candidates have image guided catheter placement performed, sometimes multiple times. The American College of Chest Physicians (ACCP) formed a CPE panel and published guidelines for treating CPE. Percutaneous image-guided drainage is the most common approach for CPE. The panel recognizes the cumulative data that supports the use of fibrinolytics, VATS, and thoracotomy. The CPE panel acknowledged the lack of randomized clinical trials to determine efficacy and safety of these modalities in CPE and strongly encourages the research to take place.

Fibrinolytic therapy is a relatively noninvasive, easy to use, and is relatively inexpensive. If successful, it will prevent sepsis and septic shock, decrease hospital stay, morbidity and mortality and prevent any surgical procedures. Multiple doses of fibrinolytics have been used in CPE with no evidence of systemic anti-fibrinolytic activity. Complications with these medications are also very uncommon and only isolated instances are reported. The benefit from successful pleural drainage using these agents will decrease morbidity, mortality, surgical procedures, and hospital stay.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Response to Instillation of Activase in the Pleural Cavity vs Placebo in the Management of Complicated Pleural Effusion/Empyema
• Study Start Date: Apr 1, 2004
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Alteplase, Placebo- intapleural instillation Either 25 mg of Alteplase or Placebo instilled daily. Response to therapy after three days. cross over to the other drug if no response was noted.	Drug: Alteplase; 25 Mg of Alteplase in 100 cc of normal saline was instilled intrapeurally for daily for three days; Drug: Placebo; Placebo in 100 cc of normal saline was instilled intrapleurally daily for three days; Other Names: TPA, Activase
Active Comparator: Placebo, Alteplase -2nd arm If the first arm fails then the 2nd arm ( cross over to either Placebo or Alteplase not used in the first arm) instilled intrapleurally daily for three days	Drug: Alteplase; 25 Mg of Alteplase in 100 cc of normal saline was instilled intrapeurally for daily for three days; Drug: Placebo; Placebo in 100 cc of normal saline was instilled intrapleurally daily for three days; Other Names: TPA, Activase

Outcome Measures

Primary Outcome Measures

1. No Surgical Intervention [patients were followed six weeks per protocol. Most patients treated with Alteplase were also followed for up to six months]

   CT scans of the chest and Chest X rays (CXR) were used to determine resolution of Pleural effusions/empyema/ pneumonia after 3 days of Alteplase/ Placebo therapy. If no response was noted with the first intervention patients were offered surgery --Decortiation/ Video Assisted Thoracic Surgery (VATS) or to receive the second intervention. Patients that failed the second intervention were offered surgery.

Secondary Outcome Measures

1. Number of Participants With Pneumonia That Responded to Therapy [6 weeks]

   patients were followed for 6 weeks and CXR and CT scan were done to document resolution of pneumonia

2. Number of Participants With Pleural Effusion/Empyema That Responded to Therapy [6 weeks]

   patients were followed for 6 weeks and CXR and CT scan were done to document resolution of pleural effusion/empyema

3. Number of Participants With Shortness of Breath That Responded to Therapy [6 weeks]

   patients were followed for 6 weeks and clinical symptoms of resolution of shortness of breath were documented

4. Number of Participants With Clinical Symptoms of Sepsis That Responded to Therapy [6 weeks]

   patients were followed for 6 weeks and resolution of sepsis was documented

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosed with complicated pleural effusions

• Ability to provide written informed consent and comply with study assessments for the full duration of the study.

• Age > 18 years

Exclusion Criteria

• Current use of oral anticoagulants (e.g., warfarin sodium) with an International Normalized Ratio (INR) >5- Activated partial thromboplastin time (aPPT) > 80, Platelet count < 100,000/mm3;

• Severe uncontrolled hypertension

• Recognized hypersensitivity to Activase; or any component of its formulation; Traumatic pleural effusion

• Pregnancy (positive pregnancy test)

• In another study for this condition

• Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated

• Participation in another simultaneous medical investigation

• Recent stroke

• Intracranial hemorrhage

• arteriovenous malformation or aneurysm

• Intracranial neoplasm

• Acute myocardial infarction

• Acute pulmonary embolus

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114

Sponsors and Collaborators

• Midwest Pulmonary and Critical Care
• Genentech, Inc.

Investigators

• Principal Investigator: George Thommi, MD, Midwest Pulmonary and Critical Care, PC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GEORGE THOMMI, MD, Midwest Pulmonary and Critical Care
• ClinicalTrials.gov Identifier: NCT00468104
• Other Study ID Numbers: 11415
• First Posted: May 2, 2007
• Last Update Posted: Apr 30, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by GEORGE THOMMI, MD, Midwest Pulmonary and Critical Care: parapneumonic pleural effusion; empyema; TPA (Activase, Alteplase)
• Additional relevant MeSH terms: Tuberculosis; Empyema; Pleural Effusion; Tissue Plasminogen Activator

Study Results

Participant Flow

Recruitment Details	Patients with loculated pleural effusions that failed to respond to chest tube placement and standard medical treatment and were considered for surgery were given the option to enter into a double blind cross over trial
Pre-assignment Detail	108 patients were evaluated but only 100 entered the trial. 2 patients refused, 2 patients admitting physicians opted out of the trial, 3 patients chest tube removed inadvertently, 1 patient for coagulopathy

Arm/Group Title	Alteplase Then Placebo	Placebo Then Alteplase
Arm/Group Description	25 mg of Alteplase in 100 cc of normal saline was instilled intrapleurally daily for three days. Chest CT scans were performed on the fourth day . If less than a 50% reduction in the pleural effusion was determined, the patient was given the option to go to surgery or to the second intervention of the trial (with Placebo)	Placebo in 100 cc of normal saline was instilled intrapleurally daily for three days. Chest CT scans were performed on the fourth day . If less than a 50% reduction in the pleural effusion was determined, the patient was given the option to go to surgery or to the second intervention of the trial (with Alteplase)
Period Title: First Intervention
STARTED	54	46
COMPLETED	45	45
NOT COMPLETED	9	1
Period Title: First Intervention
STARTED	8	41
COMPLETED	3	37
NOT COMPLETED	5	4

Baseline Characteristics

Arm/Group Title	Alteplase; Placebo
Arm/Group Description	25mg of Alteplase in 100 cc of normal saline instilled intrapleurally; 100 cc of normal saline instilled intrapleurally
Overall Participants	100
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	39 39%
>=65 years	61 61%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67 (15)
Sex: Female, Male (Count of Participants)
Female	36 36%
Male	64 64%
Region of Enrollment (participants) [Number]
United States	100 100%

Outcome Measures

1. Primary Outcome

Title	No Surgical Intervention
Description	CT scans of the chest and Chest X rays (CXR) were used to determine resolution of Pleural effusions/empyema/ pneumonia after 3 days of Alteplase/ Placebo therapy. If no response was noted with the first intervention patients were offered surgery --Decortiation/ Video Assisted Thoracic Surgery (VATS) or to receive the second intervention. Patients that failed the second intervention were offered surgery.
Time Frame	patients were followed six weeks per protocol. Most patients treated with Alteplase were also followed for up to six months

Outcome Measure Data

Analysis Population Description

intention to treat

Arm/Group Title	Alteplase	Placebo
Arm/Group Description	25mg of Alteplase in 100 cc of normal saline given intrapleurally daily for 3 days either in the first or second arm	Placebo in 100 cc of normal saline given daily intrapleurally for 3 days either in the first or second arm
Measure Participants	81	47
Number [participants]	66 66%	6 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alteplase, Placebo
	Comments	A univariate analysis was done to identify possible predictors of successful resolution of symptoms. The chi-square analysis was used to compare the percent successful.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments

2. Secondary Outcome

Title	Number of Participants With Pneumonia That Responded to Therapy
Description	patients were followed for 6 weeks and CXR and CT scan were done to document resolution of pneumonia
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

protocol design prevented assigning symptom resolution to a specific intervention therefore secondary outcome measures in 6 weeks were not analyzed

Arm/Group Title	Alteplase	Placebo
Arm/Group Description	25mg of Alteplase in 100 cc of normal saline instilled intrapleurally	100 cc of normal saline instilled intrapleurally
Measure Participants	0	0

3. Secondary Outcome

Title	Number of Participants With Pleural Effusion/Empyema That Responded to Therapy
Description	patients were followed for 6 weeks and CXR and CT scan were done to document resolution of pleural effusion/empyema
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

protocol design prevented assigning symptom resolution to a specific intervention therefore secondary outcome measures in 6 weeks were not analyzed

Arm/Group Title	Alteplase	Placebo
Arm/Group Description	25mg of Alteplase in 100 cc of normal saline instilled intrapleurally	100 cc of normal saline instilled intrapleurally
Measure Participants	0	0

4. Secondary Outcome

Title	Number of Participants With Shortness of Breath That Responded to Therapy
Description	patients were followed for 6 weeks and clinical symptoms of resolution of shortness of breath were documented
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

protocol design prevented assigning symptom resolution to a specific intervention therefore secondary outcome measures in 6 weeks were not analyzed

Arm/Group Title	Alteplase	Placebo
Arm/Group Description	25mg of Alteplase in 100 cc of normal saline instilled intrapleurally	100 cc of normal saline instilled intrapleurally
Measure Participants	0	0

5. Secondary Outcome

Title	Number of Participants With Clinical Symptoms of Sepsis That Responded to Therapy
Description	patients were followed for 6 weeks and resolution of sepsis was documented
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

protocol design prevented assigning symptom resolution to a specific intervention therefore secondary outcome measures in 6 weeks were not analyzed

Arm/Group Title	Alteplase	Placebo
Arm/Group Description	25mg of Alteplase in 100 cc of normal saline instilled intrapleurally	100 cc of normal saline instilled intrapleurally
Measure Participants	0	0

Adverse Events

Time Frame	soon after drug instillation and for the first 24 hours in the hospital and then followed up for six months
Adverse Event Reporting Description	adverse events that occurred in patients after they received both Alteplase and Placebo were placed in a separate group as we were unable to determine which intervention ( Alteplase or Placebo) caused the problem
Arm/Group Title	Received Alteplase Only		Received Placebo Only		Received Both Alteplase and Placebo
Arm/Group Description	These patients received only Alteplase and were not crossed over		These patients received Placebo only and were not crossed over		These patients were crossed over and received both Alteplase and Placebo
All Cause Mortality
	Received Alteplase Only		Received Placebo Only		Received Both Alteplase and Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Received Alteplase Only		Received Placebo Only		Received Both Alteplase and Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/42 (2.4%)		0/8 (0%)		0/40 (0%)
General disorders
Shortness of breath, worsening sepsis	0/42 (0%)	0	0/8 (0%)	0	0/40 (0%)	0
Skin and subcutaneous tissue disorders
serious bleeding at the chest tube site	1/42 (2.4%)	1	0/8 (0%)	0	0/40 (0%)	0
Other (Not Including Serious) Adverse Events
	Received Alteplase Only		Received Placebo Only		Received Both Alteplase and Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/42 (23.8%)		5/8 (62.5%)		8/40 (20%)
Blood and lymphatic system disorders
blood loss--pleural fluid	3/42 (7.1%)	3	0/8 (0%)	3	0/40 (0%)	3
General disorders
severe chest pain post drug instillation	1/42 (2.4%)	12	0/8 (0%)	12	1/40 (2.5%)	12
mild to moderate chest pain	6/42 (14.3%)	12	1/8 (12.5%)	12	3/40 (7.5%)	12
hypotension and worsening renal function	0/42 (0%)	4	0/8 (0%)	4	4/40 (10%)	4
Infections and infestations
worsening sepsis	0/42 (0%)	2	2/8 (25%)	2	0/40 (0%)	2
Respiratory, thoracic and mediastinal disorders
increasing shortness of breath	0/42 (0%)	0	2/8 (25%)	2	0/40 (0%)	2

Limitations/Caveats

The sample size for secondary outcomes in the Placebo group is small

More Information

Certain Agreements

Principal Investigators are NOT 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.