IMPI 2 - A Trial of Intrapericardial Alteplase in Large Pericardial Effusion (IMPI-2)
Primary Purpose
Pericardial Effusion
Status
Unknown status
Phase
Phase 3
Locations
South Africa
Study Type
Interventional
Intervention
Pericardiocentesis with Alteplase
Conventional Pericardiocentesis
Sponsored by
About this trial
This is an interventional treatment trial for Pericardial Effusion
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 18 years of age;
- Confirmed large pericardial effusion on echocardiography (i.e., echo free space ≥1 cm anterior to the right ventricle of the heart in diastole);
- Willingness to participate for the full duration of the trial (i.e., 12 months); and
- Provision of written informed consent.
Exclusion Criteria:
- Age < 18 years;
- Uraemic pericarditis (i.e., urea > 21.4 mmol/l);
- Thrombocytopenia (i.e., < 100,000 platelets per µl);
- Presence of a contra-indication to the administration of a fibrinolytic agent (i.e., major haemorrhage or major trauma; coincidental stroke; major surgery in the previous 5 days; blood pressure >200/100 mmHg).
Sites / Locations
- Groote Schuur HospitalRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Other
Arm Label
Pericardiocentesis with Alteplase
Conventional Pericardiocentesis
Arm Description
Complete percutaneous pericardial drainage facilitated by intrapericardial alteplase.
Conventional pericardiocentesis when indicated.
Outcomes
Primary Outcome Measures
Composite outcome of cardiac tamponade requiring pericardiocentesis or constrictive pericarditis.
Cardiac tamponade requiring pericardiocentesis shall refer to a combination of physical and echocardiographic findings, i.e., patients with clinical signs of tachycardia (> 90 bpm), hypotension (systolic blood pressure < 100 mmHg), elevated jugular venous pressure and/or pulsus paradoxus > 10 mmHg plus evidence of a large pericardial effusion with echocardiographic signs of tamponade in the absence of other cardiac disease, as defined in the IMPI trial.
Constrictive pericarditis shall refer to a combination of physical and echocardiographic findings (i.e., patients with a prior history of pericardial effusion who have pulsus paradoxus, a raised jugular venous pressure with or without evidence of pericardial thickening on imaging) in the absence of either large pericardial effusion or other cardiac disease, as described in the IMPI trial.
Secondary Outcome Measures
Major bleeding
Defined as clinically overt bleeding accompanied by one or more of the following: a decrease in the haemoglobin level of 2 g per decilitre or more over a 24-hour period, transfusion of 2 or more units of packed red cells, bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding
Clinically relevant non-major bleeding
Defined as clinically overt bleeding that does not satisfy the criteria for major bleeding and that leads to hospital admission, physician-guided medical or surgical treatment.
Any bleeding
Any other form of bleeding that is not covered by safety outcomes 1-3
Other adverse events
Any other adverse events
Persistent pericardial effusion without cardiac tamponade
Refers to the echocardiographic presence of a pericardial effusion without criteria for cardiac tamponade requiring pericarditis during follow-up visits. The pericardial effusion is the same size or larger than that measured at the time of enrollment (where no pericardiocentesis was done) or post-pericardiocentesis.
Recurrent pericardial effusion without cardiac tamponade
Refers to the echocardiographic presence of a pericardial effusion without criteria for cardiac tamponade requiring pericarditis during follow-up visits. Recurrence is present in the context of re-appearance of a pericardial effusion in the context where complete drainage was performed.
Hospitalisation for any cause; and death from any cause
Refers to admission to hospital for at least 24 hours for any reason.
Cardiac tamponade requiring pericardiocentesis
Cardiac tamponade requiring pericardiocentesis shall refer to a combination of physical and echocardiographic findings, i.e., patients with clinical signs of tachycardia (> 90 bpm), hypotension (systolic blood pressure < 100 mmHg), elevated jugular venous pressure and/or pulsus paradoxus > 10 mmHg plus evidence of a large pericardial effusion with echocardiographic signs of tamponade in the absence of other cardiac disease, as defined in the IMPI trial.
Constrictive pericarditis
Constrictive pericarditis shall refer to a combination of physical and echocardiographic findings (i.e., patients with a prior history of pericardial effusion who have pulsus paradoxus, a raised jugular venous pressure with or without evidence of pericardial thickening on imaging) in the absence of either large pericardial effusion or other cardiac disease, as described in the IMPI trial.
Death
Death from any cause
Full Information
NCT ID
NCT02673879
First Posted
February 1, 2016
Last Updated
April 30, 2018
Sponsor
University of Cape Town
Collaborators
Walter Sisulu University, Population Health Research Institute
1. Study Identification
Unique Protocol Identification Number
NCT02673879
Brief Title
IMPI 2 - A Trial of Intrapericardial Alteplase in Large Pericardial Effusion
Acronym
IMPI-2
Official Title
A Trial of Complete Percutaneous Pericardial Drainage Facilitated by Intrapericardial Alteplase Compared to Conventional Pericardiocentesis When Indicated in Adults With Large Pericardial Effusion Due to Tuberculous and Non-tuberculous Pericarditis
Study Type
Interventional
2. Study Status
Record Verification Date
February 2016
Overall Recruitment Status
Unknown status
Study Start Date
February 2016 (undefined)
Primary Completion Date
July 2019 (Anticipated)
Study Completion Date
January 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cape Town
Collaborators
Walter Sisulu University, Population Health Research Institute
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The Second Investigation of the Management of Pericarditis (IMPI-2) Trial will compare the effectiveness and safety of complete percutaneous pericardial drainage facilitated by intrapericardial alteplase (recombinant human tissue-type plasminogen activator) to conventional pericardiocentesis when indicated in 2176 patients with large pericardial effusion due to tuberculous and non-tuberculous pericarditis. An internal pilot study of 218 patients will initially confirm the feasibility of conducting a large-scale multi-centre clinical trial of intrapericardial fibrinolysis in patients with large pericardial effusion, and also provide preliminary safety data, following a dose finding study of intrapericardial alteplase.
Detailed Description
Intrapericardial fibrinolytic agents are used in the drainage of tuberculous, purulent, neoplastic and other inflammatory pericardial effusions to prevent recurrent effusions and constrictive pericarditis. This use is based on evidence from case reports and a small trial that did not have the statistical power to reliably evaluate the effect of pericardial drainage facilitated by intrapericardial fibrinolysis on safety and important clinical outcomes.
The Second Investigation of the Management of Pericarditis (IMPI-2) Trial will compare the effectiveness and safety of complete percutaneous pericardial drainage facilitated by intrapericardial alteplase (recombinant human tissue-type plasminogen activator) to conventional pericardiocentesis when indicated in 2176 patients with large pericardial effusion due to tuberculous and non-tuberculous pericarditis. An internal pilot study of 218 patients will initially confirm the feasibility of conducting a large-scale multi-centre clinical trial of intrapericardial fibrinolysis in patients with large pericardial effusion, and also provide preliminary safety data, following a dose finding study of intrapericardial alteplase.
Hypothesis: We hypothesise that patients with large pericardial effusion randomized to intrapericardial alteplase to ensure complete pericardial drainage will have at least a 35% reduction in cardiac tamponade requiring pericardiocentesis or constrictive pericarditis compared to conventional pericardiocentesis when indicated.
Objectives: The primary objectives of the IMPI-2 Trial are:
To demonstrate the feasibility of conducting a multicentre clinical trial of intrapericardial fibrinolysis in patients with large pericardial effusion, and to assess the safety of intrapericardial alteplase in an internal pilot study, and
To determine the effectiveness of intrapericardial alteplase in reducing the composite outcome of cardiac tamponade requiring pericardiocentesis or constrictive pericarditis in patients with large pericardial effusion in the full trial.
Should the internal pilot study demonstrate feasibility and safety; all 218 patients will be rolled-over into the full scale IMPI-2 trial of 2176 participants. The primary outcome is the first occurrence of cardiac tamponade requiring pericardiocentesis or constrictive pericarditis. The secondary safety endpoint is safety of intrapericardial fibrinolysis measured by effect on major bleeding, and serious and non-serious adverse events. The secondary efficacy outcomes are constrictive pericarditis, and cardiac tamponade requiring pericardiocentesis, analysed separately, and persistent or recurrent pericardial effusion without cardiac tamponade, hospitalisation, and death. The secondary diagnostic outcomes are proportion with bacteriologically confirmed tuberculosis from any organ or tissue; time to diagnosis of bacteriologically confirmed tuberculosis in days; accuracy of novel tests for the diagnosis of tuberculosis; proportion with specific diagnosis of any pericardial disease; time to diagnosis of a specific pericardial disease in days.
Study Design: IMPI-2 is a prospective randomized open blinded end-point trial that will enroll 2176 patients with large pericardial effusion over 36 months from up to 30 centres in South Africa and Africa. Eligible patients will be randomly assigned to receive complete pericardial drainage facilitated by intrapericardial fibrinolysis or conventional pericardiocentesis when indicated on enrollment to the study. Patients will be followed at 2 weeks, 6 weeks, 12 weeks, and in months 6, and 12 after enrollment. The IMPI Project Office, University of Cape Town, South Africa will manage and coordinate the study in association with the Pericarditis Research Unit, Walter Sisulu University, South Africa and the Population Health Research Institute, McMaster University, Canada.
Importance: IMPI-2 addresses very serious complications of large pericardial effusion (i.e., cardiac tamponade and constrictive pericarditis), which are associated with high mortality despite pericardiocentesis or pericardiectomy. This study will utilise the research network that was established by the IMPI trial which was completed in 2014.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pericardial Effusion
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
2176 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Pericardiocentesis with Alteplase
Arm Type
Active Comparator
Arm Description
Complete percutaneous pericardial drainage facilitated by intrapericardial alteplase.
Arm Title
Conventional Pericardiocentesis
Arm Type
Other
Arm Description
Conventional pericardiocentesis when indicated.
Intervention Type
Other
Intervention Name(s)
Pericardiocentesis with Alteplase
Intervention Description
Complete percutaneous pericardial drainage facilitated by intrapericardial alteplase
Intervention Type
Other
Intervention Name(s)
Conventional Pericardiocentesis
Intervention Description
Conventional pericardiocentesis when indicated
Primary Outcome Measure Information:
Title
Composite outcome of cardiac tamponade requiring pericardiocentesis or constrictive pericarditis.
Description
Cardiac tamponade requiring pericardiocentesis shall refer to a combination of physical and echocardiographic findings, i.e., patients with clinical signs of tachycardia (> 90 bpm), hypotension (systolic blood pressure < 100 mmHg), elevated jugular venous pressure and/or pulsus paradoxus > 10 mmHg plus evidence of a large pericardial effusion with echocardiographic signs of tamponade in the absence of other cardiac disease, as defined in the IMPI trial.
Constrictive pericarditis shall refer to a combination of physical and echocardiographic findings (i.e., patients with a prior history of pericardial effusion who have pulsus paradoxus, a raised jugular venous pressure with or without evidence of pericardial thickening on imaging) in the absence of either large pericardial effusion or other cardiac disease, as described in the IMPI trial.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Major bleeding
Description
Defined as clinically overt bleeding accompanied by one or more of the following: a decrease in the haemoglobin level of 2 g per decilitre or more over a 24-hour period, transfusion of 2 or more units of packed red cells, bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding
Time Frame
12 months
Title
Clinically relevant non-major bleeding
Description
Defined as clinically overt bleeding that does not satisfy the criteria for major bleeding and that leads to hospital admission, physician-guided medical or surgical treatment.
Time Frame
12 months
Title
Any bleeding
Description
Any other form of bleeding that is not covered by safety outcomes 1-3
Time Frame
12 months
Title
Other adverse events
Description
Any other adverse events
Time Frame
12 months
Title
Persistent pericardial effusion without cardiac tamponade
Description
Refers to the echocardiographic presence of a pericardial effusion without criteria for cardiac tamponade requiring pericarditis during follow-up visits. The pericardial effusion is the same size or larger than that measured at the time of enrollment (where no pericardiocentesis was done) or post-pericardiocentesis.
Time Frame
12 months
Title
Recurrent pericardial effusion without cardiac tamponade
Description
Refers to the echocardiographic presence of a pericardial effusion without criteria for cardiac tamponade requiring pericarditis during follow-up visits. Recurrence is present in the context of re-appearance of a pericardial effusion in the context where complete drainage was performed.
Time Frame
12 months
Title
Hospitalisation for any cause; and death from any cause
Description
Refers to admission to hospital for at least 24 hours for any reason.
Time Frame
12 months
Title
Cardiac tamponade requiring pericardiocentesis
Description
Cardiac tamponade requiring pericardiocentesis shall refer to a combination of physical and echocardiographic findings, i.e., patients with clinical signs of tachycardia (> 90 bpm), hypotension (systolic blood pressure < 100 mmHg), elevated jugular venous pressure and/or pulsus paradoxus > 10 mmHg plus evidence of a large pericardial effusion with echocardiographic signs of tamponade in the absence of other cardiac disease, as defined in the IMPI trial.
Time Frame
12 months
Title
Constrictive pericarditis
Description
Constrictive pericarditis shall refer to a combination of physical and echocardiographic findings (i.e., patients with a prior history of pericardial effusion who have pulsus paradoxus, a raised jugular venous pressure with or without evidence of pericardial thickening on imaging) in the absence of either large pericardial effusion or other cardiac disease, as described in the IMPI trial.
Time Frame
12 months
Title
Death
Description
Death from any cause
Time Frame
12 months
Other Pre-specified Outcome Measures:
Title
Proportion with proven tuberculosis
Description
The proportion with bacteriologically confirmed tuberculosis from any organ or tissue in each group will be based on findings on microscopy, Xpert MRB/RIF, culture, and / histology .
Time Frame
12 months
Title
Time to diagnosis of proven tuberculosis
Description
The time to diagnosis of bacteriologically confirmed tuberculosis in days in each group will be based on the date of sample collection and the date of first bacteriological confirmation from any organ or tissue.
Time Frame
12 months
Title
Proportion with proven tuberculosis on novel tests who are not put on treatment
Description
The proportion of culture-positive tuberculosis cases who are not placed on treatment in either arm, or the proportion of these which would have been detected by the novel rapid index tests.
Time Frame
12 months
Title
Diagnostic accuracy of novel tests of tuberculosis
Description
The diagnostic accuracy of novel tests (e.g., Xpert MTB/RIF, Xpert ULTRA, InterGam) for the detection of culture-positive pericardial tuberculosis (a secondary analysis will be performed using clinically-diagnosed tuberculosis as reference standard)
Time Frame
12 months
Title
Drug resistant tuberculosis
Description
The proportion of drug-resistant tuberculosis cases detected.
Time Frame
12 months
Title
Specific diagnosis of tuberculous pericarditis
Description
The proportion with a specific diagnosis of pericardial disease in each group will be based on findings on results of investigations for tuberculosis, cancer, purulent pericarditis and other disease.
Time Frame
12 months
Title
Time to diagnosis of specific pericardial disease
Description
The time to diagnosis of a specific pericardial disease in days in each group will be based on the date of sample collection and the date of first definitive result.
Time Frame
12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age ≥ 18 years of age;
Confirmed large pericardial effusion on echocardiography (i.e., echo free space ≥1 cm anterior to the right ventricle of the heart in diastole);
Willingness to participate for the full duration of the trial (i.e., 12 months); and
Provision of written informed consent.
Exclusion Criteria:
Age < 18 years;
Uraemic pericarditis (i.e., urea > 21.4 mmol/l);
Thrombocytopenia (i.e., < 100,000 platelets per µl);
Presence of a contra-indication to the administration of a fibrinolytic agent (i.e., major haemorrhage or major trauma; coincidental stroke; major surgery in the previous 5 days; blood pressure >200/100 mmHg).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Veronica Francis
Phone
+27832449895
Email
veronica.francis@uct.ac.za
First Name & Middle Initial & Last Name or Official Title & Degree
Abolade A Awotedu, MBBS
Phone
+27822007694
Email
bolaawotedu@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bongani M Mayosi, DPhil
Organizational Affiliation
University of Cape Town
Official's Role
Principal Investigator
Facility Information:
Facility Name
Groote Schuur Hospital
City
Cape Town
State/Province
Western Cape
ZIP/Postal Code
7925
Country
South Africa
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shaheen Pandie, MMed (Med)
Phone
+27823199030
Email
s.pandie@uct.ac.za
First Name & Middle Initial & Last Name & Degree
Veronica Francis
Phone
+27832449895
Email
veronica.francis@uct.ac.za
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual patient data will be made available on request at the end of the study, subject to approval by the Steering Committee of the IMPI-2 Trial.
Learn more about this trial
IMPI 2 - A Trial of Intrapericardial Alteplase in Large Pericardial Effusion
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