IMPI 2 - A Trial of Intrapericardial Alteplase in Large Pericardial Effusion (IMPI-2)

• ClinicalTrials.gov Identifier: NCT02673879
• Recruitment Status: Unknown
• First Posted: February 4, 2016
• Last Update Posted: May 2, 2018
• Sponsor: University of Cape Town
• Collaborators: Walter Sisulu University; Population Health Research Institute
• Information provided by (Responsible Party): Bongani M Mayosi, University of Cape Town

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.

Condition or disease	Intervention/treatment	Phase
Pericardial Effusion	Other: Pericardiocentesis with Alteplase; Other: Conventional Pericardiocentesis	Phase 3

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:

1. 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
2. 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 2176 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: February 2016
• Estimated Primary Completion Date: July 2019
• Estimated Study Completion Date: January 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Pericardiocentesis with Alteplase; Complete percutaneous pericardial drainage facilitated by intrapericardial alteplase.	Other: Pericardiocentesis with Alteplase; Complete percutaneous pericardial drainage facilitated by intrapericardial alteplase
Conventional Pericardiocentesis; Conventional pericardiocentesis when indicated.	Other: Conventional Pericardiocentesis; Conventional pericardiocentesis when indicated

Outcome Measures

Primary Outcome Measures :

1. Composite outcome of cardiac tamponade requiring pericardiocentesis or constrictive pericarditis. [ Time Frame: 12 months ]

   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 :

1. Major bleeding [ Time Frame: 12 months ]
   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
2. Clinically relevant non-major bleeding [ Time Frame: 12 months ]
   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.
3. Any bleeding [ Time Frame: 12 months ]
   Any other form of bleeding that is not covered by safety outcomes 1-3
4. Other adverse events [ Time Frame: 12 months ]
   Any other adverse events
5. Persistent pericardial effusion without cardiac tamponade [ Time Frame: 12 months ]
   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.
6. Recurrent pericardial effusion without cardiac tamponade [ Time Frame: 12 months ]
   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.
7. Hospitalisation for any cause; and death from any cause [ Time Frame: 12 months ]
   Refers to admission to hospital for at least 24 hours for any reason.
8. Cardiac tamponade requiring pericardiocentesis [ Time Frame: 12 months ]
   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.
9. Constrictive pericarditis [ Time Frame: 12 months ]
   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.
10. Death [ Time Frame: 12 months ]
    Death from any cause

Other Outcome Measures:

1. Proportion with proven tuberculosis [ Time Frame: 12 months ]
   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 .
2. Time to diagnosis of proven tuberculosis [ Time Frame: 12 months ]
   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.
3. Proportion with proven tuberculosis on novel tests who are not put on treatment [ Time Frame: 12 months ]
   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.
4. Diagnostic accuracy of novel tests of tuberculosis [ Time Frame: 12 months ]
   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)
5. Drug resistant tuberculosis [ Time Frame: 12 months ]
   The proportion of drug-resistant tuberculosis cases detected.
6. Specific diagnosis of tuberculous pericarditis [ Time Frame: 12 months ]
   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.
7. Time to diagnosis of specific pericardial disease [ Time Frame: 12 months ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥ 18 years of age;
2. Confirmed large pericardial effusion on echocardiography (i.e., echo free space ≥1 cm anterior to the right ventricle of the heart in diastole);
3. Willingness to participate for the full duration of the trial (i.e., 12 months); and
4. Provision of written informed consent.

Exclusion Criteria:

1. Age < 18 years;
2. Uraemic pericarditis (i.e., urea > 21.4 mmol/l);
3. Thrombocytopenia (i.e., < 100,000 platelets per µl);
4. 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).

Contacts and Locations

Contacts

Contact: Veronica Francis; +27832449895; veronica.francis@uct.ac.za

Contact: Abolade A Awotedu, MBBS; +27822007694; bolaawotedu@gmail.com

Locations

South Africa

Groote Schuur Hospital; Recruiting

Cape Town, Western Cape, South Africa, 7925

Contact: Shaheen Pandie, MMed (Med) +27823199030 s.pandie@uct.ac.za

Contact: Veronica Francis +27832449895 veronica.francis@uct.ac.za

Sponsors and Collaborators

University of Cape Town

Walter Sisulu University

Population Health Research Institute

Investigators

• Principal Investigator: Bongani M Mayosi, DPhil; University of Cape Town

More Information

• Responsible Party: Bongani M Mayosi, Professor of Medicine, University of Cape Town
• ClinicalTrials.gov Identifier: NCT02673879
• Other Study ID Numbers: HREC REF No. 370/2015
• First Posted: February 4, 2016
• Last Update Posted: May 2, 2018
• Last Verified: February 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.

Additional relevant MeSH terms:

Pericardial Effusion; Heart Diseases; Cardiovascular Diseases; Tissue Plasminogen Activator; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action