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