Clinical trial NCT02673879: IMPI 2 - A Trial of Intrapericardial Alteplase in Large Pericardial Effusion
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
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Pericardial Effusion
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: Walter Sisulu University
name: Population Health Research Institute
First posted: 2016-02-04
Enrollment: 2176
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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:

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.

Eligibility 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).

Primary outcomes:
measure: Composite outcome of cardiac tamponade requiring pericardiocentesis or constrictive pericarditis.
timeFrame: 12 months
Secondary outcomes:
measure: Major bleeding
timeFrame: 12 months
measure: Clinically relevant non-major bleeding
timeFrame: 12 months
measure: Any bleeding
timeFrame: 12 months
measure: Other adverse events
timeFrame: 12 months
measure: Persistent pericardial effusion without cardiac tamponade
timeFrame: 12 months
measure: Recurrent pericardial effusion without cardiac tamponade
timeFrame: 12 months
measure: Hospitalisation for any cause; and death from any cause
timeFrame: 12 months
measure: Cardiac tamponade requiring pericardiocentesis
timeFrame: 12 months
measure: Constrictive pericarditis
timeFrame: 12 months
measure: Death
timeFrame: 12 months
Other outcomes:
measure: Proportion with proven tuberculosis
timeFrame: 12 months
measure: Time to diagnosis of proven tuberculosis
timeFrame: 12 months
measure: Proportion with proven tuberculosis on novel tests who are not put on treatment
timeFrame: 12 months
measure: Diagnostic accuracy of novel tests of tuberculosis
timeFrame: 12 months
measure: Drug resistant tuberculosis
timeFrame: 12 months
measure: Specific diagnosis of tuberculous pericarditis
timeFrame: 12 months
measure: Time to diagnosis of specific pericardial disease
timeFrame: 12 months
Locations:
city: Cape Town
country: South Africa
facility: Groote Schuur Hospital
state: Western Cape
Study officials:
affiliation: University of Cape Town
name: Bongani M Mayosi, DPhil
role: PRINCIPAL_INVESTIGATOR
References: