## Protocol Section
### Identification Module
**NCT ID:** NCT02673879

**Acronym:** IMPI-2

**Brief Title:** 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

#### Organization Study ID Info
**ID:** HREC REF No. 370/2015
#### Organization
**Class:** OTHER
**Full Name:** University of Cape Town
### Status Module
#### Completion Date
**Date:** 2020-01

**Type:** ESTIMATED

#### Expanded Access Info
**Last Known Status:** RECRUITING
#### Last Update Post Date
**Date:** 2018-05-02

**Type:** ACTUAL

**Last Update Submit Date:** 2018-04-30

**Overall Status:** UNKNOWN

#### Primary Completion Date
**Date:** 2019-07

**Type:** ESTIMATED

#### Start Date
**Date:** 2016-02

**Status Verified Date:** 2016-02

#### Study First Post Date
**Date:** 2016-02-04
**Type:** ESTIMATED
**Study First Submit Date:** 2016-02-01
**Study First Submit QC Date:** 2016-02-01
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** Walter Sisulu University

**Class:** OTHER

**Name:** Population Health Research Institute

#### Lead Sponsor

**Class:** OTHER

**Name:** University of Cape Town

#### Responsible Party

**Investigator Affiliation:** University of Cape Town

**Investigator Full Name:** Bongani M Mayosi

**Investigator Title:** Professor of Medicine

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Oversight Has DMC:** True

### Description Module

**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.

### Conditions Module

**Conditions:**

- Pericardial Effusion

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** SINGLE

**Who Masked:**

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 2176

**Type:** ESTIMATED

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Complete percutaneous pericardial drainage facilitated by intrapericardial alteplase.

**Intervention Names:**

- Other: Pericardiocentesis with Alteplase

**Label:** Pericardiocentesis with Alteplase

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** Conventional pericardiocentesis when indicated.

**Intervention Names:**

- Other: Conventional Pericardiocentesis

**Label:** Conventional Pericardiocentesis

**Type:** OTHER

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Pericardiocentesis with Alteplase

**Description:** Complete percutaneous pericardial drainage facilitated by intrapericardial alteplase

**Name:** Pericardiocentesis with Alteplase

**Type:** OTHER

#### Intervention 2

**Arm Group Labels:**

- Conventional Pericardiocentesis

**Description:** Conventional pericardiocentesis when indicated

**Name:** Conventional Pericardiocentesis

**Type:** OTHER

### Outcomes Module

#### Other Outcomes

**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 .

**Measure:** Proportion with proven tuberculosis

**Time Frame:** 12 months

**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.

**Measure:** Time to diagnosis of proven tuberculosis

**Time Frame:** 12 months

**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.

**Measure:** Proportion with proven tuberculosis on novel tests who are not put on treatment

**Time Frame:** 12 months

**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)

**Measure:** Diagnostic accuracy of novel tests of tuberculosis

**Time Frame:** 12 months

**Description:** The proportion of drug-resistant tuberculosis cases detected.

**Measure:** Drug resistant tuberculosis

**Time Frame:** 12 months

**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.

**Measure:** Specific diagnosis of tuberculous pericarditis

**Time Frame:** 12 months

**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.

**Measure:** Time to diagnosis of specific pericardial disease

**Time Frame:** 12 months

#### Primary Outcomes

**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.

**Measure:** Composite outcome of cardiac tamponade requiring pericardiocentesis or constrictive pericarditis.

**Time Frame:** 12 months

#### Secondary Outcomes

**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

**Measure:** Major bleeding

**Time Frame:** 12 months

**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.

**Measure:** Clinically relevant non-major bleeding

**Time Frame:** 12 months

**Description:** Any other form of bleeding that is not covered by safety outcomes 1-3

**Measure:** Any bleeding

**Time Frame:** 12 months

**Description:** Any other adverse events

**Measure:** Other adverse events

**Time Frame:** 12 months

**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.

**Measure:** Persistent pericardial effusion without cardiac tamponade

**Time Frame:** 12 months

**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.

**Measure:** Recurrent pericardial effusion without cardiac tamponade

**Time Frame:** 12 months

**Description:** Refers to admission to hospital for at least 24 hours for any reason.

**Measure:** Hospitalisation for any cause; and death from any cause

**Time Frame:** 12 months

**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.

**Measure:** Cardiac tamponade requiring pericardiocentesis

**Time Frame:** 12 months

**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.

**Measure:** Constrictive pericarditis

**Time Frame:** 12 months

**Description:** Death from any cause

**Measure:** Death

**Time Frame:** 12 months

### Eligibility Module

**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).

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** veronica.francis@uct.ac.za

**Name:** Veronica Francis

**Phone:** +27832449895

**Role:** CONTACT

**Contact 2:**

**Email:** bolaawotedu@gmail.com

**Name:** Abolade A Awotedu, MBBS

**Phone:** +27822007694

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Cape Town

**Contacts:**

***Contact 1:***

- **Email:** s.pandie@uct.ac.za

- **Name:** Shaheen Pandie, MMed (Med)

- **Phone:** +27823199030

- **Role:** CONTACT

***Contact 2:***

- **Email:** veronica.francis@uct.ac.za

- **Name:** Veronica Francis

- **Phone:** +27832449895

- **Role:** CONTACT

**Country:** South Africa

**Facility:** Groote Schuur Hospital

**State:** Western Cape

**Status:** RECRUITING

**Zip:** 7925

#### Overall Officials

**Official 1:**

**Affiliation:** University of Cape Town

**Name:** Bongani M Mayosi, DPhil

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**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.

**IPD Sharing:** YES

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000006331

- Term: Heart Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC01

- Name: Infections

### Condition Browse Module - Browse Leaves

- ID: M13403

- Name: Pericarditis

- Relevance: LOW

- As Found: Unknown

- ID: M17127

- Name: Tuberculosis

- Relevance: LOW

- As Found: Unknown

- ID: M13400

- Name: Pericardial Effusion

- Relevance: HIGH

- As Found: Pericardial Effusion

- ID: M9419

- Name: Heart Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000010490

- Term: Pericardial Effusion

### Intervention Browse Module - Ancestors

- ID: D000005343

- Term: Fibrinolytic Agents

- ID: D000050299

- Term: Fibrin Modulating Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

### Intervention Browse Module - Browse Branches

- Abbrev: FiAg

- Name: Fibrinolytic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M13849

- Name: Tissue Plasminogen Activator

- Relevance: HIGH

- As Found: Bearing

- ID: M13848

- Name: Plasminogen

- Relevance: LOW

- As Found: Unknown

- ID: M8473

- Name: Fibrinolytic Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000010959

- Term: Tissue Plasminogen Activator

### Misc Info Module

- Version Holder: 2024-05-24
