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Intraventricular Tissue Plasminogen Activator (tPA) in the Management of Aneurysmal Subarachnoid Hemorrhage

Primary Purpose

Aneurysmal Subarachnoid Hemorrhage, Intraventricular Hemorrhage

Status

Unknown status

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Tissue Plasminogen Activator

Placebo

About this trial

This is an interventional treatment trial for Aneurysmal Subarachnoid Hemorrhage

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Adult patients (> 18 years old) with a proven ruptured cerebral aneurysm
Aneurysm has been / will be treated with coil embolization
EVD has been / will be placed as part of routine care
Modified Fisher score is 4 (cisternal blood > 1 mm thick with concomitant IVH)
CT scan after EVD placement shows "stability" with no increase in the amount of intracranial blood (Note: there is sometimes layering of blood, especially in the occipital horns of the lateral ventricles, that develops during the first 24-48 hours after a ruptured aneurysm due to circulation of blood in the CSF - this does not necessarily constitute an exclusion criterion).
Study drug can be administered within 72 hours of the time of SAH.

Exclusion Criteria:

Concern expressed by endovascular neurosurgeon / interventional radiologist that aneurysm has only been incompletely treated / isolated by coil embolization.
Patient requires craniotomy and clipping of the culprit aneurysm.
CT scan performed post-EVD insertion OR post-coiling shows increase in amount of intracranial blood.
Uncorrected coagulation disturbance (INR > 1.5, PTT > 45); correction is permitted (if coagulation disturbance develops during the study, subsequent doses of TPA should simply be withheld until coagulation can be corrected).
Uncorrected thrombocytopenia (platelets < 50,000); correction with platelet transfusions is permitted.
Involvement in another clinical trial
Uncontrolled active internal hemorrhage
Known allergy to study drug
Patient is pregnant
Any other condition the investigator believes would place the subject at risk if included in the study.

Sites / Locations

Foothills Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

Placebo

tPA (tissue plaminogen activator)

Arm Description

Placebo will be administered every 12 hours for a total five doses. Patients will be followed for a total of 6 months.

Intraventricular TPA will be administered every 12 hours for a total five doses. Patients will be followed for a total of 6 months.

Outcomes

Primary Outcome Measures

Determine rate and variance of ventricular and cisternal clot clearance (with and without TPA).

In order to plan the sample size for a future "proof-of-concept" trial, we need to better define the primary endpoint (the rate of ventricular and cisternal clot clearance, as well as the degree of variance in this rate, both with and without TPA).

Secondary Outcome Measures

Confirm the safety of intraventricular TPA.

Intrathecal TPA has been administered to many hundreds of patients world-wide, and continues to be widely used despite a paucity of strong evidence demonstrating efficacy. Thus, we believe the safety has been relatively well established. On the other hand, much of the existing data is observational and retrospective, and could therefore be vulnerable to reporting bias. Experience is more limited among patients who have been managed with endovascular coil embolization, such that our study will provide important additional safety information.

Assess feasibility of a future multi-center trial

By performing a single center, prospective, randomized, double-blind, placebo-controlled trial, we will be able to (1) Estimate the recruitment rate; (2) Establish whether clinicians can be successfully blinded to treatment allocation (TPA vs. placebo); (3) Ensure that clinicians will comply with a treatment protocol

Full Information

NCT ID

NCT01098890

First Posted

April 1, 2010

Last Updated

November 10, 2010

Sponsor

University of Calgary

1. Study Identification

Unique Protocol Identification Number

NCT01098890

Brief Title

Intraventricular Tissue Plasminogen Activator (tPA) in the Management of Aneurysmal Subarachnoid Hemorrhage

Official Title

Intraventricular Tissue Plasminogen Activator in the Management of Aneurysmal Subarachnoid Hemorrhage: a Randomized Controlled Pilot Study

Study Type

Interventional

2. Study Status

Record Verification Date

April 2010

Overall Recruitment Status

Unknown status

Study Start Date

October 2009 (undefined)

Primary Completion Date

October 2011 (Anticipated)

Study Completion Date

April 2012 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor

University of Calgary

4. Oversight

5. Study Description

Brief Summary

The proposed study is to evaluate the acceleration the clearance of intraventricular blood (IVH) and subarachnoid hemorrhage (SAH) following ruptured intracranial aneurysms, thereby ameliorating complications, such as cerebral vasospasm, hydrocephalus and intracranial hypertension. The primary objectives are: Estimate the rate and variance of hematoma clearance following aneurysmal SAH, thereby facilitating sample size determination for a subsequent larger study; Assess the feasibility of a randomized controlled trial of intraventricular tissue plasminogen activator (TPA) among patients with SAH (enrollment rate, ability to blind investigators, protocol compliance); Confirm the safety of intraventricular TPA.

Detailed Description

Outcome Measures: Safety will be assessed through adverse events, hemorrhagic complications and the development of ventriculostomy-related infections. The volume and clearance of intracranial blood will be determined (in ml) using computerized software, as well as validated semi-quantitative ordinal scales (SAH Sum Score, Modified Graeb Score). The amount of IVH and SAH will be assessed at baseline (day 0), 72 hours after treatment onset, and on post-SAH day 8. Additional secondary outcomes will include: The occurrence of vasospasm, as determined using transcranial Doppler ultrasonography The occurrence of radiographic vasospasm, using CT angiography. The occurrence of "clinical" (symptomatic) vasospasm The rate of catheter-related central nervous system infections Levels of cytokines, endothelin and matrix metalloproteases in cerebrospinal fluid (CSF) and plasma Levels of fibrin-derived products (FDP), TPA and plasminogen-activator inhibitor in CSF Levels of S100β and neuron-specific enolase (NSE) in CSF and serum Intracranial pressure Volume of CSF drainage Extended Glasgow Outcome Scale, modified Rankin scale, EuroQOL at 6 months post-SAH Duration that ventriculostomy is required; need for permanent shunt Fever burden

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Aneurysmal Subarachnoid Hemorrhage, Intraventricular Hemorrhage

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

12 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo will be administered every 12 hours for a total five doses. Patients will be followed for a total of 6 months.

Arm Title

tPA (tissue plaminogen activator)

Arm Type

Active Comparator

Arm Description

Intraventricular TPA will be administered every 12 hours for a total five doses. Patients will be followed for a total of 6 months.

Intervention Type

Drug

Intervention Name(s)

Tissue Plasminogen Activator

Other Intervention Name(s)

Cathflo

Intervention Description

2mg tPA will be given every twelve hours for a maximum of 5 doses

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo will be administered every 12 hours for a maximum of 5 doses.

Primary Outcome Measure Information:

Title

Determine rate and variance of ventricular and cisternal clot clearance (with and without TPA).

Description

Time Frame

8 Days post bleed

Secondary Outcome Measure Information:

Title

Confirm the safety of intraventricular TPA.

Description

Time Frame

6 months

Title

Assess feasibility of a future multi-center trial

Description

Time Frame

6 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Adult patients (> 18 years old) with a proven ruptured cerebral aneurysm Aneurysm has been / will be treated with coil embolization EVD has been / will be placed as part of routine care Modified Fisher score is 4 (cisternal blood > 1 mm thick with concomitant IVH) CT scan after EVD placement shows "stability" with no increase in the amount of intracranial blood (Note: there is sometimes layering of blood, especially in the occipital horns of the lateral ventricles, that develops during the first 24-48 hours after a ruptured aneurysm due to circulation of blood in the CSF - this does not necessarily constitute an exclusion criterion). Study drug can be administered within 72 hours of the time of SAH. Exclusion Criteria: Concern expressed by endovascular neurosurgeon / interventional radiologist that aneurysm has only been incompletely treated / isolated by coil embolization. Patient requires craniotomy and clipping of the culprit aneurysm. CT scan performed post-EVD insertion OR post-coiling shows increase in amount of intracranial blood. Uncorrected coagulation disturbance (INR > 1.5, PTT > 45); correction is permitted (if coagulation disturbance develops during the study, subsequent doses of TPA should simply be withheld until coagulation can be corrected). Uncorrected thrombocytopenia (platelets < 50,000); correction with platelet transfusions is permitted. Involvement in another clinical trial Uncontrolled active internal hemorrhage Known allergy to study drug Patient is pregnant Any other condition the investigator believes would place the subject at risk if included in the study.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Andreas Kramer, MD

Organizational Affiliation

University of Calgary

Official's Role

Principal Investigator

Facility Information:

Facility Name

Foothills Medical Center

City

Calgary

State/Province

Alberta

ZIP/Postal Code

T2N 2T9

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Andreas Kramer, M.D

Phone

403-944-4749

andreas.kramer@albertahealthservices.ca

First Name & Middle Initial & Last Name & Degree

Stephanie Todd, BSc. MBT, CCRP

Phone

403-944-3414

stephanie.todd@albertahealthservices.ca

First Name & Middle Initial & Last Name & Degree

Andreas Kramer, MD

First Name & Middle Initial & Last Name & Degree

John Wong, MD

First Name & Middle Initial & Last Name & Degree

David Zygun, MD

First Name & Middle Initial & Last Name & Degree

Michael Hill, MD

12. IPD Sharing Statement

Learn more about this trial

Intraventricular Tissue Plasminogen Activator (tPA) in the Management of Aneurysmal Subarachnoid Hemorrhage

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