Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III

Study Overview
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Brief Summary
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The overall objective of this Phase III clinical trial is to obtain information from a population of 500 ICH subjects with intraventricular hemorrhage (IVH), representative of current clinical practice and national demographics of ICH regarding the benefit (or lack thereof) of IVH clot removal on subject function as measured by modified Rankin Scale (mRS). This application requests funding for five years to initiate a Phase III randomized clinical trial (RCT) testing the benefit of clot removal for intraventricular hemorrhage. The investigators propose to compare extraventricular drainage (EVD) use plus recombinant tissue plasminogen activator (rt-PA; Alteplase; Genentech, Inc., San Francisco, CA) with EVD+ placebo in the management and treatment of subjects with small intracerebral hemorrhage (ICH) and large intraventricular hemorrhage (IVH defined as ICH < 30 cc and obstruction of the 3rd or 4th ventricles by intraventricular blood clot).

Official Title
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Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Phase III

Conditions
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Intraventricular Hemorrhage

Intervention / Treatment
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* Drug: Alteplase
* Other: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-80 Symptom onset less than 24 hrs prior to diagnostic CT scan Spontaneous ICH less than or equal to 30 cc or primary IVH IVH obstructing 3rd and/or 4th ventricles ICH clot stability at 6 hours or more post IVC placement IVH clot stability at 6 hours or more post IVC placement Catheter tract bleeding stability 6 hours or more post IVC placement EVD placed per standard medical care SBP less than 200 mmHg sustained for 6 hours prior to drug administration Able to randomize within 72 hours of diagnostic CT scan Historical Rankin of 0 or 1 Exclusion Criteria: Suspected or untreated ruptured cerebral aneurysm, AVM, or tumor Presence of a choroid plexus vascular malformation or Moyamoya Clotting disorders Platelet count less than 100,000, INR greater than 1.4 Pregnancy Infratentorial hemorrhage SAH at clinical presentation ICH/IVH enlargement that cannot be stabilized in the treatment time window Ongoing internal bleeding Superficial or surface bleeding Prior enrollment in the study Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated Planned or simultaneous participation (between screening and Day-30) in another interventional medical investigation or clinical trial. No subject or legal representative to give written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alteplase<br>administration of alteplase via the intraventricular catheter | Drug: Alteplase<br>* 1.0 mg of alteplase will be administered via the intraventricular catheter every 8 hours for up to 12 doses<br>* Other names: rt-PA;|
| Placebo Comparator: Saline Placebo<br>1 ml of normal saline administered via the intraventricular catheter | Other: Normal saline<br>* 1 ml of normal saline will be administered via the intraventricular catheter every 8 hours for up to 12 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Modified Rankin Scale (mRS) <=3 - Dichotomized Analysis | Analysis modified on September 29, 2015 to account for adaptive randomization. The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Participant Score on the Modified Rankin Scale (mRS) - Ordinal Analysis | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Participants With Modified Rankin Scale (mRS) <=4 - Dichotomized Analysis | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Random Effects Assessment of Site Effect on Modified Rankin Scale (mRS) <= 3 | The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Longitudinal Assessment of Participants With Modified Rankin Scale (mRS) <=3 | Comparing longitudinal modified Rankin Scale (mRS) scores 0-3 at Day 30 and Day 180. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 30 days and 180 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cause Mortality |  | 180 days | 
| Clot Removal (Amount of Residual Blood) | Change in blood volume measured between stability scan and end of treatment scan | 72 hours | 
| Intensity of Critical Care Management - Hospital Days | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 30 days | 
| Intensity of Critical Care Management - ICU Days | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 30 days | 
| Intensity of Critical Care Management - ICP Management | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 30 days | 
| Intensity of Critical Care Management - Mechanical Ventilation | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 30 days | 
| Intensity of Critical Care Management - Pressors | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 30 days | 
| Intensity of Critical Care Management - Shunts | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 30 days | 
| Intensity of Critical Care Management - All Infections | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 30 days | 
| Intensity of Critical Care Management - Pneumonia | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 30 days | 
| Intensity of Critical Care Management - All Infections | Intensity of critical care management as measured by hospital and ICU length of stay, frequency of ICP >20 mmHg events, use of mechanical ventilation, pressors, and ventriculoperitioneal shunts, frequency of systemic infections. | 180 days | 
| Safety/Mortality - Mortality Within 30 Days | Frequency of bacterial brain infections, symptomatic brain bleeds, and mortality. | 30 days | 
| Safety/Mortality - Bacterial Brain Infections Within 30 Days | Frequency of bacterial brain infections, symptomatic brain bleeds, and mortality. | 30 days | 
| Safety/Mortality - Systematic Bleeds Within 72 Hours | Frequency of bacterial brain infections, symptomatic brain bleeds, and mortality. | 72 hours | 
| Safety/Mortality - Systematic Bleeds Within 30 Days | Frequency of bacterial brain infections, symptomatic brain bleeds, and mortality. | 30 days | 
| Adverse and Serious Adverse Events | Assessment of number of adverse and serious adverse events by treatment group. | 180 days | 
| Predicting Hazards of Death by Treatment Group | Cox Proportional Hazards Model is used to predict the hazards ratio by treatment group. | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Race (African-American) | Assessment of modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Race (White) | Assessment of modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Gender (Female) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Gender (Male) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Age (65 Years or Under) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Age (Over 65 Years) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (Less Than 20ml) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (20-50ml) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by IVH Size (Greater Than 50ml) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Location (Thalamic) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Sub-Group Analyses - Difference in Modified Rankin Scale (mRS) 0-3 Proportion by Location (Non-Thalamic) | Assessment of Modified Rankin Scale (mRS) score 0-3 compared by race, gender, age, IVH size, and ICH location. The mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It is scored from 0 (perfect health without symptoms) to 6 (death). | 180 days | 
| Functional Status - Barthel Index | Assessment of NIHSS, Barthel Index, eGOS (dichotomy and ordinal) by group. The Barthel Index (BI) assesses ten functional tasks of daily living, and each task provides a measure for level of independence. Scores range from 0 and 100, with a higher score indicating greater independence. | 180 days | 
| Functional Status - Participants With Extended Glasgow Outcome (eGOS) Score >=Upper Severe Disability | Assessment of NIHSS, Barthel Index, eGOS (dichotomy and ordinal) by group. The extended Glasgow Outcome Scale (eGOS) is a global scale for functional outcome with eight categories: 1 - Death, 2 - Vegetative State, 3 - Lower Severe Disability, 4 - Upper Severe Disability, 5 - Lower Moderate Disability, 6 - Upper Moderate Disability, 7 - Lower Good Recovery, 8 - Upper Good Recovery. | 180 days | 
| Functional Status - National Institutes of Health Stroke Scale (NIHSS) | Assessment of NIHSS, Barthel Index, eGOS (dichotomy and ordinal) by group. The National Institutes of Health Stroke Scale (NIHSS) is a 15-item scale that assesses language, motor function, sensory loss, consciousness, visual fields, extraocular movements, coordination, neglect, and speech. It is scored from 0 (no stroke symptoms) to 42 (severe stroke). | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Strength | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Mobility | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Hand Function | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Activities of Daily Living | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Communication | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Thinking | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Emotion | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Participation | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - Stroke Impact Scale (SIS) - Recovery | Assessment of SIS and EuroQol Visual Analog Scale by group. The Stroke Impact Scale (SIS) covers 8 dimensions of stroke outcomes: strength, hand function, activities of daily living/instrumental activities of daily living, mobility, communication, emotion, memory and thinking, participation. It is scored on a scale of 0 to 100 for each dimension, with higher scores indicating better self-reported health. | 180 days | 
| Quality of Life - EuroQol Visual Analogue Scale (EQ-VAS) | Assessment of SIS and EuroQol Visual Analog Scale by group. EuroQol Visual Analogue Scale (EQ-VAS) is a self-reported measure of health status. It is a marked scale where individuals draw a line to indicate their health, with end points of 0 (the worst health you can imagine) and 100 (the best health you can imagine). | 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intraventricular hemorrhage thrombolysis