Intraventricular Hemorrhage
Conditions
Keywords
Intraventricular hemorrhage (IVH), rt-PA
Brief summary
The specific objective of this trial is to determine the lowest dose and dose frequency possible with the best pharmacokinetic and safety profile and it's ability to remove a blood clot from the ventricular system.
Detailed description
The purpose of this trial is to determine the efficacy and pharmacokinetics of intraventricular injections of multiple low doses of rt-PA. Sixteen subjects were already randomized to receive intraventricular injections of with 0.3 mg or 1.0 mg of rt-PA every 12 hours for up to 8 doses. Results of this stage (n=16) were then analyzed and the most effective dose of 1.0 mg was chosen to be used in the second stage (n=36) to determine the optimal frequency of dosing. We propose to test if this intervention facilitates more rapid clot resolution, complete recovery function and decreased mortality from this condition.
Interventions
DRUGtissue plasminogen activator, rt-PA (thrombolytic) (Cathflo)
0.3 mg and 1.0 mg of rt-PA (Cathflo) were administered every 12 hours (dose finding) and every 8 hours (dose frequency) via the intraventricular catheter to treat intraventricular hemorrhage.
Sponsors
FDA Office of Orphan Products Development
Genentech, Inc.
Johns Hopkins University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-75 2. IVC placed as standard of care using less than or equal to 2 complete passes. 3. Spontaneous ICH less than or equal to 30 cc. 4. Able to receive first dose within 48 hours of CT scan diagnosing IVH (providing the time of symptom onset to diagnostic CT does not exceed 12 hours). 5. Clot size measured on CT scan done 6 hours after IVC placement must be equal to the presentation clot size plus or minus 5 cc (as determined by the AxBxC)/2 method). 6. ON stability CT scan either the 3rd or 4th ventricles are occluded with blood (no evidence of CSF flow on CT). 7. SBP \< 200 mmHg sustained for 6 hours. 8. Historical Rankin of 0 or 1.
Exclusion criteria
1. Suspected or untreated aneurysm or AVM (unless ruled out by angiogram or MRA/MRI). 2. Clotting disorders. 3. Patients with platelet count \< 100,000, INR \> 1.7, PT \> 15s, or an elevated APTT. 4. Pregnancy (positive pregnancy test). 5. Infratentorial hemorrhage (i.e., parenchymal/posterior fossa hematoma; all cerebellar hematomas excluded). 6. SAH (An angiogram should be obtained when the diagnostic CT scan demonstrates subarachnoid hemorrhage or any hematoma location or appearance not strongly associated with hypertension. If the angiogram does not demonstrate a bleeding source that accounts for the hemorrhage, the patient is eligible for the study). 7. ICH enlargement during the 6-hour stabilization period (6 hour after IVC placement). 8. Internal bleeding, involving retroperitoneal sites, or the gastrointestinal, genitourinary, or respiratory tracts. 9. Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures) or site of recent surgical intervention. 10. Known risk for embolization, including history of left heart thrombus, mitral stenosis with atrial fibrillation, acute pericarditis, and subacute bacterial endocarditis. 11. Prior enrollment in the study. 12. Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated. 13. Participation in another simultaneous medical investigation or trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 30-day Mortality | 30 days | The number of subjects who died at or before the 30-day follow-up visit were determined as a measure of safety. If more than 50% of the subjects died at or before the 30-day follow-up visit, the study would have been stopped for full DSMB review. |
| Incidence of Bacterial Ventriculitis, Meningitis | 30 days | The incidence of bacterial ventriculitis/meningitis was recorded to determine the safety of intraventricular administration of rt-PA. If 30% or more subjects experienced this event, the study would have been stopped for full DSMB review. |
| Rate of Symptomatic Bleeding Events | 30-days | The rate of symptomatic brain bleeding events were recorded to determine the safety of intraventricular administrations of rt-PA. If 35% or more subjects experienced a symptomatic bleeding event prior to the 30-day follow-up visit, the study would have been stopped for a full DSMB review. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 180 Day Follow-Up Modified Rankin Scale (mRS) Score | 180 days | 180 day follow-up visit mRS score. 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 to 6: 0. No Symptoms, 1. No Significant Disability, 2. Slight Disability, 3. Moderate Disability, 4. Moderately Severe Disability, 5. Severe Disability and 6. Dead. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected) |
| Average Daily Percentage Clot Size Resolution Over the First 3 Days | 3 days | Daily IVH clot volume resolution, as a percentage of stability CT IVH volume, averaged over the first 3 days, determined by CT scans |
| 180 Day Follow-Up Glasgow Outcome Scale (GOS) Score | 180 days | 180 day follow-up visit GOS score. The GOS is a scale used to determine the degree of recovery from patients with brain injury. There are five categories: 1. Dead, 2. Vegetative State, 3. Severe Disability, 4. Moderate Disability and 5. Good Recovery. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected) |
| 90 Day Follow-Up Modified Rankin Scale (mRS) Score | 90 days | 90 day follow-up visit mRS score. 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 to 6: 0. No Symptoms, 1. No Significant Disability, 2. Slight Disability, 3. Moderate Disability, 4. Moderately Severe Disability, 5. Severe Disability and 6. Dead. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected) |
| 90 Day Follow-Up Glasgow Outcome Scale (GOS) Score | 90 days | 90 day follow-up visit GOS score. The GOS is a scale used to determine the degree of recovery from patients with brain injury. There are five categories: 1. Dead, 2. Vegetative State, 3. Severe Disability, 4. Moderate Disability and 5. Good Recovery. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected) |
Countries
Canada, Germany, United Kingdom, United States
Participant flow
Recruitment details
Recruitment began for protocol stage 1 in August 2005 and ended for protocol stage 2 on February 6, 2008. Subjects were screened by clinical stroke service personnel in the Emergency Department or by direct transfer from an outside hospital.
Participants by arm
| Arm | Count |
|---|---|
| 0.3 mg Rt-PA q12h Stage 1 (Dose Finding) | 8 |
| 1.0 mg Rt-PA q12h Stage 1 (Dose Finding) | 8 |
| 1.0 mg Rt-PA q8h Stage 2 (Dose Optimization) | 36 |
| Total | 52 |
Baseline characteristics
| Characteristic | 0.3 mg Rt-PA q12h | 1.0 mg Rt-PA q12h | 1.0 mg Rt-PA q8h | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 10 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 6 Participants | 26 Participants | 39 Participants |
| Age, Continuous | 47.6 years STANDARD_DEVIATION 9.8 | 57.3 years STANDARD_DEVIATION 8.3 | 57.0 years STANDARD_DEVIATION 10.2 | 55.6 years STANDARD_DEVIATION 10.3 |
| Region of Enrollment Canada | 0 participants | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Germany | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United Kingdom | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 8 participants | 8 participants | 31 participants | 47 participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 11 Participants | 18 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 25 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 8 | 8 / 8 | 32 / 36 |
| serious Total, serious adverse events | 3 / 8 | 2 / 8 | 11 / 36 |
Outcome results
Primary
30-day Mortality
The number of subjects who died at or before the 30-day follow-up visit were determined as a measure of safety. If more than 50% of the subjects died at or before the 30-day follow-up visit, the study would have been stopped for full DSMB review.
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Rt-PA q12h | 30-day Mortality | 1 Number of participants |
| 1.0 mg Rt-PA q12h | 30-day Mortality | 1 Number of participants |
| 1.0 mg Rt-PA q8h | 30-day Mortality | 6 Number of participants |
Primary
Incidence of Bacterial Ventriculitis, Meningitis
The incidence of bacterial ventriculitis/meningitis was recorded to determine the safety of intraventricular administration of rt-PA. If 30% or more subjects experienced this event, the study would have been stopped for full DSMB review.
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Rt-PA q12h | Incidence of Bacterial Ventriculitis, Meningitis | 0 Number of participants |
| 1.0 mg Rt-PA q12h | Incidence of Bacterial Ventriculitis, Meningitis | 1 Number of participants |
| 1.0 mg Rt-PA q8h | Incidence of Bacterial Ventriculitis, Meningitis | 1 Number of participants |
Primary
Rate of Symptomatic Bleeding Events
The rate of symptomatic brain bleeding events were recorded to determine the safety of intraventricular administrations of rt-PA. If 35% or more subjects experienced a symptomatic bleeding event prior to the 30-day follow-up visit, the study would have been stopped for a full DSMB review.
Time frame: 30-days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 0.3 mg Rt-PA q12h | Rate of Symptomatic Bleeding Events | 0 participants |
| 1.0 mg Rt-PA q12h | Rate of Symptomatic Bleeding Events | 0 participants |
| 1.0 mg Rt-PA q8h | Rate of Symptomatic Bleeding Events | 2 participants |
Secondary
180 Day Follow-Up Glasgow Outcome Scale (GOS) Score
180 day follow-up visit GOS score. The GOS is a scale used to determine the degree of recovery from patients with brain injury. There are five categories: 1. Dead, 2. Vegetative State, 3. Severe Disability, 4. Moderate Disability and 5. Good Recovery. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)
Time frame: 180 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1.0 mg Rt-PA q8h | 180 Day Follow-Up Glasgow Outcome Scale (GOS) Score | 2.3 GOS score |
Secondary
180 Day Follow-Up Modified Rankin Scale (mRS) Score
180 day follow-up visit mRS score. 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 to 6: 0. No Symptoms, 1. No Significant Disability, 2. Slight Disability, 3. Moderate Disability, 4. Moderately Severe Disability, 5. Severe Disability and 6. Dead. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)
Time frame: 180 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1.0 mg Rt-PA q8h | 180 Day Follow-Up Modified Rankin Scale (mRS) Score | 4.0 mRS score |
Secondary
90 Day Follow-Up Glasgow Outcome Scale (GOS) Score
90 day follow-up visit GOS score. The GOS is a scale used to determine the degree of recovery from patients with brain injury. There are five categories: 1. Dead, 2. Vegetative State, 3. Severe Disability, 4. Moderate Disability and 5. Good Recovery. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)
Time frame: 90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1.0 mg Rt-PA q8h | 90 Day Follow-Up Glasgow Outcome Scale (GOS) Score | 2.3 GOS score |
Secondary
90 Day Follow-Up Modified Rankin Scale (mRS) Score
90 day follow-up visit mRS score. 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 to 6: 0. No Symptoms, 1. No Significant Disability, 2. Slight Disability, 3. Moderate Disability, 4. Moderately Severe Disability, 5. Severe Disability and 6. Dead. (Stage 1 patients only had 30 day scores, Stage 2 patients had 30 day, 90 day and 180 day scores collected)
Time frame: 90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1.0 mg Rt-PA q8h | 90 Day Follow-Up Modified Rankin Scale (mRS) Score | 4.3 mRS score |
Secondary
Average Daily Percentage Clot Size Resolution Over the First 3 Days
Daily IVH clot volume resolution, as a percentage of stability CT IVH volume, averaged over the first 3 days, determined by CT scans
Time frame: 3 days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 0.3 mg Rt-PA q12h | Average Daily Percentage Clot Size Resolution Over the First 3 Days | 22.19 Percent of stability CT volume resolved |
| 1.0 mg Rt-PA q12h | Average Daily Percentage Clot Size Resolution Over the First 3 Days | 24.20 Percent of stability CT volume resolved |
| 1.0 mg Rt-PA q8h | Average Daily Percentage Clot Size Resolution Over the First 3 Days | 19.99 Percent of stability CT volume resolved |